U.S. patent application number 15/783993 was filed with the patent office on 2018-09-06 for apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases.
The applicant listed for this patent is AbbVie, Inc.. Invention is credited to Milan Bruncko, Yujia Dai, Hong Ding, George A. Doherty, Steven W. Elmore, Lisa Hasvold, Laura Hexamer, Aaron R. Kunzer, Robert A. Mantei, William J. McClellan, Chang H. Park, Cheol-Min Park, Andrew M. Petros, Xiaohong Song, Andrew J. Souers, Gerard M. Sullivan, Zhi-Fu Tao, Gary T. Wang, Le Wang, Xilu Wang, Michael D. Wendt.
Application Number | 20180251426 15/783993 |
Document ID | / |
Family ID | 42463423 |
Filed Date | 2018-09-06 |
United States Patent
Application |
20180251426 |
Kind Code |
A1 |
Bruncko; Milan ; et
al. |
September 6, 2018 |
APOPTOSIS-INDUCING AGENTS FOR THE TREATMENT OF CANCER AND IMMUNE
AND AUTOIMMUNE DISEASES
Abstract
Disclosed are compounds which inhibit the activity of
anti-apoptotic Bcl-2 proteins, compositions containing the
compounds and methods of treating diseases during which is
expressed anti-apoptotic Bcl-2 protein.
Inventors: |
Bruncko; Milan; (Green Oaks,
IL) ; Dai; Yujia; (Gurnee, IL) ; Ding;
Hong; (Gurnee, IL) ; Doherty; George A.;
(Libertyville, IL) ; Elmore; Steven W.;
(Northbrook, IL) ; Hasvold; Lisa; (Grayslake,
IL) ; Hexamer; Laura; (Grayslake, IL) ;
Kunzer; Aaron R.; (Arlington Heights, IL) ; Mantei;
Robert A.; (Franklin, WI) ; Park; Chang H.;
(Wadsworth, IL) ; Park; Cheol-Min; (Gurnee,
IL) ; Petros; Andrew M.; (Mundelein, IL) ;
Song; Xiaohong; (Grayslake, IL) ; Souers; Andrew
J.; (Evanston, IL) ; Sullivan; Gerard M.;
(Lake Villa, IL) ; Tao; Zhi-Fu; (Gurnee, IL)
; Wang; Gary T.; (Libertyville, IL) ; Wang;
Le; (Vernon Hills, IL) ; Wang; Xilu;
(Grayslake, IL) ; Wendt; Michael D.; (Vernon
Hills, IL) ; McClellan; William J.; (Waukegan,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie, Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
42463423 |
Appl. No.: |
15/783993 |
Filed: |
October 13, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15048901 |
Feb 19, 2016 |
|
|
|
15783993 |
|
|
|
|
14582144 |
Dec 23, 2014 |
9303025 |
|
|
15048901 |
|
|
|
|
13952278 |
Jul 26, 2013 |
8952157 |
|
|
14582144 |
|
|
|
|
12631367 |
Dec 4, 2009 |
|
|
|
13952278 |
|
|
|
|
61119844 |
Dec 4, 2008 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 213/84 20130101;
C07D 209/08 20130101; C07D 405/12 20130101; Y02A 50/411 20180101;
A61P 37/00 20180101; C07D 213/74 20130101; C07D 277/24 20130101;
C07D 413/12 20130101; C07D 405/14 20130101; C07D 417/12 20130101;
C07D 309/04 20130101; C07D 231/56 20130101; C07D 235/06 20130101;
A61P 35/02 20180101; C07D 309/08 20130101; C07D 295/30 20130101;
C07D 401/12 20130101; Y02A 50/401 20180101; C07D 471/04 20130101;
A61P 43/00 20180101; Y02A 50/409 20180101; A61P 35/00 20180101;
A61P 25/00 20180101; C07D 401/14 20130101; C07D 403/12 20130101;
C07D 211/58 20130101; Y02A 50/30 20180101; A61K 31/635
20130101 |
International
Class: |
C07D 209/08 20060101
C07D209/08; A61K 31/635 20060101 A61K031/635; C07D 211/58 20060101
C07D211/58; C07D 401/12 20060101 C07D401/12; C07D 309/08 20060101
C07D309/08; C07D 471/04 20060101 C07D471/04; C07D 413/12 20060101
C07D413/12; C07D 405/14 20060101 C07D405/14; C07D 405/12 20060101
C07D405/12; C07D 403/12 20060101 C07D403/12; C07D 401/14 20060101
C07D401/14; C07D 309/04 20060101 C07D309/04; C07D 295/30 20060101
C07D295/30; C07D 277/24 20060101 C07D277/24; C07D 235/06 20060101
C07D235/06; C07D 231/56 20060101 C07D231/56; C07D 213/84 20060101
C07D213/84; C07D 213/74 20060101 C07D213/74; C07D 417/12 20060101
C07D417/12 |
Claims
1. A compound having Formula (I) ##STR00024## or a therapeutically
acceptable salt, prodrug or salt of prodrug thereof, wherein
A.sup.1 is N or C(A.sup.2); A.sup.2 is H, R.sup.1, OR.sup.1,
SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1,
NHC(O)OR.sup.1, NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2,
NHC(O)NHR.sup.1, NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2,NHSO.sub.2R.sup.1,NR.sup.1SO.sub.2R.sup.1,NHSO.s-
ub.2NHR.sup.1,NHSO.sub.2N(R.sup.1).sub.2,
NR.sup.1SO.sub.2NHR.sup.1, NR.sup.1SO.sub.2N(R.sup.1).sub.2,
C(O)NHNOH, C(O)NHNOR.sup.1, C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2,
C(NH)NHR.sup.1, C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; B.sup.1 is H, R.sup.1, OR.sup.1,
SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1,
NHC(O)OR.sup.1, NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2,
NHC(O)NHR.sup.1, NHC(O)N(R.sup.1)2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; D.sup.1 is H, R.sup.1, OR.sup.1,
SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1,
NHC(O)OR.sup.1, NR.sup.1(O)R.sup.1, NHC(O)NH.sub.2,
NHC(O)NHR.sup.1, NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,N(CH.sub.3)SO.sub.2N(CH3)R.sup.1, F,
Cl, Br, I, CN, NO.sub.2, N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3),
CF.sub.3, C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A; E.sup.1 is H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1,
F, Cl, Br, I, CN, NO.sub.2,N.sub.3, OH, C(O)H, CHNOH,
CH(NOCH.sub.3), CF.sub.3, C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A;
and Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17,
SO.sub.2R.sup.17, NH.sub.2, NHR.sup.17, N(R.sup.17).sub.2,
NHC(O)R.sup.17, C(O)NH.sub.2, C(O)NHR.sup.17,
C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17 or NHSO.sub.2R.sup.17; or
E.sup.1 and Y.sup.1, together with the atoms to which they are
attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and A.sup.2,
B.sup.1, and D.sup.1 are independently selected H, R.sup.1,
OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1,
C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2,
C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1,
NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1, NR.sup.1C(O)OR.sup.1,
NHC(O)NH.sub.2, NHO(O)NHR.sup.1, NHC(O)N(R.sup.1).sub.2,
NR.sup.1C(O)NHR.sup.1, NR.sup.1C(O)N(R.sup.1).sub.2,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1, SO.sub.2N(R.sup.1).sub.2,
NHSO.sub.2R.sup.1, NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1)2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or Y.sup.1 and B.sup.1, together
with the atoms to which they are attached, are benzene,
naphthylene, heteroarene cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; and A.sup.2, D.sup.1, and
E.sup.1 are independently selected H, R.sup.1, OR.sup.1, SR.sup.1,
S(O)R.sup.1, SO2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO2R.sup.1, NR.sup.1SO.sub.2R.sup.1,
NHSO.sub.2NHR.sup.1, NHSO.sub.2N(R.sup.1).sub.2,
NR.sup.1SO.sub.2NHR.sup.1, NR.sup.1SO.sub.2N(R.sup.1).sub.2,
C(O)NHNOH, C(O)NHNOR.sup.1, C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2,
C(NH)NHR, C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN,
NO.sub.2,N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3,
C(O)OH, C(O)NH.sub.2 or C(O)OR.sup.1A; or A.sup.2 and B.sup.1,
together with the atoms to which they are attached, are benzene,
naphthylene, heteroarene cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; and D.sup.1, E.sup.1, and
Y.sup.1 are independently selected H, R.sup.1, OR.sup.1, SR.sup.1,
S(O)R.sup.1, SO2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHCC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or A.sup.2 and D.sup.1, together
with the atoms to which they are attached, are benzene,
naphthalene, heteroarene, cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; and B.sup.1, E.sup.1, and
Y.sup.1 are independently selected H, R.sup.1, OR.sup.1, SR.sup.1,
S(O)R.sup.1, SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1,
OC(O)R.sup.1, NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1,
C(O)N(R.sup.1).sub.2, NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1,
NHC(O)OR.sup.1, NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2,
NHC(O)NHR.sup.1, NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN,
NO.sub.2,N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3,
C(O)OH, C(O)NH.sub.2or C(O)OR.sup.1A; R.sup.1 is R.sup.2, R.sup.3,
R.sup.4 or R.sup.5; R.sup.1A is cycloalkyl, cycloalkenyl or
cycloalkynyl; R.sup.2 is phenyl, which is unfused or fused with
benzene, heteroarene or R.sup.2A; R.sup.2A is cycloalkane or
heterocycloalkane; R.sup.3 is heteroaryl, which is unfused or fused
with benzene, heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane; R.sup.4 is cycloalkyl, cycloalkenyl,
heterocycloalkyl or heterocycloalkenyl, each of which is unfused or
fused with benzene, heteroarene or R.sup.4A; R.sup.4A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7,
OR.sup.7, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2,C(O)NHR.sup.7,
C(O)N(R.sup.7).sub.2, NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7,
NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2; R.sup.6A and R.sup.6B are independently selected
alkyl or, together with the N to which they are attached, R.sup.6C;
R.sup.6C is aziridin-l-yl, azetidin-l-yl, pyrrolidin-l-yl or
piperidin-l-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH;
R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11; R.sup.8 is
phenyl, which is unfused or fused with benzene, heteroarene or
R.sup.8A; R.sup.8A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.9 is heteroaryl, which is unfused or
fused with benzene, heteroarene or R.sup.9A; R.sup.9A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.11 is alkyl, alkenyl
or alkynyl, each of which is unsubstituted or substituted with one
or two or three of independently selected R.sup.12, OR.sup.12,
SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12,
CO(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16; R.sup.13is
phenyl, which is unfused or fused with benzene, heteroarene or
R.sup.13A; R.sup.13A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.14 is heteroaryl, which is unfused or
fused with benzene, heteroarene or R.sup.14A; R.sup.14A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.16 is alkyl, alkenyl
or alkynyl; R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
R.sup.18 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.19 is heteroaryl,
which is unfused or fused with benzene, heteroarene or R.sup.19A;
R.sup.19A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; R.sup.20 is cycloalkyl, cycloalkenyl,
heterocycloalkyl or heterocycloalkenyl each of which is unfused or
fused with benzene, heteroarene or R.sup.20A; R.sup.20A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.22, OR.sup.22, SR.sup.22,
S(O)R.sup.22, SO.sub.2R.sup.22, C(O)R.sup.22, CO(O)R.sup.22,
OC(O)R.sup.22, OC(O)OR.sup.22, NH.sub.2, NHR.sup.22,
N(R.sup.22).sub.2, NHC(O)R.sup.22, NR.sup.22C(O)R.sup.22,
NHS(O).sub.2R.sup.22, NR.sup.22S(O).sub.2R.sup.22, NHC(O)OR.sup.22,
NR.sup.22C(O)OR.sup.22, NHC(O)NH.sub.2, NHC(O)NHR.sup.22,
NHC(O)N(R.sup.22).sub.2, NR.sup.22C(O)NHR.sup.22,
NR.sup.22C(O)N(R.sup.22).sub.2, C(O)NH.sub.2, C(O)NHR.sup.22,
C(O)N(R.sup.22).sub.2, C(O)NHOH, C(O)NHOR.sup.22,
C(O)NHSO.sub.2R.sup.22, C(O)NR.sup.22SO.sub.2R.sup.22,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.22, SO.sub.2N(R.sup.22).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.22, C(N)N(R.sup.22).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.22 is R.sup.23, R.sup.24 or R.sup.25; R.sup.23 is phenyl,
which is unfused or fused with benzene, heteroarene or R.sup.23A;
R.sup.23A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; R.sup.24 is heteroarene, which is unfused or
fused with benzene, heteroarene or R.sup.24A; R.sup.24A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.25 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.25A; R.sup.25A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; Z.sup.1 is R.sup.26 or
R.sup.27; Z.sup.2 is R.sup.28, R.sup.29 or R.sup.30; Z.sup.1A and
Z.sup.2A are both absent or are taken together to form CH.sub.2,
CH.sub.2CH.sub.2 or Z.sup.12A; Z.sup.12A is
C.sub.2-C.sub.6-alkylene having one or two CH.sub.2 moieties
replaced by NH, N(CH.sub.3), S, S(O) or SO.sub.2; L.sup.1 is a
R.sup.37
, OR.sup.37, SR.sup.37, S(O)R.sup.37, SO.sub.2R.sup.37,
C(O)R.sup.37, CO(O)R.sup.37, OC(O)R.sup.37, OC(O)OR.sup.37,
NHR.sup.37, C(O)NH, C(O)NR.sup.37, C(O)NHOR.sup.37,
C(O)NHSO.sub.2R.sup.37, SO.sub.2NH, SO.sub.2NHR.sup.37, C(N)NH,
C(N)NHR.sup.37; R.sup.26 is phenylene, which is unfused or fused
with benzene or heteroarene or R.sup.26A; R.sup.26A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; R.sup.27 is
heteroarylene, which is unfused or fused with benzene or
heteroarene or R.sup.27A; R.sup.27A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.28 is phenylene,
which is unfused or fused with benzene, heteroarene or R.sup.28A;
R.sup.28A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; R.sup.29 is heteroarylene, which is unfused or
fused with benzene or heteroarene or R.sup.29A; R.sup.29A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.30 is cycloalkylene, cycloalkenylene, heterocycloalkylene or
heterocycloalkenylene, each of which is unfused or fused with
benzene, heteroarene or R.sup.30A; R.sup.30A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; R.sup.37 is a
bond or R.sup.27A; R.sup.37A is alkylene, alkenylene, or
alkynylene, each of which is unsubstituted or substituted with one
or two or three independently selected R.sup.37B, OR.sup.37B,
SR.sup.37B, S(O)R.sup.37B, SO.sub.2R.sup.37B, C(O)R.sup.37B,
CO(O)R.sup.37B, OC(O)R.sup.37B, OC(O)OR.sup.37B, NH.sub.2,
NHR.sup.37B, N(R.sup.37B).sub.2, NHC(O)R.sup.37B,
NR.sup.37BC(O)R.sup.37B, NHS(O).sub.2R.sup.37B,
NR.sup.37BS(O).sub.2R.sup.37B, NHC(O)OR.sup.37B,
NR.sup.37BC(O)OR.sup.37B, NHC(O)NH.sub.2, NHC(O)NHR.sup.37B,
NHC(O)N(R.sup.37B).sub.2, NR.sup.37BC(O)NHR.sup.37B,
NR.sup.37BC(O)N(R.sup.37B).sub.2, C(O)NH.sub.2, C(O)NHR.sup.37B,
C(O)N(R.sup.37B).sub.2, C(O)NHOH, C(O)NHOR.sup.37B,
C(O)NHSO.sub.2R.sup.37B, C(O)NR.sup.37BSO.sub.2R.sup.37B,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.37B, SO.sub.2N(R.sup.37B).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.37B,
C(N)N(R.sup.37B).sub.2, CNOH, CNOCH.sub.3,OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br and I substituents; R.sup.37B is alkyl, alkenyl, alkynyl,
phenyl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl; Z.sup.3 is R.sup.38, R.sup.39 or R.sup.40;
R.sup.38 is phenyl, which is unfiised or fused with benzene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.39 is heteroaryl,
which is unfused or fused with benzene, heteroarene or R.sup.39A;
R.sup.39A is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene; R.sup.40 is cycloalkyl, cycloalkenyl,
heterocycloalkyl or heterocycloalkenyl, each of which is unfused or
fused with benzene, heteroarene or R.sup.40A; R.sup.40A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein the moieties represented by .sup.26 and R.sup.27 are
substituted (i.e., if Z.sup.1A and Z.sup.2A are absent) or further
substituted (i.e., if Z.sup.1A and Z.sup.2A are present) with one
or two or three or four of independently selected R.sup.41,
OR.sup.41, SR.sup.41, S(O)R.sup.41, SO.sub.2R.sup.41, C(O)R.sup.41,
CO(O)R.sup.41, OC(O)R.sup.41, OC(O)OR.sup.41, NH.sub.2, NHR.sup.41,
N(R.sup.41).sub.2, NHC(O)R.sup.41, NR.sup.41C(O)R.sup.41,
NHS(O).sub.2R.sup.41, NR.sup.41S(O).sub.2R.sup.41, NHC(O)OR.sup.41,
NR.sup.41C(O)OR.sup.41, NHC(O)NH.sub.2, NHC(O)NHR.sup.41,
NHC(O)N(R.sup.41).sub.2, NR.sup.41C(O)NHR.sup.41,
NR.sup.41C(O)N(R.sup.41).sub.2, C(O)NH.sub.2, C(O)NHR.sup.41,
C(O)N(R.sup.41).sub.2, C(O)NHOH, C(O)NHOR.sup.41,
C(O)NHSO.sub.2R.sup.41, C(O)NR.sup.41SO.sub.2R.sup.41,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.41, SO.sub.2N(R.sup.41).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.41, C(N)N(R.sup.41).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45; R.sup.42 is
phenyl, which is unfused or fused with benzene, heteroarene or
R.sup.42A; R.sup.42A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.43 is heteroaryl, which is unfused or
fused with benzene, heteroarene or R.sup.43A; R.sup.43A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.44 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.44A; R.sup.44A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.45 is alkyl, alkenyl
or alkynyl, each of which is unsubstitutcd or substituted with one
or two or three of independently selected R.sup.46, OR.sup.46,
SR.sup.46, S(O)R.sup.46, SO.sub.2R.sup.46, C(O)R.sup.46,
CO(O)R.sup.46, OC(O)R.sup.46, OC(O)OR.sup.46, NH.sub.2, NHR.sup.46,
N(R.sup.46).sub.2, NHC(O)R.sup.46, NR.sup.46C(O)R.sup.46,
NHS(O).sub.2R.sup.46, NR.sup.46S(O).sub.2R.sup.46, NHC(O)OR.sup.46,
NR.sup.46C(O)OR.sup.46, NHC(O)NH.sub.2, NHC(O)NHR.sup.46,
NHC(O)N(R.sup.46).sub.2, NR.sup.46C(O)NHR.sup.46,
NR.sup.46C(O)N(R.sup.46).sub.2, C(O)NH.sub.2, C(O)NHR.sup.46,
C(O)N(R.sup.46).sub.2, C(O)NHOH, C(O)NHOR.sup.46,
C(O)NHSO.sub.2R.sup.46, C(O)NR.sup.46SO.sub.2R.sup.46,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.46, SO.sub.2N(R.sup.46).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR4.sup.46,
C(N)N(R.sup.46).sub.22, CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I; R.sup.46 is alkyl, alkenyl, alkynyl, R.sup.47,
R.sup.48 or R.sup.49; R.sup.47 is phenyl, which is unfased or fused
with benzene, heteroarene or R.sup.47A; R.sup.47A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; R.sup.48 is
heteroaryl, which is unfused or fused with benzene, heteroarene or
R.sup.48A; R.sup.48A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.49 is cycloalkyl, cycloalkenyl,
heterocycloalkyl or heterocycloalkenyl, each of which is unfused or
fused with benzene, heteroarene or R.sup.49A; R.sup.49A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
wherein the moieties represented by R.sup.42, R.sup.42A, R.sup.43,
R.sup.43A, R.sup.44, R.sup.44A, R.sup.47, R.sup.47A, R.sup.48,
R.sup.48A, R.sup.49, and R.sup.49A are independently substituted
with one or two or three or four of independently selected
R.sup.50, OR.sup.50, SR.sup.50, S(O)R.sup.50, SO.sub.2R.sup.50,
C(O)R.sup.50, CO(O)R.sup.50, OC(O)R.sup.50, OC(O)OR.sup.50,
NH.sub.2, NHR.sup.50, N(R.sup.50).sub.2, NHC(O)R.sup.50,
NR.sup.50C(O)R.sup.50, NHS(O).sub.2R.sup.50,
NR.sup.50S(O).sub.2R.sup.50, NHC(O)OR.sup.50,
NR.sup.50C(O)OR.sup.50, NHC(O)NH.sub.2, NHC(O)NHR.sup.50,
NHC(O)N(R.sup.50).sub.2, NR.sup.50C(O)NHR.sup.50,
NR.sup.50C(O)N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.50SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54; R.sup.51is
phenyl, which is unfused or fused with benzene, heteroarene or
R.sup.51A; R.sup.51A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.52 is heteroaryl, which is unfused or
fused with benzene, heteroarene or R.sup.52A; R.sup.52A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.53 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.53A; R.sup.53A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.54 is alkyl, alkenyl
or alkynyl, each of which is unsubstituted or substituted with one
or two or three of independently selected R.sup.55, OR.sup.55,
SR.sup.55, S(O)R.sup.55, SO.sub.2R.sup.55, C(O)R.sup.55,
CO(O)R.sup.55, OC(O)R.sup.55, OC(O)OR.sup.55, NH.sub.2, NHR.sup.55,
N(R.sup.55).sub.2, NHC(O)R.sup.55, NR.sup.55C(O)R.sup.55,
NHS(O).sub.2R.sup.55, NR.sup.55S(O).sub.2R.sup.55, NHC(O)OR.sup.55,
NR.sup.55C(O)OR.sup.55, NHC(O)NH.sub.2, NHC(O)NHR.sup.55,
NHC(O)N(R.sup.55).sub.2, NR.sup.55C(O)NHR.sup.55,
NR.sup.55C(O)N(R.sup.55).sub.2, C(O)NH.sub.2, C(O)NHR.sup.55,
C(O)N(R.sup.55).sub.2, C(O)NHOH, C(O)NHOR.sup.55,
C(O)NHSO.sub.2R.sup.55, C(O)NR.sup.55SO.sub.2R.sup.55,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55, SO.sub.2N(R.sup.55).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.55, C(N)N(R.sup.55).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.57A, R.sup.57, OR.sup.57, SR.sup.57,
S(O)R.sup.57, SO.sub.2R.sup.57, C(O)R.sup.57, CO(O)R.sup.57,
OC(O)R.sup.57, OC(O)OR.sup.57, NH.sub.2, NHR.sup.57,
N(R.sup.57).sub.2, NHC(O)R.sup.57, NR.sup.57C(O)R.sup.57,
NHS(O).sub.2R.sup.57, NR.sup.57S(O).sub.2R.sup.57, NHC(O)OR.sup.57,
NR.sup.57C(O)OR.sup.57, NHC(O)NH.sub.2, NHC(O)NHR.sup.57,
NHC(O)N(R.sup.57).sub.2 NR.sup.57C(O)NHR.sup.57,
NR.sup.57C(O)N(R.sup.57).sub.2, C(O)NH.sub.2, C(O)NHR.sup.57,
C(O)N(R.sup.57).sub.2, C(O)NHOH, C(O)NHOR.sup.57,
C(O)NHSO.sub.2R.sup.57, C(O)NR.sup.57SO.sub.2R.sup.57,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.57, SO.sub.2N(R.sup.57).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.57, C(N)N(R.sup.57).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.57A is spirocyclyl; R.sup.57 is R.sup.58, R.sup.59, R.sup.60
or R.sup.61 ; R.sup.58 is phenyl, which is unfused or fused with
benzene, heteroarene or R.sup.58A; R.sup.58A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; R.sup.59 is
heteroaryl, which is unfused or fused with benzene, heteroarene or
R.sup.59A; R.sup.59A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.60 is cycloalkyl, cycloalkenyl,
heterocycloalkyl or heterocycloalkenyl, each of which is unfused or
fused with benzene, heteroarene or R.sup.60A; R.sup.60A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.61 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.62, OR.sup.62, SR.sup.62,
S(O)R.sup.62, SO.sub.2R.sup.62, C(O)R.sup.62, CO(O)R.sup.62,
OC(O)R.sup.62, OC(O)O.sup.62, NH.sub.2, NHR.sup.62,
N(R.sup.62).sub.2, NHC(O)R.sup.62, N.sup.62C(O)R.sup.62,
NHS(O).sub.2R.sup.62, N.sup.62S(O).sub.2R.sup.62, NHC(O)OR.sup.62,
N.sup.62C(O)OR.sup.62, NHC(O)NH.sub.2, NHC(O)NH.sup.62,
NHC(O)N(R.sup.62).sub.2, N.sup.62C(O)NHR.sup.62,
NR.sup.62C(O)N(R.sup.62).sub.2, C(O)NH.sub.2, C(O)NHR.sup.62,
C(O)N(R.sup.62).sub.2, C(O)NH0H, C(O)NHOR.sup.62,
CfOJNHSO.sub.2R.sup.62, C(O)NR.sup.62SO.sub.2R.sup.62,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.62, SO.sub.2N(R.sup.62).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.62, C(N)N(R.sup.62).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.62 is R.sup.63, R.sup.64, R.sup.65 or R.sup.66; R.sup.63 is
phenyl, which is unfused or fused with benzene, heteroarene or
R.sup.63A; R.sup.63A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.64 is heteroaryl, which is unfused or
fused with benzene, heteroarene or R.sup.64A; R.sup.64A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.65 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.65A; R.sup.65A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.66 is alkyl, alkenyl
or alkenyl, each of which is unsubstituted or substituted with one
or two or three of independently selected R.sup.67, OR.sup.67,
SR.sup.67, S(O)R.sup.67, SO.sub.2R.sup.67, C(O)R.sup.67,
CO(O)R.sup.67, OC(O)R.sup.67, OC(O)OR.sup.67, NH.sub.2, NHR.sup.67,
N(R.sup.67).sub.2, NHC(O)R.sup.67, NR.sup.67C(O)R.sup.67,
NHS(O).sub.2R.sup.67, NR.sup.67S(O).sub.2R.sup.67, NHC(O)OR.sup.67,
NR.sup.67C(O)OR.sup.67, NHC(O)NH.sub.2, NHC(O)NHR.sup.67,
NHC(O)N(R.sup.67).sub.2, NR.sup.67C(O)NHR.sup.67,
NR.sup.67C(O)N(R6.sup.67).sub.2, C(O)NH.sub.2, C(O)NHR.sup.67,
C(O)N(R.sup.67).sub.2, C(O)NHOH, C(O)NHOR.sup.67,
C(O)NHSO.sub.2R.sup.67, C(O)NR.sup.67SO.sub.2R.sup.67,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.67, SO.sub.2N(R.sup.67).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.67, C(N)N(R.sup.67).sub.2,
CNOH, CNOCH3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents; R.sup.67 is alkyl, alkenyl, alkynyl, phenyl,
heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl; wherein the moieties represented by R.sup.57A,
R.sup.58, R.sup.59, R.sup.60, R.sup.63, R.sup.64, R.sup.65, and
R.sup.67 are unsubstituted or substituted with one or two or three
or four of independently selected R.sup.68, OR.sup.68, SR.sup.68,
S(O)R.sup.68, SO.sub.2R.sup.68, C(O)R.sup.68,
CO(O)R.sup.68,OC(O)R.sup.68, OC(O)OR.sup.68, NH.sub.2, NHR.sup.68,
N(R.sup.68).sub.2, NHC(O)R.sup.68, NR.sup.68C(O)R.sup.68,
NHS(O).sub.2R.sup.68, NR.sup.68S(O).sub.2R.sup.68, NHC(O)OR.sup.68,
NR.sup.68C(O)OR.sup.68, NHC(O)NH.sub.2, NHC(O)NHR.sup.68,
NHCC(O)N(R.sup.68).sub.2, NR.sup.68C(O)NHR.sup.68,
NR.sup.68C(O)N(R.sup.68).sub.2, C(O)NH.sub.2, C(O)NHR.sup.68,
C(O)N(R.sup.68).sub.2, C(O)NHOH, C(O)NHOR.sup.68,
C(O)NHSO.sub.2R.sup.68, C(O)NR.sup.68SO.sub.2R.sup.68,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.68, SO.sub.2N(R.sup.68).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.68, C(N)N(R.sup.68).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.68 is R6.sup.69, R.sup.70, R.sup.71 or R.sup.72; R.sup.69 is
phenyl, which is unfused or fused with benzene, heteroarene or
R.sup.69A; R.sup.69A is cycloalkane, cycloalkene, heterocycloalkane
or heterocycloalkene; R.sup.70 is heteroaryl, which is unfused or
fused with benzene, heteroarene or R.sup.70A ; R.sup.70A is
cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
R.sup.71 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.71A; R.sup.71A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.72 is alkyl, alkenyl
or alkenyl, each of which is unsubstituted or substituted with one
or two or three of independently selected R.sup.73, OR
.sup.73, SR.sup.73, S(O)R.sup.73, SO.sub.2R.sup.73, C(O)R.sup.73,
CO(O)R.sup.73, OC(O)R.sup.73, OC(O)OR.sup.73, NH.sub.2, NHR.sup.73,
N(R.sup.73).sub.2, NHC(O)R.sup.73, NR.sup.73C(O)R.sup.73,
NHS(O).sub.2R.sup.73, NR.sup.73S(O).sub.2R.sup.73, NHC(O)OR.sup.73,
NR.sup.73C(O)OR.sup.73, NHC(O)NH.sub.2, NHC(O)NHR.sup.73,
NHC(O)N(R.sup.73).sub.2, NR.sup.73C(O)NHR.sup.73,
NR.sup.73C(O)N(R.sup.73).sub.2, C(O)NH.sub.2, C(O)NHR.sup.73,
C(O)N(R.sup.73).sub.2, C(O)NHOH, C(O)NHOR.sup.73,
C(O)NHSO.sub.2R.sup.73, C(O)NR.sup.73SO.sub.2R.sup.73,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.73, SO.sub.2N(R.sup.73).sub.2,
C(O)H, C(O)0H, C(N)NH.sub.2, C(N)NHR.sup.73, C(N)N(R.sup.73).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
R.sup.73 is alkyl, alkenyl, alkenyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and the moieties represented by R.sup.69, R.sup.70 , and R.sup.71
are unsubstituted or substituted with one or two or three or four
of independently selected NH.sub.2, C(O)NH.sub.2, C(O)NHOH,
SO.sub.2NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH,
C(N)NH.sub.2, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I.
2-12. (canceled)
Description
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 61/119,844 filed Dec. 4, 2008, which is
incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention pertains to compounds which inhibit the
activity of Bcl-2 anti-apoptotic proteins, compositions containing
the compounds, and methods of treating diseases during which
anti-apoptotic Bcl-2 proteins are expressed.
BACKGROUND OF THE INVENTION
[0003] Anti-apoptotic Bcl-2 proteins are associated with a number
of diseases. There is therefore an existing need in the therapeutic
arts for compounds which inhibit the activity of anti-apoptotic
Bcl-2 proteins.
[0004] Overexpression of Bcl-2 proteins correlates with resistance
to chemotherapy, clinical outcome, disease progression, overall
prognosis or a combination thereof in various cancers and disorders
of the immune system.
[0005] Involvement of Bcl-2 proteins in bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical cancer, chronic
lymphocytic leukemia, colorectal cancer, esophageal cancer,
hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,
lymphoid malignancies of T-cell or D-cell origin, melanoma,
myelogenous leukemia, myeloma, oral cancer, ovarian cancer,
non-small cell lung cancer, prostate cancer, small cell lung
cancer, spleen cancer, and the like is described in commonly-owned
PCT US 2004/36770, published as WO 2005/049593, and PCT US
2004/37911, published as WO 2005/024636.
[0006] Involvement of Bcl-2 proteins in immune and autoimmune
diseases is described in Current Allergy and Asthma Reports 2003,
3, 378-384; British Journal of Haematology 2000, 110 (3), 584-90;
Blood 2000, 95 (4), 1283-92; and New England Journal of Medicine
2004, 351 (14), 1409-1419. Involvement of Bcl-2 proteins in
arthritis is disclosed in commonly-owned U.S. Provisional Patent
Application Ser. No. 60/988,479. Involvement of Bcl-2 proteins in
bone marrow transplant rejection is disclosed in commonly-owned
U.S. patent application Ser. No. 11/941,196.
SUMMARY OF THE INVENTION
[0007] One embodiment of this invention, therefore, pertains to
compounds or therapeutically acceptable salts, prodrugs or salts of
prodrugs thereof, which are useful as inhibitors of anti-apoptotic
Bcl-2 proteins, the compounds having Formula I
##STR00001##
wherein [0008] A.sup.1 is N or C(A.sup.2);
[0009] A.sup.2 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0010] B.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0011] D.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0012] E.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; and
[0013] Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17,
SO.sub.2R.sup.17, NH.sub.2, NHR.sup.17, N(R.sup.17).sub.2,
NHC(O)R.sup.17, C(O)NH.sub.2, C(O)NHR.sup.17,
C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17, or NHSO.sub.2R.sup.17;
or
[0014] E.sup.1 and Y.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0015] A.sup.2, B.sup.1, and D.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0016] Y.sup.1 and B.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0017] A.sup.2, D.sup.1, and E.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2, or C(O)OR.sup.1A; or
[0018] A.sup.2 and B.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene, cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0019] D.sup.1, E.sup.1, and Y.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2, or C(O)OR.sup.1A; or
[0020] A.sup.2 and D.sup.1, together with the atoms to which they
are attached, are benzene, naphthalene, heteroarene, cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0021] B.sup.1, and E.sup.1, and Y.sup.1 are independently selected
H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0022] R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
[0023] R.sup.1A is cycloalkyl, cycloalkenyl ar cycloalkynyl;
[0024] R.sup.2 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane or
heterocycloalkane;
[0025] R.sup.3 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
[0026] R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0027] R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7,
OR.sup.7, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
C(O)N(R.sup.7).sub.2, NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7,
NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0028] R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
[0029] R.sup.6A and R.sup.6B are independently selected alkyl or,
together with the N to which they are attached, R.sup.6C;
[0030] R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
[0031] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0032] R.sup.8 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.8A; R.sup.8A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0033] R.sup.9 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0034] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0035] R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12, CO(O)R.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0036] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0037] R.sup.13 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0038] R.sup.14 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloakene, heterocycloalkane or heterocycloalkene;
[0039] R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0040] R.sup.16 is alkyl, alkenyl or alkynyl;
[0041] R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
[0042] R.sup.18 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0043] R.sup.19 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.19A; R.sup.19A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0044] R.sup.20 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.20A; R.sup.20A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0045] R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.22, OR.sup.22, SR.sup.22,
S(O)R.sup.22, SO.sub.2R.sup.22, C(O)R.sup.22, CO(O)R.sup.22,
OC(O)R.sup.22, OC(O)OR.sup.22, NH.sub.2, NHR.sup.22,
N(R.sup.22).sub.2, NHC(O)R.sup.22, NR.sup.22C(O)R.sup.22,
NHS(O).sub.2R.sup.22, NR.sup.22S(O).sub.2R.sup.22, NHC(O)OR.sup.22,
NR.sup.22C(O)OR.sup.22, NHC(O)NH.sub.2, NHC(O)NHR.sup.22,
NHC(O)N(R.sup.22).sub.2, NR.sup.22C(O)NHR.sup.22,
NR.sup.22C(O)N(R.sup.22).sub.2, C(O)NH.sub.2, C(O)NHR.sup.22,
C(O)N(R.sup.22).sub.2, C(O)NHOH, C(O)NHOR.sup.22,
C(O)NHSO.sub.2R.sup.22, C(O)NR.sup.22SO.sub.2R.sup.22,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.22, SO.sub.2N(R.sup.22).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.22, C(N)N(R.sup.22).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0046] R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
[0047] R.sup.23 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloakane or heterocycloalkene;
[0048] R.sup.24 is heteroarene, which is unfused or fused with
benzene, heteroarene or R.sup.24A; R.sup.24A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0049] R.sup.25 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.25A; R.sup.25A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0050] Z.sup.1 is R.sup.26 or R.sup.27;
[0051] Z.sup.2 is R.sup.28, R.sup.29 or R.sup.30;
[0052] Z.sup.1A and Z.sup.2A are both absent or are taken together
to form CH.sub.2, CH.sub.2CH.sub.2 or Z.sup.12A;
[0053] Z.sup.12A is C.sub.2-C.sub.6-alkylene having one or two
CH.sub.2 moieties replaced by NH, N(CH.sub.3), S, S(O) or
SO.sub.2;
[0054] L.sup.1 is R.sup.37, OR.sup.37, SR.sup.37, S(O)R.sup.37,
SO.sub.2R.sup.37, C(O)R.sup.37, CO(O)R.sup.37, OC(O)R.sup.37,
OC(O)OR.sup.37, NHR.sup.37, C(O)NH, C(O)NR.sup.37, C(O)NHOR.sup.37,
C(O)NHSO.sub.2R.sup.37, SO.sub.2NH, SO.sub.2NHR.sup.37, C(N)NH,
C(N)NHR.sup.37;
[0055] R.sup.26 is phenylene, which is unfused or fused with
benzene or heteroarene or R.sup.26A; R.sup.26A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0056] R.sup.27 is heteroarylene, which is unfused or fused with
benzene or heteroarene or R.sup.27A; R.sup.27A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0057] R.sup.28 is phenylene, which is unfused or fused with
benzene, heteroarene or R.sup.28A; R.sup.28A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0058] R.sup.29 is heteroarylene, which is unfused or fused with
benzene or heteroarene or R.sup.29A; R.sup.29A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0059] R.sup.30 is cycloalkylene, cycloalkenylene,
heterocycloalkylene or heterocycloalkenylene, each of which is
unfused or fused with benzene, heteroarene or R.sup.30A; R.sup.30A
is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0060] R.sup.37 is a bond or R.sup.37A;
[0061] R.sup.37A is alkylene, alkenylene, or alkynylene, each of
which is unsubstituted or substituted with one or two or three
independently selected R.sup.37B, OR.sup.37B, SR.sup.37B,
S(O)R.sup.37B, SO.sub.2R.sup.37B, C(O)R.sup.37B, CO(O)R.sup.37B,
OC(O)R.sup.37B, OC(O)OR.sup.37B, NH.sub.2, NHR.sup.37B,
N(R.sup.37B).sub.2, NHC(O)R.sup.37B, NR.sup.37BC(O)R.sup.37B,
NHS(O).sub.2R.sup.37B, NR.sup.37BS(O).sub.2R.sup.37B,
NHC(O)OR.sup.37B, NR.sup.37BC(O)OR.sup.37B, NHC(O)NH.sub.2,
NHC(O)NHR.sup.37B, NHC(O)N(R.sup.37B).sub.2,
NR.sup.37BC(O)NHR.sup.37B, NR.sup.37BC(O)N(R.sup.37B).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.37B, C(O)N(R.sup.37B).sub.2, C(O)NHOH,
C(O)NHOR.sup.37B, C(O)NHSO.sub.2R.sup.37B,
C(O)NR.sup.37BSO.sub.2R.sup.37B, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.37B, SO.sub.2N(R.sup.37B).sub.2, C(O)H, C(O)OH,
C(N)NH.sub.2, C(N)NHR.sup.37B, C(N)N(R.sup.37B).sub.2, CNOH,
CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl Br and I
substituents;
[0062] R.sup.37B is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl;
[0063] Z.sup.3 is R.sup.38, R.sup.39 or R.sup.40;
[0064] R.sup.38 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0065] R.sup.39 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.39A; R.sup.39A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0066] R.sup.40 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.40A; R.sup.40A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0067] wherein the moieties represented by R.sup.26 and R.sup.27
are substituted (i.e., if Z.sup.1A and Z.sup.2A are absent) or
further substituted (i.e., if Z.sup.1A and Z.sup.2A are present)
with one or two or three or four of independently selected
R.sup.41, OR.sup.41, SR.sup.41, S(O)R.sup.41, SO.sub.2R.sup.41,
C(O)R.sup.41, CO(O)R.sup.41, OC(O)R.sup.41, OC(O)OR.sup.41,
NH.sub.2, NHR.sup.41, N(R.sup.41).sub.2, NHC(O)R.sup.41,
NR.sup.41C(O)R.sup.41, NHS(O).sub.2R.sup.41,
NR.sup.41S(O).sub.2R.sup.41, NHC(O)OR.sup.41,
NR.sup.41C(O)OR.sup.41, NHC(O)NH.sub.2, NHC(O)NHR.sup.41,
NHC(O)N(R.sup.41).sub.2, NR.sup.41C(O)NHR.sup.41,
NR.sup.41C(O)N(R.sup.41).sub.2, C(O)NH.sub.2, C(O)NHR.sup.41,
C(O)N(R.sup.41).sub.2, C(O)NHOH, C(O)NHOR.sup.41,
C(O)NHSO.sub.2R.sup.41, C(O)NR.sup.41SO.sub.2R.sup.41,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.41, SO.sub.2N(R.sup.41).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.41, C(N)N(R.sup.41).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0068] R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
[0069] R.sup.42 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0070] R.sup.43 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.43A; R.sup.43A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0071] R.sup.44 is is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.44A; R.sup.44A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0072] R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.46, OR.sup.46, SR.sup.46,
S(O)R.sup.46, C(O)R.sup.46, CO(O)R.sup.46, OC(O)R.sup.46,
OC(O)OR.sup.46, NH.sub.2, NHR.sup.46, N(R.sup.46).sub.2,
NHC(O)R.sup.46, NR.sup.46C(O)R.sup.46, NHS(O).sub.2R.sup.46,
NR.sup.46S(O).sub.2R.sup.46, NHC(O)OR.sup.46,
NR.sup.46C(O)OR.sup.46, NHC(O)NH.sub.2, NHC(O)NHR.sup.46,
NHC(O)N(R.sup.46).sub.2, NR.sup.46C(O)NHR.sup.46,
NR.sup.46C(O)N(R.sup.46).sub.2, C(O)NH.sub.2, C(O)NHR.sup.46,
C(O)N(R.sup.46).sub.2, C(O)NHOH, C(O)NHOR.sup.46,
C(O)NHSO.sub.2R.sup.46, C(O)NR.sup.46SO.sub.2R.sup.46,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.46, SO.sub.2N(R.sup.46).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.46, C(N)N(R.sup.46).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0073] R.sup.46 is alkyl, alkenyl, alkynyl, R.sup.47, R.sup.48 or
R.sup.49;
[0074] R.sup.47 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0075] R.sup.48 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0076] R.sup.49 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.49A; R.sup.49A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0077] wherein the moieties represented by R.sup.42, R.sup.42A,
R.sup.43, R.sup.43A, R.sup.44, R.sup.44A, R.sup.47, R.sup.47A,
R.sup.48, R.sup.48A, R.sup.49, and R.sup.49A are independently
substituted with one or two or three or four of independently
selected R.sup.50, OR.sup.50, SR.sup.50, S(O)R.sup.50,
SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50, OC(O)R.sup.50,
OC(O)OR.sup.50, NH.sub.2, NHR.sup.50, N(R.sup.50).sub.2,
NHC(O)R.sup.50, NR.sup.50C(O)R.sup.50, NHS(O).sub.2R.sup.50,
NR.sup.50S(O).sub.2R.sup.50, NHC(O)OR.sup.50,
NR.sup.50C(O)OR.sup.50, NHC(O)NH.sub.2, NHC(O)NHR.sup.50,
NHC(O)N(R.sup.50).sub.2, NR.sup.50C(O)NHR.sup.50,
NR.sup.50C(O)N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.50SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0078] R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
[0079] R.sup.51 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.51A; R.sup.51A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0080] R.sup.52 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.52A; R.sup.52A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0081] R.sup.53 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heteracycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.53A; R.sup.53A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0082] R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.55, OR.sup.55, SR.sup.55,
S(O)R.sup.55, SO.sub.2R.sup.55, C(O)R.sup.55, CO(O)R.sup.55,
OC(O)R.sup.55, OC(O)OR.sup.55, NH.sub.2, NHR.sup.55,
N(R.sup.55).sub.2, NHC(O)R.sup.55, NR.sup.55C(O)R.sup.55,
NHS(O).sub.2R.sup.55, NR.sup.55S(O).sub.2R.sup.55, NHC(O)OR.sup.55,
NR.sup.55C(O)OR.sup.55, NHC(O)NH.sub.2, NHC(O)NHR.sup.55,
NHC(O)N(R.sup.55).sub.2, NR.sup.55C(O)NHR.sup.55,
NR.sup.55C(O)N(R.sup.55).sub.2, C(O)NH.sub.2, C(O)NHR.sup.55,
C(O)N(R.sup.55).sub.2, C(O)NHOH, C(O)NHOR.sup.55,
C(O)NHSO.sub.2R.sup.55, C(O)NR.sup.55SO.sub.2R.sup.55,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55, SO.sub.2N(R.sup.55).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.55, C(N)N(R.sup.55).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0083] R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and
[0084] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.57A, R.sup.57, OR.sup.57, SR.sup.57,
S(O)R.sup.57, SO.sub.2R.sup.57, C(O)R.sup.57, CO(O)R.sup.57,
OC(O)R.sup.57, OC(O)OR.sup.57, NH.sub.2, NHR.sup.57,
N(R.sup.57).sub.2, NHC(O)R.sup.57, NR.sup.57C(O)R.sup.57,
NHS(O).sub.2R.sup.57, NR.sup.57S(O).sub.2R.sup.57, NHC(O)OR.sup.57,
NR.sup.57C(O)OR.sup.57, NHC(O)NH.sub.2, NHC(O)NHR.sup.57,
NHC(O)N(R.sup.57).sub.2, NR.sup.57C(O)NHR.sup.57,
NR.sup.57C(O)N(R.sup.57).sub.2, C(O)NH.sub.2, C(O)NHR.sup.57,
C(O)N(R.sup.57).sub.2, C(O)NHOH, C(O)NHOR.sup.57,
C(O)NHSO.sub.2R.sup.57, C(O)NR.sup.57SO.sub.2R.sup.57,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.57, SO.sub.2N(R.sup.57).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.57, C(N)N(R.sup.57).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0085] R.sup.57A is spirocyclyl;
[0086] R.sup.57 is R.sup.58, R.sup.59, R.sup.60 or R.sup.61;
[0087] R.sup.58 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.58; R.sup.58A is cycloalkane, cycloalkane,
heterocycloalkane or heterocycloalkene;
[0088] R.sup.59 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.59A; R.sup.59A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0089] R.sup.60 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.60A; R.sup.60A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0090] R.sup.61 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.62, OR.sup.62, SR.sup.62,
S(O)R.sup.62, SO.sub.2R.sup.62, C(O)R.sup.62, CO(O)R.sup.62,
OC(O)R.sup.62, OC(O)OR.sup.62, NH.sub.2, NHR.sup.62,
N(R.sup.62).sub.2, NHC(O)R.sup.62, NR.sup.62C(O)R.sup.62,
NHS(O).sub.2R.sup.62, NR.sup.62S(O).sub.2R.sup.62, NHC(O)OR.sup.62,
NR.sup.62C(O)OR.sup.62, NHC(O)NH.sub.2, NHC(O)NHR.sup.62,
NHC(O)N(R.sup.62).sub.2, NR.sup.62C(O)NHR.sup.62,
NR.sup.62C(O)N(R.sup.62).sub.2, C(O)NH.sub.2, C(O)NHR.sup.62,
C(O)N(R.sup.62).sub.2, C(O)NHOH, C(O)NHOR.sup.62,
C(O)NHSO.sub.2R.sup.62, C(O)NR.sup.62SO.sub.2R.sup.62,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.62, SO.sub.2N(R.sup.62).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.62, C(N)N(R.sup.62).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0091] R.sup.62 is R.sup.63, R.sup.64, R.sup.65 or R.sup.66;
[0092] R.sup.63 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.63A; R.sup.63A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0093] R.sup.64 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.64A; R.sup.64A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0094] R.sup.65 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.65A; R.sup.65A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0095] R.sup.66 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.67, OR.sup.67, SR.sup.67,
S(O)R.sup.67, SO.sub.2R.sup.67, C(O)R.sup.67, CO(O)R.sup.67,
OC(O)R.sup.67, OC(O)OR.sup.67, NH.sub.2, NHR.sup.67,
N(R.sup.67).sub.2, NHC(O)R.sup.67, NR.sup.67C(O)R.sup.67,
NHS(O).sub.2R.sup.67, NR.sup.67S(O).sub.2R.sup.67, NHC(O)OR.sup.67,
NR.sup.67C(O)OR.sup.67, NHC(O)NH.sub.2, NHC(O)NHR.sup.67,
NHC(O)N(R.sup.67).sub.2, NR.sup.67C(O)NHR.sup.67,
NR.sup.67C(O)N(R.sup.67).sub.2, C(O)NH.sub.2, C(O)NHR.sup.67,
C(O)N(R.sup.67).sub.2, C(O)NHOH, C(O)NHOR.sup.67,
C(O)NHSO.sub.2R.sup.67, C(O)NR.sup.67SO.sub.2R.sup.67,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.67, SO.sub.2N(R.sup.67).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.67, C(N)N(R.sup.67).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
[0096] R.sup.67 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl;
[0097] wherein the moieties represented by R.sup.57A, R.sup.58,
R.sup.59, R.sup.60, R.sup.63, R.sup.64, R.sup.65, and R.sup.67 are
unsubstituted or substituted with one or two or three or four of
independently selected R.sup.68, OR.sup.68, SR.sup.68,
S(O)R.sup.68, SO.sub.2R.sup.68, C(O)R.sup.68, CO(O)R.sup.68,
OC(O)R.sup.68, OC(O)OR.sup.68, NH.sub.2, NHR.sup.68,
N(R.sup.68).sub.2, NHC(O)R.sup.68, NR.sup.68C(O)R.sup.68,
NHS(O).sub.2R.sup.68, NR.sup.68S(O).sub.2R.sup.68, NHC(O)OR.sup.68,
NR.sup.68C(O)OR.sup.68, NHC(O)NH.sub.2, NHC(O)NHR.sup.68,
NHC(O)N(R.sup.68).sub.2, NR.sup.68C(O)NHR.sup.68,
NR.sup.68C(O)N(R.sup.68).sub.2, C(O)NH.sub.2, C(O)NHR.sup.68,
C(O)N(R.sup.68).sub.2, C(O)NHOH, C(O)NHOR.sup.68,
C(O)NHSO.sub.2R.sup.68, C(O)NR.sup.68SO.sub.2R.sup.68,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.68, SO.sub.2N(R.sup.68).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.68, C(N)N(R.sup.68).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0098] R.sup.68 is R.sup.69, R.sup.70, R.sup.71 or R.sup.72;
[0099] R.sup.69 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.69A; R.sup.69A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0100] R.sup.70 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.70A; R.sup.70A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0101] R.sup.71 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.71A; R.sup.71A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0102] R.sup.72 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.73, OR.sup.73, SR.sup.73,
S(O)R.sup.73, SO.sub.2R.sup.73, C(O)R.sup.73, CO(O)R.sup.73,
OC(O)R.sup.73, OC(O)OR.sup.73, NH.sub.2, NHR.sup.73,
N(R.sup.73).sub.2, NHC(O)R.sup.73, NR.sup.73C(O)R.sup.73,
NHS(O).sub.2R.sup.73, NR.sup.73S(O).sub.2R.sup.73, NHC(O)OR.sup.73,
NR.sup.73C(O)OR.sup.73, NHC(O)NH.sub.2, NHC(O)NHR.sup.73,
NHC(O)N(R.sup.73).sub.2, NR.sup.73C(O)NHR.sup.73,
NR.sup.73C(O)N(R.sup.73).sub.2, C(O)NH.sub.2, C(O)NHR.sup.73,
C(O)N(R.sup.73).sub.2, C(O)NHOH, C(O)NHOR.sup.73,
C(O)NHSO.sub.2R.sup.73, C(O)NR.sup.73SO.sub.2R.sup.73,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.73, SO.sub.2N(R.sup.73).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.73, C(N)N(R.sup.73).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0103] R.sup.73 is alkyl, alkenyl, alkenyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and
[0104] the moieties represented by R.sup.69, R.sup.70 , and
R.sup.71 are unsubstituted or substituted with one or two or three
or four of independently selected NH.sub.2, C(O)NH.sub.2, C(O)NHOH,
SO.sub.2NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH,
C(N)NH.sub.2, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I.
[0105] Another embodiment pertains to a compound having Formula
(II)
##STR00002##
or a therapeutically acceptable salt thereof, wherein
[0106] R.sup.100 is as described for substituents on R.sup.26;
[0107] n is 0, 1, 2, or 3;
[0108] R.sup.101 is as described for substituents on R.sup.42;
[0109] m is 1, 2, 3, 4, or 5;
[0110] A.sup.1 is N or C(A.sup.2);
[0111] A.sup.2 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0112] B.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0113] D.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0114] E.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; and
[0115] Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17,
SO.sub.2R.sup.17, NH.sub.2, NHR.sup.17, N(R.sup.17).sub.2,
NHC(O)R.sup.17, C(O)NH.sub.2, C(O)NHR.sup.17,
C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17, or NHSO.sub.2R.sup.17;
or
[0116] E.sup.1 and Y.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0117] A.sup.2, B.sup.1, and D.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, CO(O)R.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2), NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2, or C(O)OR.sup.1A; or
[0118] Y.sup.1 and B.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane, or heterocycloalkene; and
[0119] A.sup.2, D.sup.1, and E.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, CO(O)R.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2), NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0120] A.sup.2 and B.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0121] D.sup.1, E.sup.1, and Y.sup.1are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, CO(O)R.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2), NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0122] A.sup.2 and D.sup.1, together with the atoms to which they
are attached, are benzene, naphthalene, heteroarene, cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0123] B.sup.1, E.sup.1, and Y.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, CO(O)R.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2), NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0124] R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
[0125] R.sup.1A is cycloalkyl, cycloalkenyl or cycloalkynyl;
[0126] R.sup.2 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane or
heterocycloalkane;
[0127] R.sup.3 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
[0128] R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0129] R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7,
OR.sup.7, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)CNH.sub.2, C(O)NHR.sup.7,
C(O)N(R.sup.7).sub.2, NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7,
NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0130] R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
[0131] R.sup.6A and R.sup.6B are independently selected alkyl or,
together with the N to which they are attached, R.sup.6C;
[0132] R.sup.6Cis aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
[0133] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0134] R.sup.8 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.8A; R.sup.8A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0135] R.sup.9 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0136] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0137] R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12, CO(O)R.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sub.2,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12,
CN(N)N(R.sup.12).sub.2, CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br, I;
[0138] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0139] R.sup.13 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0140] R.sup.14 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0141] R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0142] R.sup.16 is alkyl, alkenyl or alkynyl;
[0143] R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
[0144] R.sup.18 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0145] R.sup.19 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.19A; R.sup.19A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0146] R.sup.20 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.20A; R.sup.20A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0147] R.sup.21 is alkyl, aikenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.22, OR.sup.22, SR.sup.22,
S(O)R.sup.22, SO.sub.2R.sup.22, C(O)R.sup.22, CO(O)R.sup.22,
OC(O)R.sup.22, OC(O)OR.sup.22, NH.sub.2, NHR.sup.22,
N(R.sup.22).sub.2, NHC(O)R.sup.22, NR.sup.22C(O)R.sup.22,
NHS(O).sub.2R.sup.22, NR.sup.22S(O).sub.2R.sup.22, NHC(O)OR.sup.22,
NR.sup.22C(O)OR.sup.22, NHC(O)NH.sub.2, NHC(O)NHR.sup.22,
NHC(O)N(R.sup.22).sub.2, NR.sup.22C(O)NHR.sup.22,
NR.sup.22C(O)N(R.sup.22).sub.2, C(O)NH.sub.2, C(O)NHR.sup.22,
C(O)N(R.sup.22).sub.2, C(O)NHOH, C(O)NHOR.sup.22,
C(O)NHSO.sub.2R.sup.22, C(O)NR.sup.22SO.sub.2R.sup.22,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.22, SO.sub.2N(R.sup.22).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.22, C(N)N(R.sup.22).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0148] R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
[0149] R.sup.22 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0150] R.sup.24 is heteroarene, which is unfused or fused with
benzene, heteroarene or R.sup.24A; R.sup.24A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0151] R.sup.25 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.25A; R.sup.25A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0152] Z.sup.2 is R.sup.28, R.sup.29 or R.sup.30;
[0153] Z.sup.1A and Z.sup.2A are both absent or are taken together
to form CH.sub.2, CH.sub.2CH.sub.2 or Z.sup.12A;
[0154] Z.sup.12A is C.sub.2-C.sub.6-alkylene having one or two
CH.sub.2 moieties replaced by NH, N(CH.sub.3), S, S(O) or
SO.sub.2;
[0155] L.sup.1 is a R.sup.37, OR.sup.37, SR.sup.37, S(O)R.sup.37,
SO.sub.2R.sup.37, C(O)R.sup.37, CO(O)R.sup.37, OC(O)R.sup.37,
OC(O)OR.sup.37, NHR.sup.37, C(O)NH, C(O)NR.sup.37, C(O)NHOR.sup.37,
C(O)NHSO.sub.2R.sup.37, SO.sub.2NH, SO.sub.2NHR.sup.37, C(N)NH,
C(N)NHR.sup.37;
[0156] R.sup.28 is phenylene, which is unfused or fused with
benzene, heteroarene or R.sup.28A; R.sup.28A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0157] R.sup.29 is heteroarylene, which is unfused or fused with
benzene or heteroarene or R.sup.29A; R.sup.29A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0158] R.sup.30 is cycloalkylene, cycloalkenylene,
heterocycloalkylene or heterocycloalkenylene, each of which is
unfused or fused with benzene, heteroarene or R.sup.30A; R.sup.30A
is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0159] R.sup.37 is a bond or R.sup.37A;
[0160] R.sup.37A is alkylene, alkenylene, or alkynylene, each of
which is unsubstituted or substituted with one or two or three
independently selected R.sup.37B, OR.sup.37B, SR.sup.37B,
S(O)R.sup.37B, SO.sub.2R.sup.37B, C(O)R.sup.37B, CO(O)R.sup.37B,
OC(O)R.sup.37B, OC(O)OR.sup.37B, NH.sub.2, NHR.sup.37B,
N(R.sup.37B).sub.2, NHC(O)R.sup.37B, NR.sup.37BC(O)R.sup.37B,
NHS(O).sub.2R.sup.37B, NR.sup.37BS(O).sub.2R.sup.37B,
NHC(O)OR.sup.37B, NR.sup.37BC(O)OR.sup.37B, NHC(O)NH.sub.2,
NHC(O)NHR.sup.37B, NHC(O)N(R.sup.37B).sub.2,
NR.sup.37BC(O)NHR.sup.37B, NR.sup.37BC(O)N(R.sup.37B).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.37B, C(O)N(R.sup.37B).sub.2, C(O)NHOH,
C(O)NHOR.sup.37B, C(O)NHSO.sub.2R.sup.37B,
C(O)NR.sup.37BSO.sub.2R.sup.37B, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.37B, SO.sub.2N(R.sup.37B).sub.2, C(O)H, C(O)OH,
C(N)NH.sub.2, C(N)NHR.sup.37B, C(N)N(R.sup.37B).sub.2, CNOH,
CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3OCF.sub.3, OCF.sub.2CF.sub.3F, Cl, Br and I
substituents;
[0161] R.sup.37B is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl;
[0162] Z.sup.3 is R.sup.38, R.sup.39 or R.sup.40;
[0163] R.sup.38 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0164] R.sup.39 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.39A; R.sup.39A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0165] R.sup.40 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.40A; R.sup.40A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0166] wherein the moieties represented by R.sup.42 are
independently substituted with one or two or three or four of
independently selected R.sup.50, OR.sup.50, SR.sup.50,
S(O)R.sup.50, SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50,
OC(O)R.sup.50, OC(O)OR.sup.50, NH.sub.2, NHR.sup.50,
N(R.sup.50).sub.2, NHC(O)R.sup.50, NR.sup.50C(O)R.sup.50,
NHS(O).sub.2R.sup.50, NR.sup.50S(O).sub.2R.sup.50, NHC(O)OR.sup.50,
NR.sup.50C(O)OR.sup.50, NHC(O)NH.sub.2, NHC(O)NHR.sup.50,
NHC(O)N(R.sup.50).sub.2, NR.sup.50C(O)NHR.sup.50,
NR.sup.50C(O)N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.50SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, CCN)NHR.sup.50, C(N)N(R.sup.50).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0167] R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
[0168] R.sup.51 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.51A; R.sup.51A is cycloalkane, cycloalkene,
heterocycloalkene or heterocycloalkene;
[0169] R.sup.52 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.52A; R.sup.52A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0170] R.sup.53 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.53A; R.sup.53A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0171] R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.55, OR.sup.55, SR.sup.55,
S(O)R.sup.55, SO.sub.2R.sup.55, C(O)R.sup.55, CO(O)R.sup.55,
OC(O)R.sup.55, OC(O)OR.sup.55, NH.sub.2, NHR.sup.55,
N(R.sup.55).sub.2, NHC(O)R.sup.55, NR.sup.55C(O)R.sup.55,
NHS(O).sub.2R.sup.55, NR.sup.55S(O).sub.2R.sup.55, NHC(O)OR.sup.55,
NR.sup.55C(O)OR.sup.55, NHC(O)NH.sub.2, NHC(O)NHR.sup.55,
NHC(O)N(R.sup.55).sub.2, NR.sup.55C(O)NHR.sup.55,
NR.sup.55C(O)N(R.sup.55).sub.2, C(O)NH.sub.2, C(O)NHR.sup.55,
C(O)N(R.sup.5S).sub.2, C(O)NHOH, C(O)NHOR.sup.55,
C(O)NHSO.sub.2R.sup.55, C(O)NR.sup.55SO.sub.2R.sup.55,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55, SO.sub.2N(R.sup.55).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.55, C(N)N(R.sup.55).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0172] R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and
[0173] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.57A, R.sup.57, OR.sup.57, SR.sup.57,
S(O)R.sup.57, SO.sub.2R.sup.57, C(O)R.sup.57, CO(O)R.sup.57,
OC(O)R.sup.57, OC(O)OR.sup.57, NH.sub.2, NHR.sup.57,
N(R.sup.57).sub.2, NHC(O)R.sup.57, NR.sup.57C(O)R.sup.57,
NHSO.sub.2R.sup.57, NR.sup.57S(O).sub.2R.sup.57, NHC(O)OR.sup.57,
NR.sup.57C(O)OR.sup.57, NHC(O)NH.sub.2, NHC(O)NHR.sup.57,
NHC(O)N(R.sup.57).sub.2, NR.sup.57C(O)NHR.sup.57,
NR.sup.57C(O)N(R.sup.57).sub.2, C(O)NH.sub.2, C(O)NHR.sup.57,
C(O)N(R.sup.57).sub.2, C(O)NHOH, C(O)NHOR.sup.57,
C(O)NHSO.sub.2R.sup.57, C(O)NR.sup.57SO.sub.2R.sup.57,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.57, SO.sub.2N(R.sup.57).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.57,
C(N)NH(R.sup.57).sub.2, CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I;
[0174] R.sup.57A is spirocyclyl;
[0175] R.sup.57 is R.sup.58, R.sup.59, R.sup.60 or R.sup.61;
[0176] R.sup.58 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.58A; R.sup.58A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0177] R.sup.59 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.59A; R.sup.59A is cycloalkane,
cycloalkene, heterecycloalkane or heterocycloalkene;
[0178] R.sup.60is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.60A; R.sup.60A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0179] R.sup.61 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.62, OR.sup.62, SR.sup.62,
S(O)R.sup.62, SO.sub.2R.sup.62, C(O)R.sup.62, CO(O)R.sup.62,
C(O)R.sup.62, OC(O)OR.sup.62, NH.sub.2, NHR.sup.62,
N(R.sup.62).sub.2, NHC(O)R.sup.62, NR.sup.62C(O)R.sup.62,
NHSO.sub.2R.sup.62, NR.sup.62S(O).sub.2R.sup.62, NHC(O)OR.sup.62,
NR.sup.62C(O)OR.sup.62, NHC(O)NH.sub.2, NHC(O)NHR.sup.62,
NHC(O)N(R.sup.62).sub.2, NR.sup.62C(O)NHR.sup.62,
NR.sup.62C(O)N(R.sup.62).sub.2, C(O)NH.sub.2, C(O)NHR.sup.62,
C(O)N(R.sup.62).sub.2, C(O)NHOH, C(O)NHOR.sup.62,
C(O)NHSO.sub.2R.sup.62, C(O)NR.sup.62SO.sub.2R.sup.62,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.62, SO.sub.2N(R.sup.62).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.62),
C(N)N(R.sup.62).sub.2, CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3,
NO.sub.3, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
Cl, Br or I;
[0180] R.sup.62 is R.sup.63, R.sup.64, R.sup.65 or R.sup.66;
[0181] R.sup.63 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.63A; R.sup.63A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0182] R.sup.64 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.64A; R.sup.64A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0183] R.sup.65 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.65A; R.sup.65A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0184] R.sup.66 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.67, OR.sup.67, SR.sup.67,
S(O)R.sup.67, SO.sub.2R.sup.67, C(O)R.sup.67, CO(O)R.sup.67,
OC(O)R.sup.67, OC(O)OR.sup.67, NH.sub.2, NHR.sup.67,
N(R.sup.67).sub.2, NHC(O)R.sup.67, NR.sup.67C(O)R.sup.67,
NHS(O).sub.2R.sup.67, NR.sup.67S(O).sub.2R.sup.67, NHC(O)OR.sup.67,
NR.sup.67C(O)OR.sup.67, NHC(O)NH.sub.2, NHC(O)NHR.sup.67,
NHC(O)N(R.sup.67).sub.2, NR.sup.67C(O)NHR.sup.67,
NR.sup.67C(O)N(R.sup.67).sub.2, C(O)NH.sub.2, C(O)NHR.sup.67,
C(O)N(R.sup.67).sub.2, C(O)NHOH, C(O)NHOR.sup.67,
C(O)NHSO.sub.2R.sup.67, C(O)NR.sup.67SO.sub.2R.sup.67,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.67, SO.sub.2N(R.sup.67).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.67, C(N)N(R.sup.67).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
[0185] R.sup.67 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl;
[0186] wherein the moieties represented by R.sup.57A, R.sup.58,
R.sup.59, R.sup.60, R.sup.63, R.sup.64, R.sup.65, and R.sup.67 are
unsubstituted or substituted with one or two or three or four of
independently selected R.sup.68, OR.sup.68, SR.sup.68,
S(O)R.sup.68, SO.sub.2R.sup.68, C(O)R.sup.68, CO(O)R.sup.68,
OC(O)R.sup.68, OC(O)OR.sup.68, NH.sub.2, NHR.sup.68,
N(R.sup.68).sub.2, NHC(O)R.sup.68, NR.sup.68C(O)R.sup.68,
NHS(O).sub.2R.sup.68, NR.sup.68S(O).sub.2R.sup.68, NHC(O)OR.sup.68,
NR.sup.68C(O)OR.sup.68, NHC(O)NH.sub.2, NHC(O)NHR.sup.68,
NHC(O)N(R.sup.68).sub.2, NR.sup.68C(O)NHR.sup.68,
NR.sup.68C(O)N(R.sup.68).sub.2, C(O)NH.sub.2, C(O)NHR.sup.68,
C(O)N(R.sup.68).sub.2, C(O)NHOH, C(O)NHOR.sup.68,
C(O)NHSO.sub.2R.sup.68, C(O)NR.sup.68SO.sub.2R.sup.68,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.68, SO.sub.2N(R.sup.68).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.68, C(N)N(R.sup.68).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0187] R.sup.68 is R.sup.69, R.sup.70, R.sup.71 or R.sup.72;
[0188] R.sup.69 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.69A; R.sup.69A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0189] R.sup.70 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.70A; R.sup.70A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0190] R.sup.71 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.71A; R.sup.71A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0191] R.sup.72 is alkenyl or alkenyl, each of which is
unsnbstituted or substituted with one or two or three of
independently selected R.sup.73, OR.sup.73, SR.sup.73,
S(O)R.sup.73, SO.sub.2R.sup.73, C(O)R.sup.73, CO(O)R.sup.73,
OC(O)R.sup.73, OC(O)OR.sup.73, NH.sub.2, NHR.sup.73,
N(R.sup.73).sub.2, NHC(O)R.sup.73, NR.sup.73C(O)R.sup.73,
NHS(O).sub.2R.sup.73, NR.sup.73S(O).sub.2R.sup.73, NHC(O)OR.sup.73,
NR.sup.73C(O)OR.sup.73, NHC(O)NH.sub.2, NHC(O)NHR.sup.73,
NHC(O)N(R.sup.73).sub.2, NR.sup.73C(O)NHR.sup.73,
NR.sup.73C(O)N(R.sup.73).sub.2, C(O)NH.sub.2, C(O)NHR.sup.73,
C(O)N(R.sup.73).sub.2, C(O)NHOH, C(O)NHOR.sup.73,
C(O)NHSO.sub.2R.sup.73, C(O)NR.sup.73SO.sub.2R.sup.73,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.73, SO.sub.2N(R.sup.73).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.73, C(N)N(R.sup.73).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0192] R.sup.73 is alkyl, alkenyl, alkenyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and
[0193] the moieties represented by R.sup.69, R.sup.70, and R.sup.71
are unsbustituted or substituted with one or two or three or four
of independently selected NH.sub.2, C(O)NH.sub.2, C(O)NHOH,
SO.sub.2NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH,
C(N)NH.sub.2, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3s F, Cl, Br or I.
[0194] Still another embodiment pertains to a compound of Formula I
or Formula II, wherein A.sup.1 is C(A.sup.2); and A.sup.2 is H.
[0195] Still another embodiment pertains to a compound of Formula I
or Formula II, wherein A.sup.2 is C(A.sup.2); A.sup.2 is H; and
B.sup.1 is NHR.sup.1.
[0196] Still another embodiment pertains to a compound of Formula I
or Formula II, wherein A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1
is NHR.sup.1; and D.sup.1 is H.
[0197] Still another embodiment pertains to a compound of Formula I
or Formula II, wherein A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1
is NHR.sup.1; D.sup.1 is H; and E.sup.1 is H.
[0198] Still another embodiment pertains to a compound of Formula I
or Formula II, wherein A.sup.1 is C(A.sup.2); A.sup.2 is H; and
B.sup.1 is NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and Y.sup.1 is
NO.sub.2.
[0199] Still another embodiment pertains to compounds having
Formula I, which are [0200]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethy-
lamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [0201]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylam-
ino)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide; [0202]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-(methylpiperidin-4-yl)am-
ino)-3-nitrophenyl)sulfonyl)benzamide; [0203]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((2methyl-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide; [0204]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-chloro-
phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfo-
nyl)benzamide; [0205]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [0206]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [0207]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide; [0208]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxym-
ethyl)phenoxy-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl-
)benzamide; [0209]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophe-
noxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzami-
de; [0210]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-
-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfo-
nyl)benzamide; [0211]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzami-
de; [0212]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-
-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfon-
yl)benzamide; [0213]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide; [0214]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophe-
noxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide; [0215]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-)-
yl)oxy)benzamide; [0216]
2-(3-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide; [0217]
2-(4-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1--
yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide; [0218]
2-(3-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1--
yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide; [0219]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyph-
enyl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide; [0220]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-dimethyla-
mino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide; [0221]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophen-
oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)b-
enzamide; [0222]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1-
,3-benzothiazol-6-yl)oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)am-
ino)phenyl)sulfonyl)benzamide; [0223]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl))-2-((2-methyl--
1,3-benzothiazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitroph-
enyl)sulfonyl)benzamide; [0224]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dime-
thylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-((2-methyl-1,3-benzothiaz-
ol-5-yl)oxy)benzamide; [0225]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimet-
hylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmeth-
yl)amino)phenyl)sulfonyl)benzamide; [0226]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimet-
hylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethy-
l)amino)phenyl)sulfonyl)benzamide; [0227]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimeth-
ylamino)propyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [0228]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimeth-
ylamino)ethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide; [0229]
2-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((te-
trahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-di-
methylbenzamide; [0230]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethy-
lamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [0231]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy-
)benzamide; [0232]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dime-
thyl-1,3-thiazol-5-yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0233]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0234]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0235]
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0236]
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-n-
itrophenyl)sulfonyl)benzamide; [0237]
2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3--
nitrophenyl)sulfonyl)benzamide; [0238]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimet-
hylamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)am-
ino)phenyl)sulfonyl)benzamide; [0239]
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-
-nitrophenyl)sulfonyl)benzamide; [0240]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide; [0241]
2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0242]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)p-
iperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide; [0243]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)am-
ino)-3-nitrophenyl)sulfonyl)benzamide; [0244]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0245]
2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0246]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0247]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin--
4-yl)amino)phenyl)sulfonyl)benzamide; [0248]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylp-
iperidin-4-yl)amino)phenyl)sulfonyl)benzamide; [0249]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide; [0250]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0251]
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-
-nitrophenyl)sulfonyl)benzamide; [0252]
2-(3-chlorophenoxy)-4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biph-
enyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylm-
ethyl)amino)phenyl)sulfonyl)benzamide; [0253]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0254]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)am-
ino)-3-nitrophenyl)sulfonyl)benzamide; [0255]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)p-
iperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide; [0256]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3--
(trifluoromethyl)phenoxy)benzamide; [0257]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahy-
droquinolin-5-yl)oxy)benzamide; [0258]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3((triflu-
oromethyl)sulfonyl)phenyl)sulfonyl)benzamide; [0259]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0260]
2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)--
3-nitrophenyl)sulfonyl)benzamide; [0261]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en--
1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide; [0262]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide; [0263]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4-
-yl)amino)-3-nitrophenyl)sulfonyl)benzamide; [0264]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-ni-
trophenyl)sulfonyl)benzamide; [0265]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide; [0266]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0267]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1-
H-indol-4-yl)oxy)
-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;
[0268]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-m-
orpholin-4-ylphenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)-
sulfonyl)benzamide; [0269]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3-
-oxopropyl)-1H-indol-5-yl)oxy)benzamide; [0270]
2-(3-benzylxoy)phenoxy)-4-(4-((4'-chloro)-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide; [0271]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [0272]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morph-
olin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-py-
ran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide; [0273]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morph-
olin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4--
ylmethyl)amino)phenyl)sulfonyl)benzamide; [0274]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4((dimethyl-
amino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide; [0275]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imid-
azol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [0276]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophen-
oxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamid-
e; [0277] tert-butyl
4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)benzyl(ethyl)carbamate; [0278] tert-butyl
3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)benzyl(ethyl)carbamate; [0279]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((ethylam-
ino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [0280]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((ethylam-
ino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [0281]
2-(4-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide; [0282] tert-butyl
4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)phenylcarbamate; [0283]
2-(1,1'-biphenyl-2-yloxy)-4-(4-((4
'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahy-
dro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide; [0284]
tert-butyl
3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)phenylcarbamate; [0285]
2-(1,1'-biphenyl-3-yloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide; [0286]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimet-
hylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide; [0287]
2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide; [0288]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-morpholin-
-4-ylphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)benzamide; [0289]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-1,-
3-benzothiazol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)am-
ino)phenyl)sulfonyl)benzamide; [0290] tert-butyl
4-(3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3--
nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbo-
nyl)phenoxy)phenyl)piperazine-1-carboxylate; [0291]
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)b-
enzamide; [0292]
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)be-
nzamide; [0293]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpho-
lin-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide; [0294]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-((2-oxo-1,2,3,4--
tetrahydroquinolin-5-yl)oxy)benzamide; [0295]
2-(4-benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipera-
zin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)ben-
zamide; [0296] tert-butyl
4-(4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((4--
((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carbonyl)pheno-
xy)phenyl)piperazine-1-caraboxylate; [0297]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)b-
enzamide; [0298]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)b-
enzamide; [0299]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)b-
enzamide; [0300]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimet-
hylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmet-
hyl)amino)phenyl)sulfonyl)benzamide; [0301]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1-
H-benzimidazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophen-
yl)sulfonyl)-benzamide; [0302]
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoy-
l)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamide;
[0303]
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dim-
ethylamino)propylamino)-3-nitrophenylsulfonyl)-2-(3-(methylcarbamoyl)pheno-
xy)benzamide; [0304]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimet-
hylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmet-
hyl)amino)phenyl)sulfonyl)benzamide; [0305]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dime-
thylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-
-ylmethyl)amino)phenyl)sulfonyl)benzamide; [0306]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dime-
thylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)phenoxy-
)benzamide; [0307]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-methoxyb-
enzyl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide; [0308]
N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrophenylsulfonyl-
-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzamide; [0309]
4-(4-((4'-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-
-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamid-
e; [0310]
N-{[4-{4-[(4'chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2--
(3,5-dichlorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3--
nitrobenzamide; [0311]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0312]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide; [0313]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0314]
2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperi-
din-4-yl)amino]phenyl}sulfonyl)benzamide; [0315]
2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [0316]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [0317]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0318]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [0319]
2-(2-chloro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [0320]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2,3-difluorophenoxy)benzamide; [0321]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0322]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2-fluorophenoxy)benzamide; [0323]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide; [0324]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0325]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [0326]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]-phenyl}sulfonyl)benzamide; [0327]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0328]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [0329]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [0330]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide; [0331]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(3-fluorophenoxy)benzamide; [0332]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2,3-difluorophenoxy)benzamide; [0333]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2-fluorophenoxy)benzamide; [0334]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [0335]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperid-
in-4-yl]amino}phenyl)sulfonyl]benzamide; [0336]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2--
fluorophenoxy)benzamide; [0337]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2--
fluorophenoxy)benzamide; [0338]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4--
fluorophenoxy)benzamide; [0339]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [0340]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [0341]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrop-
henyl)sulfonyl]benzamide; [0342]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [0343]
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [0344]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide; [0345]
N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-
-difluorophenoxy)benzamide; [0346]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [0347]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [0348]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropy-
l)amino]phenyl}sulfonyl)benzamide; [0349]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [0350]
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [0351]
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0352]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [0353]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-
-nitrophenyl)sulfonyl]benzamide; [0354]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-methylpiperidin-4-yl)methyl]amino-
}-3-nitrophenyl)sulfonyl]benzamide; [0355]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [0356]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[3-(methoxymethoxy)-2-methylphenoxy]-N-({4-[(1-methylpiperidin-4--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0357]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [0358]
2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide; [0359]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-n-
itrophenyl}sulfonyl)benzamide; [0360]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [0361]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2-phenylethyl)-piperidin-4-y-
l]amino}phenyl)sulfonyl]benzamide; [0362]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [0363]
2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide; [0364]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide; [0365]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-([3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide;
[0366]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide; [0367]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [0368]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(2-methoxyethoxy)ethyl]piperidin-4-
-yl}amino)-3-nitrophenyl]sulfonyl}benzamide; [0369]
2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [0370]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(3-phenylpropyl)piperidin-4-y-
l]amino}phenyl)sulfonyl]benzamide; [0371]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [0372]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-ethylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [0373]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide; [0374]
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [0375]
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [0376]
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0377]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-dimethylamino)propyl]amino}-3-nitroph-
enyl)sulfonyl]benzamide; [0378]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide; [0379]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0380]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0381]
2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl-
}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfo-
nyl)benzamide; [0382]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [0383]
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [0384]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [0385]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [0386]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [0387]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(dimethylamino)-2-oxoethyl]piperid-
in-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide; [0388]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl-
]amino}-3-nitrophenyl)sulfonyl]benzamide; [0389]
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)benzamide; [0390]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methy-
l]amino}-3-nitrophenyl)sulfonyl]benzamide; [0391]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0392]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-n-
itrophenyl)sulfonyl]benzamide; [0393]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-n-
itrophenyl)sulfonyl]benzamide; [0394]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-[3-(1H-pyrrol-2-yl)phenoxy]benzamide; [0395]
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(3-fluorophenoxy)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)meth-
yl]amino]-3-nitrophenyl}sulfonyl)benzamide; [0396]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-methylpiperazin-1-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [0397]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)-
amino]-3-nitrophenyl}sulfonyl)benzamide; [0398]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-
-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0399]
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)a-
mino]carbonyl}phenoxy)-1H-indole-1-carboxylate; [0400]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-ni-
trophenyl)sulfonyl]benzamide; [0401]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nit-
rophenyl)sulfonyl]benzamide; [0402]
Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [0403]
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chloroph-
enoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzam-
ide; [0404]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [0405]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [0406]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [0407]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyr-
an-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [0408]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-
-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide; [0409]
2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(-
4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(-
4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[0410]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfony-
l]-2-({3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide;
[0411]
2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pi-
perazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarb-
amoyl)pheonxy)-N,N-dimethylbenzamide; [0412]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide;
[0413]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [0414]
(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-
-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide; [0415]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;
[0416]
2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro--
2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0417]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)-
amino]-3-nitrophenyl}sulfonyl)benzamide; [0418]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [0419] tert-butyl
4-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)a-
mino]carbonyl}phenoxy)methyl]-1,3-thiazol-2-ylcarbamate; [0420]
2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-nitrophenyl}sulfonyl)benzamide; [0421]
2-[3-(acetylamino)phenoxy]-(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [0422]
2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4--
ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [0423]
2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-y-
lpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [0424]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-py-
ran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [0425]
2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0426]
2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-n-
itrophenyl}sulfonyl)benzamide; [0427] tert-butyl
5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-
amino}carbonyl)phenoxy]-1H-indole-1-carboxylate; [0428]
2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-
-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;
[0429]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-
-yl)propyl]amino}phenyl)sulfonyl]benzamide; [0430]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0431]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylc-
yclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide; [0432]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0433]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-[(6,7-difluoro-1H-indol-5-yl)oxy]benzamide; [0434]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0435]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperaz-
in-1-yl)propyl]amino}phenyl)sulfonyl]benzamide; [0436]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-p-
yran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0437]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydr-
o-2H-pyran-4-yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide;
[0438]
2-[(6-chloro-1H-indol-5-yl)oxy]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0439]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0440]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [0441]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-yl-
methyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide; [0442]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide;
[0443]
2-(4-amino-3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-py-
ran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0444]
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0445]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3S,4R)-3-hydroxy-1-(1,3-th-
iazol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[0446]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H--
pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide; [0447]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran--
4-ylamino)phenyl]sulfonyl}benzamide; [0448]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitro-
phenyl]sulfonyl}benzamide; [0449]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfo-
nyl}benzamide; [0450]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]a-
mino}phenyl)sulfonyl]benzamide; [0451]
2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylp-
iperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0452]
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyra-
n-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0453]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-
-yl)propyl]amino}phenyl)sulfonyl]benzamide; [0454]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H--
pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide; [0455]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3R)-tetrahydro-2H--
pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide; [0456] tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate;
[0457]
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-
-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0458]
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0459]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [0460]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran--
4-ylmethyloxy)phenyl]sulfonyl}benzamide; [0461]
2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0462]
2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0463]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]benzamide; [0464]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [0465]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [0466] tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [0467]
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-ylmethyl-
)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;
[0468]
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0469]
2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0470]
2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [0471]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,-
6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0472]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0473]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0474]
tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate; [0475]
2-[5-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide; [0476] tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [0477]
2-[3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0478]
2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [0479]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-hydroxypyridin-3-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2-H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0480]
2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pr-
yan-4ylmethyl)amino]phenyl}sulfonyl)benzamide; [0481]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-
-1H-indol-5-yl)oxy]benzamide; [0482]
2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [0483]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-
-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [0484]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-
-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [0485]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;
[0486]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-ni-
trophenyl]sulfonyl}benzamide; [0487]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino-
]-3-nitrophenyl}sulfonyl)benzamide; [0488]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(6--
fluoro-1H-indol-5-yl)oxy]benzamide; [0489]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0490]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimet-
hyl-5,6-dihydro
2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)a-
mino]-3-nitrophenyl}sulfonyl)benzamide; [0491]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyc-
lohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0492]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-
-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [0493]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro--
2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [0494]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl-
]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0495]
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0496]
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-
-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0497]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0498]
2-[(6-amino-5-fluoropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0499]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0500]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]benzamide;
[0501]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide; [0502]
N-{[5-bromo-6-(1,4-dioxan-2ylmethoxy)pyridino-3-yl]sulfonyl}-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6--
fluoro-1H-indol-5-yl)oxy]benzamide; [0503]
Trans-N-({5-bromo-6-[(4-morpholin-4ylcyclohexyl)amino]pyridin-3-yl}sulfon-
yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0504]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0505]
2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide; [0506]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide; [0507]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)oxy]-3-nitrophenyl}sulfonyl)benzamide; [0508]
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3--
yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0509]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [0510]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-t-
etrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[0511]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-t-
etrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0512]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-
-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0513]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)-
oxy]-3-nitrophenyl}sulfonyl)benzamide; [0514]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0515]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-
-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0516]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [0517]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-
-dihydro-1H-indol-4-yl)oxy]benzamide;
[0518]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl-
]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0519]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-y-
l]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0520]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-y-
lcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0521]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridi-
n-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0522]
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0523]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0524]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(-
6-fluoro-1H-indol-5-yl)oxy]benzamide; [0525]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2-
H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide; [0526]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-
-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [0527]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl-
)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0528]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-y-
lmethyl)amino]phenyl}sulfonyl)benzamide; [0529]
Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0530]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-[(4-{[4-dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)-
sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0531]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-
-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide;
[0532]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-tetrahyd-
ro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamide;
[0533]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro--
2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[0534]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)-
methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0535]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(-
tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[0536]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methyl-
piperazin-1-yl)amino]-3nitrophenyl}sulfonyl)benzamide; [0537]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl-
}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0538]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-{[1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro-
-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[0539]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpipera-
zin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0540]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy-
)-3-nitrophenyl]sulfonyl}benzamide; [0541]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclo-
hexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0542]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl-
)amino]-3-nitrophenyl}sulfonyl)benzamide; [0543]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropy-
l)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[0544]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-
-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamid-
e; [0545]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorot-
etrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[0546]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahy-
dro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0547]
2-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-
sulfonyl)amino]carbonyl}phenoxy)nicotinamide; [0548]
2-amino-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahyd-
ro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0549]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroe-
thyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[0550]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[0551]
2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0552]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetr-
ahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0553]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amin-
o-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;
[0554]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidi-
n-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [0555]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl-
)amino]-3-nitrophenyl}sulfonyl)benzamide; [0556]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [0557]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)-
amino]-3-nitrophenyl}sulfonyl)benzamide; [0558]
2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0559]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2-
H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0560]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-yl-
piperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [0561]
2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-di-
methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0562]
2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahyd-
ro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0563]
Trans-2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycycloh-
exyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0564]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-N-({3-nitr-
o-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[0565]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropyl-
morpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[0566]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyr-
rolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0567]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro--
1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benza-
mide; [0568] tert-butyl
6bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]ph-
enyl}sulfonyl)amino]carbonyl}phenyoxy)pyridin-2-ylcarbamate; [0569]
tert-butyl
-4-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazi-
n-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methylamino)phenylsulfonylc-
arbamoyl)phenoxy)pyridine-2,6-diyldicarbamate; [0570]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-{[6-(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydr-
o-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0571]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4--
(methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[0572]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(t-
etrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[0573]
2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4-
,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetra-
hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0574]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluor-
omethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide-
; [0575]
2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0576]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(2,6-diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyra-
n-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0577]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H--
pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide; [0578]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(f-
luoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide;
[0579] tert-butyl
5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [0580]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tet-
rahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0581]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide; [0582]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)-
methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0583]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimet-
hyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetra-
hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0584]
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]m-
ethyl}piperazin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]benzamide;
[0585]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofur-
an-3-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0586]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-
-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,-
6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)benzamide;
[0587]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3--
[2-fluoro-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide; [0588]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isoprop-
yl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(t-
etrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[0589]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylgly-
cyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chl-
orophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[0590]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluo-
ro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}ben-
zamide; [0591]
2-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0592]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohex-
yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0593]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4'-chloro-3-[2-(dimethylamin-
o)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [0594]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-
-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)b-
enzamide; [0595]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluo-
roethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[0596]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophen-
yl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-
cyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [0597]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetr-
ahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;
[0598]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroeth-
yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]4-(4-{[2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[0599]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotet-
rahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4-
,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[0600]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro--
1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-
-yl]sulfonyl}benzamide; [0601]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide; [0602]
2-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-py-
ran-4- ylmethyl)amino]phenyl}sulfonyl)benzamide; [0603]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-[2-(1H-pyrazol-5-yl)phenoxy]benzamide; [0604]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4-difluorocycloh-
exyl)methoxy]pyridin-3-yl}sulfonyl)-4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide; [0605]
N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4--
(4-{[4-(4-chlorphenyl-6,6-dimehyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperaz-
in-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [0606]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; and therapeutically
acceptable salts, prodrugs, salts of prodrugs and metabolites
thereof.
[0607] Still another embodiment pertains to
2-[(6-amino-5-chloropyriidn-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-ntiro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; and
therapeutically acceptable salts, prodrugs, salts of prodrug and
metabolites thereof.
[0608] Another embodiment pertains to a composition for treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic lymphocytic leukemia, colorectal cancer,
esophageal cancer, hepatocellular cancer, lymphoblastic leukemia,
follicular lymphoma, lymphoid malignancies of T-cell or B-cell
origin, melanoma, myelogenous leukemia, myeloma, oral cancer,
ovarian cancer, non-small cell lung cancer, chronic lymphocytic
leukemia, myeloma, prostate cancer, small cell lung cancer or
spleen cancer, said composition comprising an excipient and a
therapeutically effective amount of the compound of Formula
(I).
[0609] Another embodiment pertains to a method of treating bladder
cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal
cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell origin,
melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian
cancer, non-small cell lung cancer, chronic lymphocytic leukemia,
myeloma, prostate cancer, small cell lung cancer or spleen cancer
in a patient, said method comprising administering to the patient a
therapeutically effective amount of Formula (I).
[0610] Another embodiment pertains to a method of treating bladder
cancer, brain cancer, breast cancer, bone marrow cancer, cervical
cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal
cancer, hepatocellular cancer, lymphoblastic leukemia, follicular
lymphoma, lymphoid malignancies of T-cell or B-cell origin,
melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian
cancer, non-small cell lung cancer, chronic lymphocytic leukemia,
myeloma, prostate cancer, small cell lung cancer or spleen cancer
in a patient, said method comprising administering to the patient
therapeutically effective amount of the compound of Formula (I) and
a therapeutically effective amount of one additional therapeutic
agent or more than one additional therapuetic agent.
DETAILED DESCRIPTION OF THE INVENTION
[0611] Variable moieties herein are represented by identifiers
(capital letters with numerical and/or alphabetical superscripts)
and may be specifically embodied.
[0612] It is meant to be understood that proper valences are
maintained for all moieties and combinations thereof, that
monovalent moieties having more than one atom are drawn from left
to right and are attached through their left ends, and that
divalent moieties are also drawn from left to right.
[0613] It is also meant to be understood that a specific embodiment
of a variable moiety herein may be the same or different as another
specific embodiment having the same identifier.
[0614] 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. The term
"C.sub.x-C.sub.y alkyl" means a straight or branched hydrocarbon
chain containing at least one carbon-carbon double bond containing
x to y carbon atoms. The term "C.sub.2-C.sub.4 alkenyl" means an
alkenyl group containing 2-4carbon atoms. Representative examples
of alkenyl include, but are not limited to buta-2,3-dienyl,
ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,
5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.
[0615] 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. The term
"C.sub.x-C.sub.y alkylene" means a a divalent group derived from a
straight or branched hydrocarbon chain containing at least one
carbon-carbon double bond and containing x to y carbon atoms.
Representative examples of alkenylene include, but are not limited
to, --CH.dbd.CH-- and --CH.sub.2CH.dbd.CH--.
[0616] The term "alkyl" as used herein, means a straight or
branched, saturated hydrocarbon chain containing from 1 to 10
carbon atoms. The term "C.sub.x-C.sub.y alkyl" means a straight or
branched chain, saturated hydrocarbon containing x to y carbon
atoms. For example "C.sub.2-C.sub.10 alkyl" means a straight or
branched chain, saturated hydrocarbon containing 2 to 10 carbon
atoms. 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, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl,
and n-decyl.
[0617] The term "alkylene" means a divalent group derived from a
straight or branched, saturated hydrocarbon chain of 1 to 10 carbon
atoms, for example, of 1 to 4 carbon atoms. The term
"C.sub.x-C.sub.y alkylene" means a divalent group derived from a
straight or branched chain, saturated hydrocarbon containing x to y
carbon atoms. For example "C.sub.2-C.sub.6 alkylene" means a
straight or branched chain, saturated hydrocarbon containing 2 to 6
carbon atoms. Examples of alkylene 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.sub.2(CH.sub.3)CH.sub.2--.
[0618] The term "alkynyl" as used herein, means a straight or
branched chain hydrocarbon group containing from 2 to 10 carbon
atoms and containing at least one carbon-carbon triple bond. The
term "C.sub.x-C.sub.y alkynyl" means a straight or branched chain
hydrocarbon group containing from x to y carbon atoms.
Representative examples of alkynyl include, but are not limited, to
acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and
1-butynyl.
[0619] The term "alkynylene," as used herein, means a divalent
radical derived from a straight or branched chain hydrocarbon group
containing from 2 to 10 carbon atoms and containing at least one
carbon-carbon triple bond.
[0620] The term "aryl" as used herein, means phenyl.
[0621] The term "cyclic moiety," as used herein, means benzene,
phenyl, phenylene, cycloalkane, cycloalkyl, cycloalkylene,
cycloalkene, cycloalkenyl, cycloalkenylene, cycloalkyne,
cycloalkynyl, cycloalkynylene, heteroarene, heteroatyl,
heterocycloalkane, heterocycloalkyl, heterocycloalkene,
heterocycloalkenyl and spiroalkyl.
[0622] The term "cycloalkylene" or c ycloalky" or "cycloalkane" as
used herein, means a monocyclic or bridged hydrocarbon ring system,
The monocyclic cycloalkyl is a carbocyclic ring system containing
three to eight carbon atoms, zero heterostoms and zero double
bonds. Examples of monocyclic ring systems include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The monocyclic ring may contain one or two alkylene bridges, each
consisting of one, two, or three carbon atoms, each linking two
non-adjacent carbon atoms of the ring system. Non-limiting examples
of such bridged cycloalkyl ring systems include
bicyclo[3.1.1]heptane, bicyclo[2.1.1]heptane, bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, 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).
The monocyclic and bridged cycloalkyl can be attached to the parent
molecular moiety through any substitutable atom contained within
the ring system.
[0623] The term "cycloalkenylene," or"cycloalkenyl" or
"cycloalkene" as used herein, means a monocyclic or a bridged
hydrocarbon ring system. The monocyclic cycloalkenyl has four-,
five-, six-, seven- or eight carbon atoms and zero heteroatoms. The
four-membered ring systems have one double bond, the five- or
six-membered ring systems have one or two double bonds, and the
seven- or eight-membered ring systems have one, two, or three
double bonds. Representative examples of monocyclic cycloalkenyl
groups include, but are not limited to, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. The
monocyclic cycloalkenyl ring may contain one or two alkylene
bridges, each consisting of one, two, or three carbon atoms, each
linking two non-adjacent carbon atoms of the ring system.
Representative examples of the bicyclic cycloalkenyl groups
include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene,
octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic
and bicyclic cycloalkenyl can be attached to the parent molecular
moiety through any substitutable atom contained within the ring
systems.
[0624] The term "cycloalkyne," or "cycloalkynyl," or
"cycloalkynylene," as used herein, means a monocyclic or a bridged
hydrocarbon ring system. The monocyclic cycloalkynyl has eight or
more carbon atoms, zero heteroatoms, and one or more triple bonds.
The monocyclic cycloalkynyl ring may contain one or two alkylene
bridges, each consisting of one, two, or three carbon atoms, each
linking two non-adjacent carbon atoms of the ring system. The
monocyclic and bridged cycloalkynyl can be attached to the parent
molecular moiety through any substitutable atom contained within
the ring systems.
[0625] The term "heteroarene," or "heteroaryl," or "heteroarylene,"
as used herein, means a five-membered or six-membered aromatic ring
having at least one carbon atom and one or more than one
independently selected nitrogen, oxygen or sulfur atom. The
heteroarenes of this invention are connected through any adjacent
atoms in the ring, provided that proper valences are maintained.
Representative examples of heteroaryl include, but are not limited
to, furanyl (including, but not limited thereto, furan-2-yl),
imidazolyl (including, but not limited thereto, 1H-imidazol-1-yl),
isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl (e.g.
pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl,
pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl,
thiadiazolyl, thiazolyl, thienyl (including, but not limited
thereto, thien-2-yl, thien-3-yl), triazolyl, and triazinyl.
[0626] The term "heterocycloalkane" or "heterocycloalkyl," or
"heterocycloalkylene," as used herein, means monocyclic or bridged
three-, four-, five-, six-, seven-, or eight-membered ring
containing at least one heteroatom independently selected from the
group consisting of O, N, and S and zero double bonds. The
monocyclic and bridged heterocycloalkane are connected to the
parent molecular moiety through any substitutable carbon atom or
any substitutable nitrogen atom contained within the rings. The
nitrogen and sulfur heteroatoms in the heterocycle rings may
optionally be oxidized and the nitrogen atoms may optionally be
quarternized. Representative examples of heterocycloalkane groups
include, but are not limited to, Representative examples of
heterocycloalkane groups include, but are not limited to,
morpholinyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,
dioxolanyl, tetrahydrofuranyl, thiomorpholinyl, dioxanyl,
tetrahydrothienyl, tetrahydrothiopyranyl, oxetanyl, piperazinyl,
imidazolidinyl, azetidine, azepanyl, aziridinyi, diazepanyl,
dithiolanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
oxadiazolidinyl, oxazolidinyl, pyrazolidinyl, tetrahydrothienyl,
thiadiazolidinyl, thiazolidinyl, thiomorpholinyl, trithianyl, and
trithianyl.
[0627] The term "heterocyclalkene," or "heterocycloalkenyl," or
"heterocycloalkenylene," as used herein, means monocyclic or
bridged three-, four-, five, six-, seven-, or eight-membered ring
containing at least one heteroatom independently selected from the
group consisting of O, N, and S and one or more double bonds. The
monocyclic and bridged heterocycloalkene are connected to the
parent molecular moiety through any substitutable carbon atom or
any substitutable nitrogen atom contained within the rings. The
nitrogen and sulfur heteroatoms in the heterocycle rings may
optionally be oxidized and the nitrogen atoms may optionally be
quarternized. Representative exmaples of heterocycloalkene groups
include, but are not limited to, tetrahydrooxocinyl,
1,4,5,6-tetrahydropyridazinyl, 1,2,3,6-tetrahydropyridinyl,
dihydropyranyl, imidazolinl, isothiazolinyl, oxadiazolinyl,
isoxazolinyl, oxazolinyl, pyranyl, pyrazolinyl, pyrrolinyl,
thiadiazolinyl, thiazolinyl, and thiopyranyl.
[0628] The term "phenylene," as used herein, means a divalent
radical formed by removal of a hydrogen atom from phenyl.
[0629] The term "spiroalkyl," as used herein, means alkylene, both
ends of which are attached to the same carbon atom and is
exemplified by C.sub.2-spiroalkyl, C.sub.3-spiroalkyl,
C.sub.4-spiroalkyl, C.sub.5-spiroalkyl, C.sub.6-spiroalkyl,
C.sub.7-spiroalkyl, C.sub.8-spiroalkyl, C.sub.9-spiroalkyl and the
like.
[0630] The term "spiroheteroalkyl," as used herein, means
spiroalkyl have one or two CH.sub.2 moieties replaced with
independently selected O, C(O), CNOH, CNOCH.sub.3, S, S(O),
SO.sub.2 or NH and one or two CH moieties unreplaced or replaced
with N.
[0631] The term "spiroheteroalkenyl," as used herein, means
spiroalkenyl having one or two CH.sub.2 moieties replaced with
independently selected O, C(O), CNOH, CNOCH.sub.3, S, S(O),
SO.sub.2 or NH and one or two CH moieties unreplaced or replaced
with N and also means spiroalkenyl having one or two CH.sub.2
moieties unreplaced or replaced with independently selected O,
C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or NH and one or two CH
moieties replaced with N.
[0632] The term, "spirocyclo," as used herein, means two
substituents on the same carbon atom, that, together with the
carbon atom to which they are attached, form a cycloalkane,
heterocycloalkane, cycloalkene, or heterocycloalkene ring.
[0633] The term, "C.sub.2-C.sub.5-spiroalkyl," as used herein,
means C.sub.2-spiroalkyl, C.sub.3-spiroalkyl, C.sub.4-spiroalkyl,
and C.sub.5-spiroalkyl.
[0634] The term "C.sub.2-spiroalkyl," as used herein, means
eth-1,2-ylene, both ends of which replace hydrogen atoms of the
same CH.sub.2 moiety.
[0635] The term "C.sub.3-spiroalkyl," as used herein, means
prop-1,3-ylene both ends of which replace hydrogen atoms of the
same CH.sub.2 moiety.
[0636] The term "C.sub.4-spiroalkyl," as used herein, means
but-1,4-ylene, both ends of which replace hydrogen atoms of the
same CH.sub.2 moiety.
[0637] The term "C.sub.5-spiroalkyl," as used herein, means
pent-1,5-ylene, both ends of which replace hydrogen atoms of the
same CH.sub.2 moiety.
[0638] The term "C.sub.6-spiroalkyl," as used herein, means
hex-1,6-ylene, both ends of which replace hydrogen atoms of the
same CH.sub.2 moiety.
[0639] The term "NH protecting group," as used herein, means
trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,
para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl,
chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl,
phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl,
tert-butoxycarbonyl, para-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyl-oxycarbonyl, 4-(phenylazo)benzyloxycarbonyl,
2-furfuryl-oxycarbonyl, diphenylmethoxycarbonyl,
1,1-dimethylpropoxy-carbonyl, isopropoxycarbonyl, phthaloyl,
succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl,
8-quinolyloxycarbonyl, benzyl, diphenylmethyl, triphenyimethyl,
2-nitrophenylthio, methanesulfonyl, para-toluenesulfonyl,
N,N-dimethylaminomethylene, benzylidene, 2-hydroxybenzylidene,
2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene,
3-hydroxy-4-pyridylmethylene, cyclohexylidene.
2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene,
2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclo-hexylidene,
diphenylphosphoryl, dibenzylphosphoryl,
5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl,
triethylsilyl, and triphenylsilyl.
[0640] The term "C(O)OH protecting group," as used herein, means
methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl,
tert-butyl, phenyl, naphthyl, benzyl, diphenylmethyl,
triphenylmethyl, para-nitrobenzyl, para-methoxybenzyl,
bis(para-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl,
para-nitrobenzoylmethyl, para-bromobenzoylmethyl,
para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl
2-tetrahydrofuranyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl,
acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl,
phthalimidomethyl, succmimidomethyl, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, methoxymethyl, methoxyethoxymethyl,
2-(trimethylsilyl)ethoxymethyl, benzyloxymethyl, methylthiomethyl,
2-methylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl,
3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl,
triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, diphenylmethylsilyl, and
tert-butylmethoxyphenylsilyl.
[0641] The term "OH or SH protecting group," as used herein, means
benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl,
tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl,
isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, 2-(phenylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphonio)ethoxycarbonyl, 2-furfuryloxycarbonyl,
1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl,
S-benzythiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,
8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl,
phenoxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl,
benzyl(phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,
diphenylmethyl, triphenylmethyl, tetrahydrofuryl,
tetrahydropyranyl, tetrahydrothiopyranyl, methoxymethyl,
methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl,
2,2,2-trichloro-ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl
1-ethoxyethyl, methanesulfonyl, para-toluenesulfonyl,
trimethylsilyl, triethylsilyl, triisopropylsilyl,
diethylisopropylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl, diphenylmethylsilyl, and
tert-butytmethoxyphenylsilyl.
Compounds
[0642] Geometric isomers may exist in the present compounds.
Compounds of this invention may contain carbon-carbon double bonds
or carbon-nitrogen double bonds in the E or Z configuration,
wherein the term "E" represents higher order substituents on
opposite sides of the carbon-carbon or carbon-nitrogen double bond
and the term "Z" represents higher order substituents on the same
side of the carbon-carbon or carbon-nitrogen double bond as
determed by the Cahn-Ingold-Prelog Priority Rules. The compounds of
this invention may also exist as a mixture of "E" and "Z" isomers.
Substituents around a cycloalkyl or heterocycloalkyl are designated
as being of cis or trans configuration. Furthermore, the invention
contemplates the various isomers and mixtures thereof resulting
from the disposal of substituents around an adamantane ring system.
Two substituents around a single ring within an adamantane ring
system are designated as being of Z or E relative configuration.
For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le
Noble J. Org. Chem. 1998, 63, 2758-2760 and E. L. Eliel, and S. H.
Wilen, (1994 ) Stereochemistry of Organic Compounds, New York,
N.Y.: John Wiley & Sons, Inc.
[0643] Comounds of this invention may contain asymmetrically
substituted carbon atoms in the R or S configuration, in which the
terms "R" or "S" are as defined by the IUPAC 1974 Recommendations
for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976)
45, 13-10. Compounds having asymmetrically substituted carbon atoms
with equal amounts of R and S configuarations are racemic at those
carbon atoms. Atoms with an excess of one configuration over the
other are assigned the configuration present in the higher amount,
prefeably an excess of about 85%-90%, more preferably an excess of
about 95%-99%, and still more prefeably an excess greater than
about 99%. Accordingly, this invention includes racemic mixtures,
relative and absolute stereoisomers, and mixtures of relative and
absolute stereoisomers.
[0644] Compounds of this invention containing NH, C(O)OH, OH or SH
moieties may have attached thereto prodrug-forming moieties. The
prodrug-forming moieties are removed by metabolic processes and
release the compounds having the freed hydroxyl, amino or
carboxylic acid in vivo. Prodrugs are useful for adjusting such
pharmacokinetic properties of the compounds as solubility and/or
hydrophobicity, absorption in the gastrointestinal tract,
bioavailability, tissue penetration, and rate of clearance. An
example of a compound with a prodrug-forming moiety is
[3-chloro-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)amino]carbonyl}phenoxy)-2-iminopyridin-1-(2H)-yl]methyl
dihydrogen phosphate (EXAMPLE 397), which is a prodrug of 2-[(
6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyr-
an-4-ylmethyl)amino]phenyl}sulfonyl)benzamide (EXAMPLE 318).
Isotope Enriched or Labeled Compounds
[0645] Compounds of the invention can exist in isotope-labeled or
-enriched form containing one or more atoms ahving an atomic mass
or mass number different from the atomic mass or mass number most
abnundantly found in nature. Isotopes can be radioactive or
non-radioactive isotopes. isotopes of atoms such as hydrogen,c
arbon, phosphorous, sulfur, fluorine, chlorine, and iodine include,
but are not limited to, .sup.2H, .sup.3H, .sup.13C, .sup.14C,
.sup.15N, .sup.18O, .sup.32P, .sup.15S, .sup.18F, .sup.36Cl, and
.sup.125I. Compounds that contain other isotopes of these and/or
other atoms are within the scope of this invention.
[0646] In another embodiment, the isotope-labeled compounds contain
deuterium (.sup.2H), tritium (.sup.3H) or .sup.14C isotopes.
Isotope-labeled compounds of this invention can be prepared by the
general methods well known to persons having ordinary skill in the
art. Such isotope-labeled compounds can be conveniently prepared by
carrying out the procedures disclosed in the Examples disclosed
herein and Schemes by substituting a readily available
isotope-labeled reagent for a non-labeled reagent. In some
instances, compounds may be treated with isotope-labeled reagents
to exchange a normal atom with its isotope, for example, hydrogen
for deuterium can be exchanged by the action of a deuteric acid
such as D.sub.2SO.sub.4/D.sub.2O. In addition to the above,
relevant procedures and intermediates are disclosed, for instance,
in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996); Brickner, S J
et al., J Med Chem, 39(3), 673(1996); Mallesham, B et al., Org
Lett, 5(7), 963 (2003); PCT publications WO1997010223 ,
WO2005099353 , WO1995007271, WO2006008754; U.S. Pat. Nos.
7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421; 7,514,068;
7,511,013; and US Patent Application Publication Nos, 20090137457;
20090131485; 20090131363; 20090118238; 20090111840; 20090105338;
20090103307; 20090105147; 20090093422; 20090088416; and
20090082471, the methods are hereby incorporated by reference.
[0647] The isotope-labeled compounds of the invention may be used
as standards to determine the effectiveness of Bcl-2 inhibitors in
binding assays. Isotope containing compounds have been used in
pharmaceutical research to investigate the in vivo metabolic fate
of the compounds by evaluation of the mechanism of action and
metabolic pathway of the nonisotope-labeled parent compound (Blake
et al. J. Pharm. Sci. 64, 3, 367-391 (1975)). Such metabolic
studies are important in the design of safe, effective therapeutic
drugs, either because the in vivo active compound administered to
the patient or because the metabolites produced from the parent
compound prove to be toxic or carcinogenic (Foster et al., Advances
in Drug Research Vol. 14, pp. 2-36, Academic press, London, 1985;
Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932
(1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88
(1999).
[0648] In addition, non-radioactive isotope containing drugs, such
as deuterated drugs called "heavydrugs," can be used for the
treatment of diseases and conditions related to Bcl-2 activity.
Increasing the amount of an isotope present in a compound above its
natural abundance is called enrichment. Examples of the amount of
enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79,
84, 88, 92, 96, to about 100 mol %. Replacement of up to about 15%
of normal atom with a heavy isotope has been effected and
maintained for a period of days to weeks mmammals, including
rodents and dogs, with minimal observed adverse effects (Czajka D M
and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson J F,
Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al. Am. J.
Physiol. 1961 201: 357). Acute replacement of as high as 15%-23% in
human fluids with deuterium was found not to cause toxicity
(Blagojevic N et al. in "Dosimetry & Treatment Planning foir
Neutron Capture Therapy", Zamenhof R, Solares G and Harling O Eds.
1994. Advanced Medical Publishing, Madison Wis. pp. 125-134;
Diabetes Metab. 23: 251 (1997)).
[0649] Stable isotope labeling of a drug can alter its
physico-chemical properties such as pKa and lipid solubility. These
effects and alterations can affect the pharmacodynamic response of
the drug molecule if the isotopic substitution affects a region
involved in a ligand-receptor interaction. While some of the
physical properities of a stable isotope-labeled molecule are
different from those of the unlabeled one, the chemical and
biological properties are the same, with one important exception:
because of the increased mass of the heavy isotope, any bound
involving the heavy isotope and another atom will be stronger than
the same bond between the light isotope and that atom. Accordingly,
the incorporation of an isotope at a site of metabolism or
enzymatic transofrmation will slow said reactions potentially
altering the pharmcokinetic profile or efficacy relative to the
non-isotopic compound.
Amides, Esters and Prodrugs
[0650] Prodrugs are derivatives of an active drug designed to
ameliorate some identified, undesirable physical or biological
property. The physical properties are usually solubility (too much
or not enough lipid or aqueous solubility) or stability related,
while problematic biological properties include too rapid
metabolism or poor bioavailability which itself may be related to a
physicochemical property.
[0651] Prodrugs are usually prepared by: a) formation of ester,
hemi esters, carbonate esters, nitrate esters, amides, hydroxamic
acids, carbamates, imines, Mannich bases, phosphates, phosphate
esters, and enamines of the active drug, b) functionalizing the
drug with azo, glycoside, peptide, and ether functional groups, c)
use of aminals, hemi-aminals, polymers, salts, compleses,
phosphoramides, acetals, hemiacetals, and ketal forms of the drug.
For example, see Andrejus Korolkovas's, "Essentials of Medicinal
Chemistry", John Wiley-Interscience Publications, John Wiley and
Sons, New York (1988), pp. 97-118, which is incorporated in its
entirety by reference herein.
[0652] Esters can be prepared from substrates of formula (I)
containing either a hydroxyl group or a carboxy group by general
methods known to persons skilled in the art. The typical reactions
of these compounds are substitutions replacing one of the
heteroatoms by another atom, for example:
##STR00003##
[0653] Amides can be prepared from substrates of formula (I)
containing either an amino group or a carboxy group in similar
fashion. Esters can also react with amines or ammonia to form
amides.
##STR00004##
[0654] Another way to make amides from compounds of formula (I) is
to heat carboxylic acids and amines together.
##STR00005##
[0655] In Schemes 2 and 3 above, R and R' are independently
substrates of formula (I), alkyl or hydrogen.
[0656] Suitable groups for for A.sup.1, B.sup.1, D.sup.1, E.sup.1,
Y.sup.1, L.sup.1, Z.sup.1A, Z.sup.2A, Z.sup.1, Z.sup.2, and Z.sup.3
in compounds of Formula (I) are independently selected. The
described embodiments of the present invention may be combined.
Such combination is contemplated and within the scope of the
present invention. For example, it is contemplated that the
embodiments for any of A.sup.1, B.sup.1, D.sup.1, E.sup.1, Y.sup.1,
L.sup.1, Z.sup.1A, Z.sup.2A, Z.sup.1, Z.sup.2, and Z.sup.3 can be
combined with embodiments defined for any other of A.sup.1,
B.sup.1, D.sup.1, E.sup.1, Y.sup.1, L.sup.1, Z.sup.1A, Z.sup.2A,
Z.sup.1, Z.sup.2, and Z.sup.3.
[0657] One embodiment of this invention, therefore, pertains to
compounds or therapeutically acceptable salts, prodrugs or salts of
prodrugs thereof, which are useful as inhibitors of anti-apoptotic
Bcl-2 proteins, the compounds having Formula (I)
##STR00006##
wherein [0658] A.sup.1 is N or C(A.sup.2);
[0659] A.sup.2 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0660] B.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0661] D.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0662] E.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; and
[0663] Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17,
SO.sub.2R.sup.17, NH.sub.2, NHR.sup.17, N(R.sup.17).sub.2,
NHC(O)R.sup.17, C(O)NH.sub.2, C(O)NHR.sup.17,
C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17, or NHSO.sub.2R.sup.17;
or
[0664] E.sup.1 and Y.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0665] A.sup.2, B.sup.1, and D.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0666] Y.sup.1 and B.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0667] A.sup.2, D.sup.1, and E.sup.1 are independendy selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O).sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2, or C(O)OR.sup.1A; or
[0668] A.sup.2 and B.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene, cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0669] D.sup.1, E.sup.1, and Y.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2, or C(O)OR.sup.1A; or
[0670] A.sup.2 and D.sup.1, together with the atoms to which they
are attached, are benzene, naphthalene, heteroarene, cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0671] B.sup.1, and E.sup.1, and Y.sup.1 are independently selected
H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0672] R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
[0673] R.sup.1A is cycloalkyl, cycloalkenyl ar cycloalkynyl;
[0674] R.sup.2 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane or
heterocycloalkane;
[0675] R.sup.3 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
[0676] R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0677] R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7,
OR.sup.7, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)NH.sub.2, C(O)NHR.sup.7,
C(O)N(R.sup.7).sub.2, NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7,
NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0678] R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
[0679] R.sup.6A and R.sup.6B are independently selected alkyl or,
together with the N to which they are attached, R.sup.6C;
[0680] R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
[0681] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0682] R.sup.8 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.8A; R.sup.8A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0683] R.sup.9 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0684] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene; R.sup.11 is alkyl, alkenyl
or alkynyl, each of which is unsubstituted or substituted with one
or two or three of independently selected R.sup.12, OR.sup.12,
SR.sup.12, S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12,
C(O)R.sup.12, OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sup.12,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12, C(N)N(R.sup.12).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0685] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0686] R.sup.13 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0687] R.sup.14 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloakene, heterocycloalkane or heterocycloalkene;
[0688] R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0689] R.sup.16 is alkyl, alkenyl or alkynyl;
[0690] R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
[0691] R.sup.18 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0692] R.sup.19 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.19A; R.sup.19A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0693] R.sup.20 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.20A; R.sup.20A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0694] R.sup.21 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.22, OR.sup.22, SR.sup.22,
S(O)R.sup.22, SO.sub.2R.sup.22, C(O)R.sup.22, CO(O)R.sup.22,
OC(O)R.sup.22, OC(O)OR.sup.22, NH.sub.2, NHR.sup.22,
N(R.sup.22).sub.2, NHC(O)R.sup.22, NR.sup.22C(O)R.sup.22,
NHS(O).sub.2R.sup.22, NR.sup.22S(O).sub.2R.sup.22, NHC(O)OR.sup.22,
NR.sup.22C(O)OR.sup.22, NHC(O)NH.sub.2, NHC(O)NHR.sup.22,
NHC(O)N(R.sup.22).sub.2, NR.sup.22C(O)NHR.sup.22,
NR.sup.22C(O)N(R.sup.22).sub.2, C(O)NH.sub.2, C(O)NHR.sup.22,
C(O)N(R.sup.22).sub.2, C(O)NHOH, C(O)NHOR.sup.22,
C(O)NHSO.sub.2R.sup.22, C(O)NR.sup.22SO.sub.2R.sup.22,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.22, SO.sub.2N(R.sup.22).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.22, C(N)N(R.sup.22).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0695] R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
[0696] R.sup.23 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloakane or heterocycloalkene;
[0697] R.sup.24 is heteroarene, which is unfused or fused with
benzene, heteroarene or R.sup.24A; R.sup.24A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0698] R.sup.25 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.25A; R.sup.25A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0699] Z.sup.1 is R.sup.26 or R.sup.27;
[0700] Z.sup.2 is R.sup.28, R.sup.29 or R.sup.30;
[0701] Z.sup.1A and Z.sup.2A are both absent or are taken together
to form CH.sub.2, CH.sub.2CH.sub.2 or Z.sup.12A;
[0702] Z.sup.12A is C.sub.2-C.sub.6-alkylene having one or two
CH.sub.2 moieties replaced by NH, N(CH.sub.3), S, S(O) or
SO.sub.2;
[0703] L.sup.1 is R.sup.37, OR.sup.37, SR.sup.37, S(O)R.sup.37,
SO.sub.2R.sup.37, C(O)R.sup.37, CO(O)R.sup.37, OC(O)R.sup.37,
OC(O)OR.sup.37, NHR.sup.37, C(O)NH, C(O)NR.sup.37, C(O)NHOR.sup.37,
C(O)NHSO.sub.2R.sup.37, SO.sub.2NH, SO.sub.2NHR.sup.37, C(N)NH,
C(N)NHR.sup.37;
[0704] R.sup.26 is phenylene, which is unfused or fused with
benzene or heteroarene or R.sup.26A; R.sup.26A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0705] R.sup.27 is heteroarylene, which is unfused or fused with
benzene or heteroarene or R.sup.27A; R.sup.27A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0706] R.sup.28 is phenylene, which is unfused or fused with
benzene, heteroarene or R.sup.28A; R.sup.28A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0707] R.sup.29 is heteroarylene, which is unfused or fused with
benzene or heteroarene or R.sup.29A; R.sup.29A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0708] R.sup.30 is cycloalkylene, cycloalkenylene,
heterocycloalkylene or heterocycloalkenylene, each of which is
unfused or fused with benzene, heteroarene or R.sup.30A; R.sup.30A
is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0709] R.sup.37 is a bond or R.sup.37A;
[0710] R.sup.37A is alkylene, alkenylene, or alkynylene, each of
which is unsubstituted or substituted with one or two or three
independently selected R.sup.37B, OR.sup.37B, SR.sup.37B,
S(O)R.sup.37B, SO.sub.2R.sup.37B, C(O)R.sup.37B, CO(O)R.sup.37B,
OC(O)R.sup.37B, OC(O)OR.sup.37B, NH.sub.2, NHR.sup.37B,
N(R.sup.37B).sub.2, NHC(O)R.sup.37B, NR.sup.37BC(O)R.sup.37B,
NHS(O).sub.2R.sup.37B, NR.sup.37BS(O).sub.2R.sup.37B,
NHC(O)OR.sup.37B, NR.sup.37BC(O)OR.sup.37B, NHC(O)NH.sub.2,
NHC(O)NHR.sup.37B, NHC(O)N(R.sup.37B).sub.2,
NR.sup.37BC(O)NHR.sup.37B, NR.sup.37BC(O)N(R.sup.37B).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.37B, C(O)N(R.sup.37B).sub.2, C(O)NHOH,
C(O)NHOR.sup.37B, C(O)NHSO.sub.2R.sup.37B,
C(O)NR.sup.37BSO.sub.2R.sup.37B, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.37B, SO.sub.2N(R.sup.37B).sub.2, C(O)H, C(O)OH,
C(N)NH.sub.2, C(N)NHR.sup.37B, C(N)N(R.sup.37B).sub.2, CNOH,
CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl Br and I
substituents;
[0711] R.sup.37B is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl;
[0712] Z.sup.3 is R.sup.38, R.sup.39 or R.sup.40;
[0713] R.sup.38 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0714] R.sup.39 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.39A; R.sup.39A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0715] R.sup.40 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.40A; R.sup.40A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0716] wherein the moieties represented by R.sup.26 and R.sup.27
are substituted (i.e., if Z.sup.1A and Z.sup.2A are absent) or
further substituted (i.e., if Z.sup.1A and Z.sup.2A are present)
with one or two or three or four of independently selected
R.sup.41, OR.sup.41, SR.sup.41, S(O)R.sup.41, SO.sub.2R.sup.41,
C(O)R.sup.41, CO(O)R.sup.41, OC(O)R.sup.41, OC(O)OR.sup.41,
NH.sub.2, NHR.sup.41, N(R.sup.41).sub.2, NHC(O)R.sup.41,
NR.sup.41C(O)R.sup.41, NHS(O).sub.2R.sup.41,
NR.sup.41S(O).sub.2R.sup.41, NHC(O)OR.sup.41,
NR.sup.41C(O)OR.sup.41, NHC(O)NH.sub.2, NHC(O)NHR.sup.41,
NHC(O)N(R.sup.41).sub.2, NR.sup.41C(O)NHR.sup.41,
NR.sup.41C(O)N(R.sup.41).sub.2, C(O)NH.sub.2, C(O)NHR.sup.41,
C(O)N(R.sup.41).sub.2, C(O)NHOH, C(O)NHOR.sup.41,
C(O)NHSO.sub.2R.sup.41, C(O)NR.sup.41SO.sub.2R.sup.41,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.41, SO.sub.2N(R.sup.41).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.41, C(N)N(R.sup.41).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0717] R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
[0718] R.sup.42 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0719] R.sup.43 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.43A; R.sup.43A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0720] R.sup.44 is is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.44A; R.sup.44A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0721] R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.46, OR.sup.46, SR.sup.46,
S(O)R.sup.46, C(O)R.sup.46, CO(O)R.sup.46, OC(O)R.sup.46,
OC(O)OR.sup.46, NH.sub.2, NHR.sup.46, N(R.sup.46).sub.2,
NHC(O)R.sup.46, NR.sup.46C(O)R.sup.46, NHS(O).sub.2R.sup.46,
NR.sup.46S(O).sub.2R.sup.46, NHC(O)OR.sup.46,
NR.sup.46C(O)OR.sup.46, NHC(O)NH.sub.2, NHC(O)NHR.sup.46,
NHC(O)N(R.sup.46).sub.2, NR.sup.46C(O)NHR.sup.46,
NR.sup.46C(O)N(R.sup.46).sub.2, C(O)NH.sub.2, C(O)NHR.sup.46,
C(O)N(R.sup.46).sub.2, C(O)NHOH, C(O)NHOR.sup.46,
C(O)NHSO.sub.2R.sup.46, C(O)NR.sup.46SO.sub.2R.sup.46,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.46, SO.sub.2N(R.sup.46).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.46, C(N)N(R.sup.46).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0722] R.sup.46 is alkyl, alkenyl, alkynyl, R.sup.47, R.sup.48 or
R.sup.49;
[0723] R.sup.47 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0724] R.sup.48 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0725] R.sup.49 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.49A; R.sup.49A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0726] wherein the moieties represented by R.sup.42, R.sup.42A,
R.sup.43, R.sup.43A, R.sup.44, R.sup.44A, R.sup.47, R.sup.47A,
R.sup.48, R.sup.48A, R.sup.49, and R.sup.49A are independently
substituted with one or two or three or four of independently
selected R.sup.50, OR.sup.50, SR.sup.50, S(O)R.sup.50,
SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50, OC(O)R.sup.50,
OC(O)OR.sup.50, NH.sub.2, NHR.sup.50, N(R.sup.50).sub.2,
NHC(O)R.sup.50, NR.sup.50C(O)R.sup.50, NHS(O).sub.2R.sup.50,
NR.sup.50S(O).sub.2R.sup.50, NHC(O)OR.sup.50,
NR.sup.50C(O)OR.sup.50, NHC(O)NH.sub.2, NHC(O)NHR.sup.50,
NHC(O)N(R.sup.50).sub.2, NR.sup.50C(O)NHR.sup.50,
NR.sup.50C(O)N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.50SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.50, C(N)N(R.sup.50).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0727] R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
[0728] R.sup.51 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.51A; R.sup.51A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0729] R.sup.52 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.52A; R.sup.52A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0730] R.sup.53 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heteracycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.53A; R.sup.53A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0731] R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.55, OR.sup.55, SR.sup.55,
S(O)R.sup.55, SO.sub.2R.sup.55, C(O)R.sup.55, CO(O)R.sup.55,
OC(O)R.sup.55, OC(O)OR.sup.55, NH.sub.2, NHR.sup.55,
N(R.sup.55).sub.2, NHC(O)R.sup.55, NR.sup.55C(O)R.sup.55,
NHS(O).sub.2R.sup.55, NR.sup.55S(O).sub.2R.sup.55, NHC(O)OR.sup.55,
NR.sup.55C(O)OR.sup.55, NHC(O)NH.sub.2, NHC(O)NHR.sup.55,
NHC(O)N(R.sup.55).sub.2, NR.sup.55C(O)NHR.sup.55,
NR.sup.55C(O)N(R.sup.55).sub.2, C(O)NH.sub.2, C(O)NHR.sup.55,
C(O)N(R.sup.55).sub.2, C(O)NHOH, C(O)NHOR.sup.55,
C(O)NHSO.sub.2R.sup.55, C(O)NR.sup.55SO.sub.2R.sup.55,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55, SO.sub.2N(R.sup.55).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.55, C(N)N(R.sup.55).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0732] R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and
[0733] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.57A, R.sup.57, OR.sup.57, SR.sup.57,
S(O)R.sup.57, SO.sub.2R.sup.57, C(O)R.sup.57, CO(O)R.sup.57,
OC(O)R.sup.57, OC(O)OR.sup.57, NH.sub.2, NHR.sup.57,
N(R.sup.57).sub.2, NHC(O)R.sup.57, NR.sup.57C(O)R.sup.57,
NHS(O).sub.2R.sup.57, NR.sup.57S(O).sub.2R.sup.57, NHC(O)OR.sup.57,
NR.sup.57C(O)OR.sup.57, NHC(O)NH.sub.2, NHC(O)NHR.sup.57,
NHC(O)N(R.sup.57).sub.2, NR.sup.57C(O)NHR.sup.57,
NR.sup.57C(O)N(R.sup.57).sub.2, C(O)NH.sub.2, C(O)NHR.sup.57,
C(O)N(R.sup.57).sub.2, C(O)NHOH, C(O)NHOR.sup.57,
C(O)NHSO.sub.2R.sup.57, C(O)NR.sup.57SO.sub.2R.sup.57,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.57, SO.sub.2N(R.sup.57).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.57, C(N)N(R.sup.57).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0734] R.sup.57A is spirocyclyl;
[0735] R.sup.57 is R.sup.58, R.sup.59, R.sup.60 or R.sup.61;
[0736] R.sup.58 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.58; R.sup.58A is cycloalkane, cycloalkane,
heterocycloalkane or heterocycloalkene;
[0737] R.sup.59 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.59A; R.sup.59A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0738] R.sup.60 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.60A; R.sup.60A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0739] R.sup.61 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.62, OR.sup.62, SR.sup.62,
S(O)R.sup.62, SO.sub.2R.sup.62, C(O)R.sup.62, CO(O)R.sup.62,
OC(O)R.sup.62, OC(O)OR.sup.62, NH.sub.2, NHR.sup.62,
N(R.sup.62).sub.2, NHC(O)R.sup.62, NR.sup.62C(O)R.sup.62,
NHS(O).sub.2R.sup.62, NR.sup.62S(O).sub.2R.sup.62, NHC(O)OR.sup.62,
NR.sup.62C(O)OR.sup.62, NHC(O)NH.sub.2, NHC(O)NHR.sup.62,
NHC(O)N(R.sup.62).sub.2, NR.sup.62C(O)NHR.sup.62,
NR.sup.62C(O)N(R.sup.62).sub.2, C(O)NH.sub.2, C(O)NHR.sup.62,
C(O)N(R.sup.62).sub.2, C(O)NHOH, C(O)NHOR.sup.62,
C(O)NHSO.sub.2R.sup.62, C(O)NR.sup.62SO.sub.2R.sup.62,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.62, SO.sub.2N(R.sup.62).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.62, C(N)N(R.sup.62).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0740] R.sup.62 is R.sup.63, R.sup.64, R.sup.65 or R.sup.66;
[0741] R.sup.63 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.63A; R.sup.63A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0742] R.sup.64 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.64A; R.sup.64A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0743] R.sup.65 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.65A; R.sup.65A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0744] R.sup.66 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.67, OR.sup.67, SR.sup.67,
S(O)R.sup.67, SO.sub.2R.sup.67, C(O)R.sup.67, CO(O)R.sup.67,
OC(O)R.sup.67, OC(O)OR.sup.67, NH.sub.2, NHR.sup.67,
N(R.sup.67).sub.2, NHC(O)R.sup.67, NR.sup.67C(O)R.sup.67,
NHS(O).sub.2R.sup.67, NR.sup.67S(O).sub.2R.sup.67, NHC(O)OR.sup.67,
NR.sup.67C(O)OR.sup.67, NHC(O)NH.sub.2, NHC(O)NHR.sup.67,
NHC(O)N(R.sup.67).sub.2, NR.sup.67C(O)NHR.sup.67,
NR.sup.67C(O)N(R.sup.67).sub.2, C(O)NH.sub.2, C(O)NHR.sup.67,
C(O)N(R.sup.67).sub.2, C(O)NHOH, C(O)NHOR.sup.67,
C(O)NHSO.sub.2R.sup.67, C(O)NR.sup.67SO.sub.2R.sup.67,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.67, SO.sub.2N(R.sup.67).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.67, C(N)N(R.sup.67).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
[0745] R.sup.67 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl;
[0746] wherein the moieties represented by R.sup.57A, R.sup.58,
R.sup.59, R.sup.60, R.sup.63, R.sup.64, R.sup.65, and R.sup.67 are
unsubstituted or substituted with one or two or three or four of
independently selected R.sup.68, OR.sup.68, SR.sup.68,
S(O)R.sup.68, SO.sub.2R.sup.68, C(O)R.sup.68, CO(O)R.sup.68,
OC(O)R.sup.68, OC(O)OR.sup.68, NH.sub.2, NHR.sup.68,
N(R.sup.68).sub.2, NHC(O)R.sup.68, NR.sup.68C(O)R.sup.68,
NHS(O).sub.2R.sup.68, NR.sup.68S(O).sub.2R.sup.68, NHC(O)OR.sup.68,
NR.sup.68C(O)OR.sup.68, NHC(O)NH.sub.2, NHC(O)NHR.sup.68,
NHC(O)N(R.sup.68).sub.2, NR.sup.68C(O)NHR.sup.68,
NR.sup.68C(O)N(R.sup.68).sub.2, C(O)NH.sub.2, C(O)NHR.sup.68,
C(O)N(R.sup.68).sub.2, C(O)NHOH, C(O)NHOR.sup.68,
C(O)NHSO.sub.2R.sup.68, C(O)NR.sup.68SO.sub.2R.sup.68,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.68, SO.sub.2N(R.sup.68).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.68, C(N)N(R.sup.68).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0747] R.sup.68 is R.sup.69, R.sup.70, R.sup.71 or R.sup.72;
[0748] R.sup.69 is phenyl which is unfused or fused with benzene,
heteroarene or R.sup.69A; R.sup.69A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0749] R.sup.70 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.70A; R.sup.70A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0750] R.sup.71 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.71A; R.sup.71A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0751] R.sup.72 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.73, OR.sup.73, SR.sup.73,
S(O)R.sup.73, SO.sub.2R.sup.73, C(O)R.sup.73, CO(O)R.sup.73,
OC(O)R.sup.73, OC(O)OR.sup.73, NH.sub.2, NHR.sup.73,
N(R.sup.73).sub.2, NHC(O)R.sup.73, NR.sup.73C(O)R.sup.73,
NHS(O).sub.2R.sup.73, NR.sup.73S(O).sub.2R.sup.73, NHC(O)OR.sup.73,
NR.sup.73C(O)OR.sup.73, NHC(O)NH.sub.2, NHC(O)NHR.sup.73,
NHC(O)N(R.sup.73).sub.2, NR.sup.73C(O)NHR.sup.73,
NR.sup.73C(O)N(R.sup.73).sub.2, C(O)NH.sub.2, C(O)NHR.sup.73,
C(O)N(R.sup.73).sub.2, C(O)NHOH, C(O)NHOR.sup.73,
C(O)NHSO.sub.2R.sup.73, C(O)NR.sup.73SO.sub.2R.sup.73,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.73, SO.sub.2N(R.sup.73).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.73, C(N)N(R.sup.73).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0752] R.sup.73 is alkyl, alkenyl, alkenyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and
[0753] the moieties represented by R.sup.69, R.sup.70 , and
R.sup.71 are unsubstituted or substituted with one or two or three
or four of independently selected NH.sub.2, C(O)NH.sub.2, C(O)NHOH,
SO.sub.2NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH,
C(N)NH.sub.2, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I.
[0754] Another embodiment of this invention pertains to compounds
of Formula (I), wherein
[0755] A.sup.1 is N or C(A.sup.2);
[0756] A.sup.2 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0757] B.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0758] D.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0759] E.sup.1 is H, R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1,
SO.sub.2R.sup.1, C(O)R.sup.1, C(O)OR.sup.1, OC(O)R.sup.1,
NHR.sup.1, N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2, NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; and
[0760] Y.sup.1 is H, CN, NO.sub.2, C(O)OH, F, Cl, Br, I, CF.sub.3,
OCF.sub.3, CF.sub.2CF.sub.3, OCF.sub.2CF.sub.3, R.sup.17,
OR.sup.17, C(O)R.sup.17, C(O)OR.sup.17, SR.sup.17,
SO.sub.2R.sup.17, NH.sub.2, NHR.sup.17, N(R.sup.17).sub.2,
NHC(O)R.sup.17, C(O)NH.sub.2, C(O)NHR.sup.17,
C(O)N(R.sup.17).sub.2, NHS(O)R.sup.17, or NHSO.sub.2R.sup.17;
or
[0761] E.sup.1 and Y.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0762] A.sup.2, B.sup.1, and D.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, CO(O)R.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2), NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0763] Y.sup.1 and B.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene cycloalkane,
cycloalkene, heterocycloalkane, or heterocycloalkene; and
[0764] A.sup.2, D.sup.1, and E.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, CO(O)R.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2), NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0765] A.sup.2 and B.sup.1, together with the atoms to which they
are attached, are benzene, naphthylene, heteroarene, cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0766] D.sup.1, E.sup.1, and Y.sup.1are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, CO(O)R.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2), NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2NHSO.sub.2 NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A; or
[0767] A.sup.2 and D.sup.1, together with the atoms to which they
are attached, are benzene, naphthalene, heteroarene, cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene; and
[0768] B.sup.1, E.sup.1, and Y.sup.1 are independently selected H,
R.sup.1, OR.sup.1, SR.sup.1, S(O)R.sup.1, SO.sub.2R.sup.1,
C(O)R.sup.1, CO(O)R.sup.1, OC(O)R.sup.1, NHR.sup.1,
N(R.sup.1).sub.2, C(O)NHR.sup.1, C(O)N(R.sup.1).sub.2,
NHC(O)R.sup.1, NR.sup.1C(O)R.sup.1, NHC(O)OR.sup.1,
NR.sup.1C(O)OR.sup.1, NHC(O)NH.sub.2, NHC(O)NHR.sup.1,
NHC(O)N(R.sup.1).sub.2, NR.sup.1C(O)NHR.sup.1,
NR.sup.1C(O)N(R.sup.1).sub.2, SO.sub.2NH.sub.2, SO.sub.2NHR.sup.1,
SO.sub.2N(R.sup.1).sub.2, NHSO.sub.2R.sup.1,
NR.sup.1SO.sub.2R.sup.1, NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(R.sup.1).sub.2), NR.sup.1SO.sub.2NHR.sup.1,
NR.sup.1SO.sub.2N(R.sup.1).sub.2, C(O)NHNOH, C(O)NHNOR.sup.1,
C(O)NHSO.sub.2R.sup.1, C(NH)NH.sub.2, C(NH)NHR.sup.1,
C(NH)N(R.sup.1).sub.2 NHSO.sub.2NHR.sup.1,
NHSO.sub.2N(CH.sub.3)R.sup.1,
N(CH.sub.3)SO.sub.2N(CH.sub.3)R.sup.1, F, Cl, Br, I, CN, NO.sub.2,
N.sub.3, OH, C(O)H, CHNOH, CH(NOCH.sub.3), CF.sub.3, C(O)OH,
C(O)NH.sub.2 or C(O)OR.sup.1A;
[0769] R.sup.1 is R.sup.2, R.sup.3, R.sup.4 or R.sup.5;
[0770] R.sup.1A is cycloalkyl, cycloalkenyl or cycloalkynyl;
[0771] R.sup.2 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.2A; R.sup.2A is cycloalkane or
heterocycloalkane;
[0772] R.sup.3 is heteroaryl which is unfused or fused with
benzene, heteroarene or R.sup.3A; R.sup.3A is cycloalkane or
heterocycloalkane;
[0773] R.sup.4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.4A; R.sup.4A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0774] R.sup.5 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.6, NC(R.sup.6A)(R.sup.6B), R.sup.7,
OR.sup.7, SR.sup.7, S(O)R.sup.7, SO.sub.2R.sup.7, NHR.sup.7,
N(R.sup.7).sub.2, C(O)R.sup.7, C(O)CNH.sub.2, C(O)NHR.sup.7,
C(O)N(R.sup.7).sub.2, NHC(O)R.sup.7, NR.sup.7C(O)R.sup.7,
NHSO.sub.2R.sup.7, NHC(O)OR.sup.7, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.7, SO.sub.2N(R.sup.7).sub.2, NHC(O)NH.sub.2,
NHC(O)NHR.sup.7, NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NH.sub.2,
NHC(O)CH(CH.sub.3)NHC(O)CH(CH.sub.3)NHR.sup.1, OH, (O), C(O)OH,
N.sub.3, CN, NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, F, Cl, Br or
I;
[0775] R.sup.6 is C.sub.2-C.sub.5-spiroalkyl, each of which is
unsubstituted or substituted with OH, (O), N.sub.3, CN, CF.sub.3,
CF.sub.2CF.sub.3, F, Cl, Br, I, NH.sub.2, NH(CH.sub.3) or
N(CH.sub.3).sub.2;
[0776] R.sup.6A and R.sup.6B are independently selected alkyl or,
together with the N to which they are attached, R.sup.6C;
[0777] R.sup.6C is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or
piperidin-1-yl, each having one CH.sub.2 moiety unreplaced or
replaced with O, C(O), CNOH, CNOCH.sub.3, S, S(O), SO.sub.2 or
NH;
[0778] R.sup.7 is R.sup.8, R.sup.9, R.sup.10 or R.sup.11;
[0779] R.sup.8 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.8A; R.sup.8A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0780] R.sup.9 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.9A; R.sup.9A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0781] R.sup.10 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.10A; R.sup.10A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0782] R.sup.11 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.12, OR.sup.12, SR.sup.12,
S(O)R.sup.12, SO.sub.2R.sup.12, C(O)R.sup.12, CO(O)R.sup.12,
OC(O)R.sup.12, OC(O)OR.sup.12, NH.sub.2, NHR.sup.12,
N(R.sup.12).sub.2, NHC(O)R.sup.12, NR.sup.12C(O)R.sup.12,
NHS(O).sub.2R.sup.12, NR.sup.12S(O).sub.2R.sup.12, NHC(O)OR.sub.2,
NR.sup.12C(O)OR.sup.12, NHC(O)NH.sub.2, NHC(O)NHR.sup.12,
NHC(O)N(R.sup.12).sub.2, NR.sup.12C(O)NHR.sup.12,
NR.sup.12C(O)N(R.sup.12).sub.2, C(O)NH.sub.2, C(O)NHR.sup.12,
C(O)N(R.sup.12).sub.2, C(O)NHOH, C(O)NHOR.sup.12,
C(O)NHSO.sub.2R.sup.12, C(O)NR.sup.12SO.sub.2R.sup.12,
SO.sub.2NH.sub.2,SO.sub.2NHR.sup.12, SO.sub.2N(R.sup.12).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.12,
CN(N)N(R.sup.12).sub.2, CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br, I;
[0783] R.sup.12 is R.sup.13, R.sup.14, R.sup.15 or R.sup.16;
[0784] R.sup.13 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.13A; R.sup.13A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0785] R.sup.14 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.14A; R.sup.14A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0786] R.sup.15 is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene, each of which is unfused or fused with benzene,
heteroarene or R.sup.15A; R.sup.15A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0787] R.sup.16 is alkyl, alkenyl or alkynyl;
[0788] R.sup.17 is R.sup.18, R.sup.19, R.sup.20 or R.sup.21;
[0789] R.sup.18 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.18A; R.sup.18A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0790] R.sup.19 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.19A; R.sup.19A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0791] R.sup.20 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.20A; R.sup.20A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0792] R.sup.21 is alkyl, aikenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.22, OR.sup.22, SR.sup.22,
S(O)R.sup.22, SO.sub.2R.sup.22, C(O)R.sup.22, CO(O)R.sup.22,
OC(O)R.sup.22, OC(O)OR.sup.22, NH.sub.2, NHR.sup.22,
N(R.sup.22).sub.2, NHC(O)R.sup.22, NR.sup.22C(O)R.sup.22,
NHS(O).sub.2R.sup.22, NR.sup.22S(O).sub.2R.sup.22, NHC(O)OR.sup.22,
NR.sup.22C(O)OR.sup.22, NHC(O)NH.sub.2, NHC(O)NHR.sup.22,
NHC(O)N(R.sup.22).sub.2, NR.sup.22C(O)NHR.sup.22,
NR.sup.22C(O)N(R.sup.22).sub.2, C(O)NH.sub.2, C(O)NHR.sup.22,
C(O)N(R.sup.22).sub.2, C(O)NHOH, C(O)NHOR.sup.22,
C(O)NHSO.sub.2R.sup.22, C(O)NR.sup.22SO.sub.2R.sup.22,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.22, SO.sub.2N(R.sup.22).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.22, C(N)N(R.sup.22).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0793] R.sup.22 is R.sup.23, R.sup.24 or R.sup.25;
[0794] R.sup.22 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.23A; R.sup.23A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0795] R.sup.24 is heteroarene, which is unfused or fused with
benzene, heteroarene or R.sup.24A; R.sup.24A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0796] R.sup.25 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl each of which is unfused or fused with benzene,
heteroarene or R.sup.25A; R.sup.25A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0797] Z.sup.1 is R.sup.26 or R.sup.27;
[0798] Z.sup.2 is R.sup.28, R.sup.29 or R.sup.30;
[0799] Z.sup.1A and Z.sup.2A are both absent or are taken together
to form CH.sub.2, CH.sub.2CH.sub.2 or Z.sup.12A;
[0800] Z.sup.12A is C.sub.2-C.sub.6-alkylene having one or two
CH.sub.2 moieties replaced by NH, N(CH.sub.3), S, S(O) or
SO.sub.2;
[0801] L.sup.1 is a R.sup.37, OR.sup.37, SR.sup.37, S(O)R.sup.37,
SO.sub.2R.sup.37, C(O)R.sup.37, CO(O)R.sup.37, OC(O)R.sup.37,
OC(O)OR.sup.37, NHR.sup.37, C(O)NH, C(O)NR.sup.37, C(O)NHOR.sup.37,
C(O)NHSO.sub.2R.sup.37, SO.sub.2NH, SO.sub.2NHR.sup.37, C(N)NH,
C(N)NHR.sup.37;
[0802] R.sup.26 is phenylene, which is unfused or fused with
benzene or heteroarene or R.sup.26A; R.sup.26A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0803] R.sup.27 is heteroarylene, which is unfused or fused with
benzene or heteroarene or R.sup.27A; R.sup.27A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0804] R.sup.28 is phenylene, which is unfused or fused with
benzene, heteroarene or R.sup.28A; R.sup.28A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0805] R.sup.29 is heteroarylene, which is unfused or fused with
benzene or heteroarene or R.sup.29A; R.sup.29A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0806] R.sup.30 is cycloalkylene, cycloalkenylene,
heterocycloalkylene or heterocycloalkenylene, each of which is
unfused or fused with benzene, heteroarene or R.sup.30A; R.sup.30A
is cycloalkane, cycloalkene, heterocycloalkane or
heterocycloalkene;
[0807] R.sup.37 is a bond or R.sup.37A;
[0808] R.sup.37A is alkylene, alkenylene, or alkynylene, each of
which is unsubstituted or substituted with one or two or three
independently selected R.sup.37B, OR.sup.37B, SR.sup.37B,
S(O)R.sup.37B, SO.sub.2R.sup.37B, C(O)R.sup.37B, CO(O)R.sup.37B,
OC(O)R.sup.37B, OC(O)OR.sup.37B, NH.sub.2, NHR.sup.37B,
N(R.sup.37B).sub.2, NHC(O)R.sup.37B, NR.sup.37BC(O)R.sup.37B,
NHS(O).sub.2R.sup.37B, NR.sup.37BS(O).sub.2R.sup.37B,
NHC(O)OR.sup.37B, NR.sup.37BC(O)OR.sup.37B, NHC(O)NH.sub.2,
NHC(O)NHR.sup.37B, NHC(O)N(R.sup.37B).sub.2,
NR.sup.37BC(O)NHR.sup.37B, NR.sup.37BC(O)N(R.sup.37B).sub.2,
C(O)NH.sub.2, C(O)NHR.sup.37B, C(O)N(R.sup.37B).sub.2, C(O)NHOH,
C(O)NHOR.sup.37B, C(O)NHSO.sub.2R.sup.37B,
C(O)NR.sup.37BSO.sub.2R.sup.37B, SO.sub.2NH.sub.2,
SO.sub.2NHR.sup.37B, SO.sub.2N(R.sup.37B).sub.2, C(O)H, C(O)OH,
C(N)NH.sub.2, C(N)NHR.sup.37B, C(N)N(R.sup.37B).sub.2, CNOH,
CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3OCF.sub.3, OCF.sub.2CF.sub.3F, Cl, Br and I
substituents;
[0809] R.sup.37B is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl, or
heterocycloalkenyl;
[0810] Z.sup.3 is R.sup.38, R.sup.39 or R.sup.40;
[0811] R.sup.38 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.38A; R.sup.38A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0812] R.sup.39 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.39A; R.sup.39A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0813] R.sup.40 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.40A; R.sup.40A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0814] wherein the moieties represented by R.sup.26 and R.sup.27
are substituted wtih OR.sup.41;
[0815] R.sup.41 is R.sup.42, R.sup.43, R.sup.44 or R.sup.45;
[0816] R.sup.42 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.42A; R.sup.42A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0817] R.sup.43 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.43A; R.sup.43A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0818] R.sup.44 is is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.44A; R.sup.44A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0819] R.sup.45 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.46, OR.sup.46, SR.sup.46,
S(O)R.sup.46, C(O)R.sup.46, CO(O)R.sup.46, OC(O)R.sup.46,
OC(O)OR.sup.46, NH.sub.2, NHR.sup.46, N(R.sup.46).sub.2,
NHC(O)R.sup.46, NR.sup.46C(O)R.sup.46, NHS(O).sub.2R.sup.46,
NR.sup.46S(O).sub.2R.sup.46, NHC(O)OR.sup.46,
NR.sup.46C(O)OR.sup.46, NHC(O)NH.sub.2, NHC(O)NHR.sup.46,
NHC(O)N(R.sup.46).sub.2, NR.sup.46C(O)NHR.sup.46,
NR.sup.46C(O)N(R.sup.46).sub.2, C(O)NH.sub.2, C(O)NHR.sup.46,
C(O)N(R.sup.46).sub.2, C(O)NHOH, C(O)NHOR.sup.46,
C(O)NHSO.sub.2R.sup.46, C(O)NR.sup.46SO.sub.2R.sup.46,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.46, SO.sub.2N(R.sup.46).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.46, C(N)N(R.sup.46).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0820] R.sup.46 is alkyl, alkenyl, alkynyl, R.sup.47, R.sup.48 or
R.sup.49;
[0821] R.sup.47 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.47A; R.sup.47A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0822] R.sup.48 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.48A; R.sup.48A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0823] R.sup.49 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.49A; R.sup.49A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0824] wherein the moieties represented by R.sup.42, R.sup.42A,
R.sup.43, R.sup.43A, R.sup.44, R.sup.44A, R.sup.47, R.sup.47A,
R.sup.48, R.sup.48A, R.sup.49, and R.sup.49A are independently
substituted with one or two or three or four of independently
selected R.sup.50, OR.sup.50, SR.sup.50, S(O)R.sup.50,
SO.sub.2R.sup.50, C(O)R.sup.50, CO(O)R.sup.50, OC(O)R.sup.50,
OC(O)OR.sup.50, NH.sub.2, NHR.sup.50, N(R.sup.50).sub.2,
NHC(O)R.sup.50, NR.sup.50C(O)R.sup.50, NHS(O).sub.2R.sup.50,
NR.sup.50S(O).sub.2R.sup.50, NHC(O)OR.sup.50,
NR.sup.50C(O)OR.sup.50, NHC(O)NH.sub.2, NHC(O)NHR.sup.50,
NHC(O)N(R.sup.50).sub.2, NR.sup.50C(O)NHR.sup.50,
NR.sup.50C(O)N(R.sup.50).sub.2, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, C(O)NHOH, C(O)NHOR.sup.50,
C(O)NHSO.sub.2R.sup.50, C(O)NR.sup.50SO.sub.2R.sup.50,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.50, SO.sub.2N(R.sup.50).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, CCN)NHR.sup.50, C(N)N(R.sup.50).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0825] R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
[0826] R.sup.51 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.51A; R.sup.51A is cycloalkane, cycloalkene,
heterocycloalkene or heterocycloalkene;
[0827] R.sup.52 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.52A; R.sup.52A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0828] R.sup.53 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.53A; R.sup.53A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0829] R.sup.54 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.55, OR.sup.55, SR.sup.55,
S(O)R.sup.55, SO.sub.2R.sup.55, C(O)R.sup.55, CO(O)R.sup.55,
OC(O)R.sup.55, OC(O)OR.sup.55, NH.sub.2, NHR.sup.55,
N(R.sup.55).sub.2, NHC(O)R.sup.55, NR.sup.55C(O)R.sup.55,
NHS(O).sub.2R.sup.55, NR.sup.55S(O).sub.2R.sup.55, NHC(O)OR.sup.55,
NR.sup.55C(O)OR.sup.55, NHC(O)NH.sub.2, NHC(O)NHR.sup.55,
NHC(O)N(R.sup.55).sub.2, NR.sup.55C(O)NHR.sup.55,
NR.sup.55C(O)N(R.sup.55).sub.2, C(O)NH.sub.2, C(O)NHR.sup.55,
C(O)N(R.sup.55).sub.2, C(O)NHOH, C(O)NHOR.sup.55,
C(O)NHSO.sub.2R.sup.55, C(O)NR.sup.55SO.sub.2R.sup.55,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.55, SO.sub.2N(R.sup.55).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.55, C(N)N(R.sup.55).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0830] R.sup.55 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and
[0831] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.57A, R.sup.57, OR.sup.57, SR.sup.57,
S(O)R.sup.57, SO.sub.2R.sup.57, C(O)R.sup.57, CO(O)R.sup.57,
OC(O)R.sup.57, OC(O)OR.sup.57, NH.sub.2, NHR.sup.57,
N(R.sup.57).sub.2, NHC(O)R.sup.57, NR.sup.57C(O)R.sup.57,
NHSO.sub.2R.sup.57, NR.sup.57S(O).sub.2R.sup.57, NHC(O)OR.sup.57,
NR.sup.57C(O)QR.sup.57, NHC(O)NH.sub.2, NHC(O)NHR.sup.57,
NHC(O)N(R.sup.57).sub.2, NR.sup.57C(O)NHR.sup.57,
NR.sup.57C(O)N(R.sup.57).sub.2, C(O)NH.sub.2, C(O)NHR.sup.57,
C(O)N(R.sup.57).sub.2, C(O)NHOH, C(O)NHOR.sup.57,
C(O)NHSO.sub.2R.sup.57, C(O)NR.sup.57SO.sub.2R.sup.57,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.57, SO.sub.2N(R.sup.57).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.57,
C(N)NH(R.sup.57).sub.2, CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3,
NO.sub.2, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
F, Cl, Br or I;
[0832] R.sup.57 is R.sup.58, R.sup.59, R.sup.60 or R.sup.61;
[0833] R.sup.57A is spirocyclyl;
[0834] R.sup.58 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.58A; R.sup.58A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0835] R.sup.59 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.59A; R.sup.59A is cycloalkane,
cycloalkene, heterecycloalkane or heterocycloalkene;
[0836] R.sup.60is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.60A; R.sup.60A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0837] R.sup.61 is alkyl, alkenyl or alkynyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.62, OR.sup.62, SR.sup.62,
S(O)R.sup.62, SO.sub.2R.sup.62, C(O)R.sup.62, CO(O)R.sup.62,
C(O)R.sup.62, OC(O)OR.sup.62, NH.sub.2, NHR.sup.62,
N(R.sup.62).sub.2, NHC(O)R.sup.62, NR.sup.62C(O)R.sup.62,
NHSO.sub.2R.sup.62, NR.sup.62S(O).sub.2R.sup.62, NHC(O)OR.sup.62,
NR.sup.62C(O)OR.sup.62, NHC(O)NH.sub.2, NHC(O)NHR.sup.62,
NHC(O)N(R.sup.62).sub.2, NR.sup.62C(O)NHR.sup.62,
NR.sup.62C(O)N(R.sup.62).sub.2, C(O)NH.sub.2, C(O)NHR.sup.62,
C(O)N(R.sup.62).sub.2, C(O)NHOH, C(O)NHOR.sup.62,
C(O)NHSO.sub.2R.sup.62, C(O)NR.sup.62SO.sub.2R.sup.62,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.62, SO.sub.2N(R.sup.62).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.62),
C(N)N(R.sup.62).sub.2, CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3,
NO.sub.3, CF.sub.3, CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3,
Cl, Br or I;
[0838] R.sup.62 is R.sup.63, R.sup.64, R.sup.65 or R.sup.66;
[0839] R.sup.63 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.63A; R.sup.63A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0840] R.sup.64 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.64A; R.sup.64A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0841] R.sup.65 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.65A; R.sup.65A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0842] R.sup.66 is alkyl, alkenyl or alkenyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.67, OR.sup.67, SR.sup.67,
S(O)R.sup.67, SO.sub.2R.sup.67, C(O)R.sup.67, CO(O)R.sup.67,
OC(O)R.sup.67, OC(O)OR.sup.67, NH.sub.2, NHR.sup.67,
N(R.sup.67).sub.2, NHC(O)R.sup.67, NR.sup.67C(O)R.sup.67,
NHS(O).sub.2R.sup.67, NR.sup.67S(O).sub.2R.sup.67, NHC(O)OR.sup.67,
NR.sup.67C(O)OR.sup.67, NHC(O)NH.sub.2, NHC(O)NHR.sup.67,
NHC(O)N(R.sup.67).sub.2, NR.sup.67C(O)NHR.sup.67,
NR.sup.67C(O)N(R.sup.67).sub.2, C(O)NH.sub.2, C(O)NHR.sup.67,
C(O)N(R.sup.67).sub.2, C(O)NHOH, C(O)NHOR.sup.67,
C(O)NHSO.sub.2R.sup.67, C(O)NR.sup.67SO.sub.2R.sup.67,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.67, SO.sub.2N(R.sup.67).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.67, C(N)N(R.sup.67).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I
substituents;
[0843] R.sup.67 is alkyl, alkenyl, alkynyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl;
[0844] wherein the moieties represented by R.sup.57A, R.sup.58,
R.sup.59, R.sup.60, R.sup.63, R.sup.64, R.sup.65, and R.sup.67 are
unsubstituted or substituted with one or two or three or four of
independently selected R.sup.68, OR.sup.68, SR.sup.68,
S(O)R.sup.68, SO.sub.2R.sup.68, C(O)R.sup.68, CO(O)R.sup.68,
OC(O)R.sup.68, OC(O)OR.sup.68, NH.sub.2, NHR.sup.68,
N(R.sup.68).sub.2, NHC(O)R.sup.68, NR.sup.68C(O)R.sup.68,
NHS(O).sub.2R.sup.68, NR.sup.68S(O).sub.2R.sup.68, NHC(O)OR.sup.68,
NR.sup.68C(O)OR.sup.68, NHC(O)NH.sub.2, NHC(O)NHR.sup.68,
NHC(O)N(R.sup.68).sub.2, NR.sup.68C(O)NHR.sup.68,
NR.sup.68C(O)N(R.sup.68).sub.2, C(O)NH.sub.2, C(O)NHR.sup.68,
C(O)N(R.sup.68).sub.2, C(O)NHOH, C(O)NHOR.sup.68,
C(O)NHSO.sub.2R.sup.68, C(O)NR.sup.68SO.sub.2R.sup.68,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.68, SO.sub.2N(R.sup.68).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.68, C(N)N(R.sup.68).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0845] R.sup.68 is R.sup.69, R.sup.70, R.sup.71 or R.sup.72;
[0846] R.sup.69 is phenyl, which is unfused or fused with benzene,
heteroarene or R.sup.69A; R.sup.69A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0847] R.sup.70 is heteroaryl, which is unfused or fused with
benzene, heteroarene or R.sup.70A; R.sup.70A is cycloalkane,
cycloalkene, heterocycloalkane or heterocycloalkene;
[0848] R.sup.71 is cycloalkyl, cycloalkenyl, heterocycloalkyl or
heterocycloalkenyl, each of which is unfused or fused with benzene,
heteroarene or R.sup.71A; R.sup.71A is cycloalkane, cycloalkene,
heterocycloalkane or heterocycloalkene;
[0849] R.sup.72 is alkenyl or alkenyl, each of which is
unsnbstituted or substituted with one or two or three of
independently selected R.sup.73, OR.sup.73, SR.sup.73,
S(O)R.sup.73, SO.sub.2R.sup.73, C(O)R.sup.73, CO(O)R.sup.73,
OC(O)R.sup.73, OC(O)OR.sup.73, NH.sub.2, NHR.sup.73,
N(R.sup.73).sub.2, NHC(O)R.sup.73, NR.sup.73C(O)R.sup.73,
NHS(O).sub.2R.sup.73, NR.sup.73S(O).sub.2R.sup.73, NHC(O)OR.sup.73,
NR.sup.73C(O)OR.sup.73, NHC(O)NH.sub.2, NHC(O)NHR.sup.73,
NHC(O)N(R.sup.73).sub.2, NR.sup.73C(O)NHR.sup.73,
NR.sup.73C(O)N(R.sup.73).sub.2, C(O)NH.sub.2, C(O)NHR.sup.73,
C(O)N(R.sup.73).sub.2, C(O)NHOH, C(O)NHOR.sup.73,
C(O)NHSO.sub.2R.sup.73, C(O)NR.sup.73SO.sub.2R.sup.73,
SO.sub.2NH.sub.2, SO.sub.2NHR.sup.73, SO.sub.2N(R.sup.73).sub.2,
C(O)H, C(O)OH, C(N)NH.sub.2, C(N)NHR.sup.73, C(N)N(R.sup.73).sub.2,
CNOH, CNOCH.sub.3, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3, F, Cl, Br or I;
[0850] R.sup.73 is alkyl, alkenyl, alkenyl, phenyl, heteroaryl,
cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl;
and
[0851] the moieties represented by R.sup.69, R.sup.70, and R.sup.71
are unsbustituted or substituted with one or two or three or four
of independently selected NH.sub.2, C(O)NH.sub.2, C(O)NHOH,
SO.sub.2NH.sub.2, CF.sub.3, CF.sub.2CF.sub.3, C(O)H, C(O)OH,
C(N)NH.sub.2, OH, (O), CN, N.sub.3, NO.sub.2, CF.sub.3,
CF.sub.2CF.sub.3, OCF.sub.3, OCF.sub.2CF.sub.3s F, Cl, Br or I.
[0852] In one embodiment of Formula (I), A.sup.1 is N. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); and A.sup.2 is
H.
[0853] In one embodiment of Formula (I), B.sup.1 is OR.sup.1, or
NHR.sup.1. In another embodiment of Formula (I), A.sup.1 is
C(A.sup.2); A.sup.2 is H; and B.sup.1 is NHR.sup.1. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H; and
B.sup.1 is OR.sup.1.
[0854] In one embodiment of Formula (I), D.sup.1 H. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H; and
B.sup.1 is NHR.sup.1; and D.sup.1 is H. In another embodiment of
Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
OR.sup.1; and D.sup.1 is H.
[0855] In one embodiment of Formula (I), E.sup.1 is H. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; D.sup.1 is H; and E.sup.1 is H. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is OR.sup.1; D.sup.1 is H; and E.sup.1 is H.
[0856] In one embodiment of Formula (I), Y.sup.1 is H, CN,
NO.sub.2, F, Cl, Br, CF.sub.3, R.sup.17, or SO.sub.2R.sup.17. In
one embodiment of Formula (I), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (I), Y.sup.1 is Cl. In another embodiment of
Formula (I), Y.sup.1 is SO.sub.2R.sup.17; wherein R.sup.17 is as
defined herein. In another embodiment of Formula (I), Y.sup.1 is
SO.sub.2R.sup.17; wherein R.sup.17 is alkyl. In another embodiment
of Formula (I), Y.sup.1 is R.sup.17; wherein R.sup.17 is alkynyl.
In another embodiment of Formula (I), A.sup.1 is C(A.sup.2);
A.sup.2 is H; and B.sup.1 is NHR.sup.1; D.sup.1 is H; E.sup.1 is H;
and Y.sup.1 is NO.sub.2 or SO.sub.2R.sup.17; wherein R.sup.17 is
alkyl or alkynyl. In another embodiment of Formula (I), A.sup.1 is
C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H;
E.sup.1 is H; and Y.sup.1 is NO.sub.2. In another embodiment of
Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and Y.sup.1 is
SO.sub.2R.sup.17, wherein R.sup.17 is alkyl substituted with three
F. In another embodiment of Formula (I), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is OR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is Cl.
[0857] In one embodiment of Formula (I), R.sup.1 is R.sup.1 is
R.sup.4 or R.sup.5. In one embodiment of Formula (I), R.sup.1 is
R.sup.4. In one embodiment of Formula (I), R.sup.1 is R.sup.5. In
one embodiment of Formula (I), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (I),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl. In one embodiment of
Formual (I), R.sup.1 is R.sup.4; and R.sup.4 is
heterocycloalkyl.
[0858] In one embodiment of Formula (I), R.sup.1 is R.sup.4 ; and
R.sup.4 is cycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(I), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein thec
ycloalkyl ring is substituted as defined herein. In another
embodiment of Formula (I), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
R.sup.57, NHR.sup.57, or N(R.sup.57).sub.2. In another embodiment
of Formula (I), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl;
wherein thecycloalkyl ring is cyclohexyl; and wherein the
cyclohexyl ring is substituted with R.sup.57; and R.sup.57 is
R.sup.60. In another embodiment of Formula (I) R.sup.1 is R.sup.4;
R.sup.4is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl;
and wherein the cyclohexyl ring is substituted with R.sup.57;
R.sup.57 is R.sup.60; and R.sup.60 heterocycloalkyl. In another
embodiment of Formula (I), R.sup.1 is R.sup.4; R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein
the cyclohexyl ring is substituted with R.sup.57; R.sup.57 is
R.sup.60; R.sup.60 is heterocycloalkyl; wherein the
heterocycloalkyl ring is morpholinyl or piperazinyl. In another
embodiment of Formula (I), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (I), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (I), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2, R.sup.57 is R.sup.60, and R.sup.61 alkyl which
is unsubstituted. In another embodiment of Formula (I), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2, R.sup.57 is R.sup.60, and R.sup.61 is cycloalkyl
which is unsubstituted. In another embodiment of Formula (I),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is substituted with NHR.sup.57. In another
embodiment of Formula (I), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein
the cyclohexyl ring is substituted with NHR.sup.57. In another
embodiment of Formula (I), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein
the cyclohexyl ring is substituted with NHR.sup.57, R.sup.57 is
R.sup.60, and R.sup.61 is heteroeycloalkyl which is
unsubstituted.
[0859] In one embodiment of Formula (I), R.sup.1 is R.sup.4; and
R.sup.4 is heterocycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(I), R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein
the heterecycloalkyl ring is substituted as defined herein. In
another embodiment of Formula (I), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
substituted with R.sup.57. In another embodiment of Formula (I),
R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein the
heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or
piperizinyl; and wherein the heterocycloalkyl ring is substituted
with one or two or three or four or five more R.sup.57;
SO.sub.2R.sup.57, or OH, and R.sup.57 is R.sup.60 and R.sup.61. In
another embodiment of Formula (I), R.sup.1 is R.sup.4; R.sup.4 is
heterocycfloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted with R.sup.57; R.sup.57is R.sup.60 or R.sup.61;
R.sup.60 is cycloalkyl or heterocycloalkyl; and R.sup.61 is alkyl.
In another embodiment of Formula (I), R.sup.1 is R.sup.4; R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein
the piperidinyl, pyrrolinyl, morpholinyhl, or piperizinyl; ring is
substituted with R.sup.57; R.sup.57is R.sup.60; R.sup.60 is
heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl
or oxetanyl. In another embodiment of Formula (I), R.sup.1 is
R.sup.4; R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl
ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and
wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl;
ring is substituted with R.sup.57; R.sup.57is R.sup.60; R.sup.60 is
cycloalkyl, wherein the cycloalkyl is cyclopropyl or cyclopentyl.
In another embodiment of Formula (I), R.sup.1 is R.sup.4; R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinhyl, or piperizinyl, and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl. In another
embodiment of Formula (I), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl, and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl; wherein the
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl are unsubstituted or
substituted.
[0860] In one embodiment of Formula (I), R.sup.1 is R.sup.3;
R.sup.5 is alkyl which is unsubstituted or substituted. In one
embodiment of Formula (I), R.sup.1 is R.sup.3; R.sup.5 is alkyl
which is unsubstituted or substituted with R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, or OH.
[0861] In one embodiment of Formula (I), R.sup.7 is R.sup.10 or
R.sup.11 which are unsubstituted or substituted as defined herein.
In another embodiment of Formula (I), R.sup.7 is R.sup.10 which is
unsubstituted or substituted as defined herein. In another
embodiment of Formula (I), R.sup.7 is R.sup.11 which is
unsubstituted or substituted as defined herein.
[0862] In one embodiment of Formula (I), R.sup.10 is cycloalkyl or
heterocycloalkyl which are unsubstituted or substituted as defined
herein. In another embodiment of Formula (I), R.sup.10 is
heterocycloalkyl which is unsubstituted or substituted as defined
herein. In another embodiment of Formula (I), R.sup.10 is
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,
piperidinyl, piperizinyl, or pyrrolidinyl, which are substituted or
substituted as defined herein. In another embodiment of Formula
(I), R.sup.10 is tetrahydropyranyl, which is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(I), R.sup.10 is morpholinyl, which is unsubstituted or substituted
as defined herein. In another embodiment of Formula (I), R.sup.10
is cycloalkyl which is unsubstituted or substituted as defined
herein. In another embodiment of Formula (I), R.sup.10 is
cyclohexyl which is unsubstituted or substituted as defined
herein.
[0863] In one embodiment of Formula (I), R.sup.11 is alkyl which is
unsubstituted. In another embodiment of Formula (I), R.sup.11 is
methyl, which is unsubstituted or substituted as defined herein. In
another embodiment of Formula (I), R.sup.11 is alkyl, which is
substituted as defined herein. In another embodiment of Formula
(I), R.sup.11 is alkyl, which is substituted with OR.sup.12,
R.sup.12 is R.sup.16, and R.sup.16 is alkyl.
[0864] Another embodiment of this invention pertains to compounds
of Formula (I), wherein
[0865] A.sup.1 is N or C(A 2);
[0866] A.sup.2 is H;
[0867] B.sup.1 is OR.sup.1, NHR.sup.1;
[0868] D.sup.1 is H;
[0869] E.sup.1 is H; and
[0870] Y.sup.1 is H, CN, NO.sub.2, F, Cl, Br, CF.sub.3, R.sup.17,
or SO.sub.2R.sup.17;
[0871] R.sup.1 is R.sup.4 or R.sup.5;
[0872] R.sup.1 is cycloalkyl, or heterocycloalkyl;
[0873] R.sup.5 is alkyl or alkynyl, each of which is unsubstituted
or substituted with one or two or three of independently selected
R.sup.7, OR.sup.7, N(R.sup.7).sub.2, OH, F, Cl, Br or I;
[0874] R.sup.7 is R.sup.10 or R.sup.11;
[0875] R.sup.10 is cycloalkyl or heterocycloalkyl;
[0876] R.sup.11 is alkyl, each of which is unsubstituted or
substituted with one or two or three of independently selected F,
Cl, Br or I;
[0877] R.sup.17 is R.sup.21;
[0878] R.sup.21 is alkyl, or alkynyl, each of which is
unsubstituted or substituted with one or two or three independently
selected F, Cl, Br or I;
[0879] Z.sup.1 is R.sup.26;
[0880] Z.sup.2 is R.sup.30;
[0881] Z.sup.1A and Z.sup.2A are both absent:
[0882] L.sup.1 is a R.sup.37;
[0883] R.sup.26 is phenylene;
[0884] R.sup.30 is heterocycloalkylene;
[0885] R.sup.37 is R.sup.37A;
[0886] R.sup.37A is alkylene, alkenylene, or alkynylene, each of
which is unsubstituted or substituted with one or two or three
independently selected F, Cl, Br or I substituents;
[0887] Z.sup.3 is R.sup.38, or R.sup.40;
[0888] R.sup.38 is phenyl, which is unfused or fused with
R.sup.38AR.sup.38A is heterocycloalkane;
[0889] R.sup.38 is cycloalkenyl, or heterocycloalkenyl;
[0890] wherein the moieties represented by R.sup.26 and R.sup.27
are substituted (i.e., if Z.sup.1A and Z.sup.2A are absent) or
further substituted (i.e., if Z.sup.1A and Z.sup.2A are present)
with one or two or three or four of independently selected
R.sup.41, OR.sup.41, or NHR.sup.41;
[0891] R.sup.41 is R.sup.42, R.sup.43, or R.sup.45;
[0892] R.sup.42 is phenyl, which is unfused or fused with
heteroarene or R.sup.42A; R.sup.42A is heterocycloalkane;
[0893] R.sup.43 is heteroaryl, which is unfused or fused with
heteroarene;
[0894] R.sup.45 is alkyl, each of which is unsubstituted or
substituted with one or two or three of independently selected F,
Cl, Br or I;
[0895] R.sup.46 is R.sup.47; or R.sup.48;
[0896] R.sup.47 is phenyl;
[0897] R.sup.48 is heteroaryl;
[0898] wherein the moieties represented R.sup.42, R.sup.42A,
R.sup.43, R.sup.43A, R.sup.44, R.sup.44A, R.sup.47, R.sup.47A,
R.sup.48, R.sup.48A, R.sup.49, R.sup.49A are independently
substituted with one or two or three or four of independently
selected R.sup.50, OR.sup.50, CO(O)R.sup.50, NH.sub.2, NHR.sup.50,
N(RR.sup.50).sub.2, NHC(O)R.sup.50, NHS(O).sub.2R.sup.50,
NHC(O)OR.sup.50, C(O)NH.sub.2, C(O)NHR.sup.50,
C(O)N(R.sup.50).sub.2, OH, (O), CN, NO.sub.2, CF.sub.3, F, Cl, Br,
or I;
[0899] R.sup.50 is R.sup.51, R.sup.52, R.sup.53 or R.sup.54;
[0900] R.sup.51 is phenyl;
[0901] R.sup.52 is heteroaryl;
[0902] R.sup.53 is cycloalkyl or heterocycloalkyl;
[0903] R.sup.54 is alkyl, each of which is unsubstituted or
substituted with one or two or three of independently selected
R.sup.55, OR.sup.55, C(O)R.sup.55, NH.sub.2, NHR.sup.55,
N(R.sup.55).sub.2, NR.sup.55C(O)OR.sup.55, C(O)N(R.sup.55).sub.2,
OH, F, Cl, Br or I;
[0904] R.sup.55 is alkyl, phenyl, or heterocycloalkyl; and
[0905] wherein each foregoing cyclic moiety is independently
unsubstituted, further unsubstituted, substituted or further
substituted with one or two or three or four or five of
independently selected R.sup.57A, R.sup.57, OR.sup.57,
SO.sub.2R.sup.57, C(O)R.sup.57, C(O)R.sup.57, NH.sub.2, NHR.sup.57,
N(R.sup.57).sub.2, OH, (O), CN, F, Cl, Br or I;
[0906] R.sup.57A is spirocyclyl;
[0907] R.sup.57 is R.sup.58, R.sup.60 or R.sup.61;
[0908] R.sup.58 is phenyl;
[0909] R.sup.60 is cycloalkyl, or heterocycloalkyl;
[0910] R.sup.61 is alkyl, or alkenyl, each of which is
unsubstituted or substituted with one or two or three of
independently selected R.sup.62, OR.sup.62, N(R.sup.62).sub.2,
C(O)N(R.sup.62).sub.2, OH, F, Cl, Br or I;
[0911] R.sup.62 is R.sup.63, R.sup.64, R.sup.65 or R.sup.66;
[0912] R.sup.63 is phenyl;
[0913] R.sup.64 is heteroaryl;
[0914] R.sup.65is cycloalkyl, or heterocycloalkyl;
[0915] R.sup.66 is alkyl, each of which is unsubstituted or
substituted with one or two or three of independently selected
OR.sup.67, F, Cl, Br or I substituents;
[0916] R.sup.67 is alkyl;
[0917] wherein the moieties represented by R.sup.57A , R.sup.58,
R.sup.59, R.sup.60, R.sup.63, R.sup.64, R.sup.65, and R.sup.67 are
unsubstituted or substituted with one or two or three or four of
independently selected R.sup.68F, Cl, Br or I;
[0918] R.sup.68 is R.sup.71 or R.sup.72;
[0919] R.sup.71 heterocycloalkyl; and
[0920] R.sup.72 is alkyl which is unsubstituted or substituted with
one or two or three of independently selected F, Cl, Br or I;
[0921] Still another embodiment pertains to compounds having
Formula (I), which are [0922]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethy-
lamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [0923]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylam-
ino)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide; [0924]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)ami-
no)-3-nitrophenyl)sulfonyl)benzamide; [0925]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((2methyl-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide; [0926]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-chloro-
phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfo-
nyl)benzamide; [0927]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [0928]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [0929]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide; [0930]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxym-
ethyl)phenoxy-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl-
)benzamide; [0931]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophe-
noxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzami-
de; [0932]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-
-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfo-
nyl)benzamide; [0933]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzami-
de; [0934]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-
-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfon-
yl)benzamide; [0935]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide; [0936]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophe-
noxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide; [0937]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-)-
yl)oxy)benzamide; [0938]
2-(3-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide; [0939]
2-(4-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1--
yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide; [0940]
2-(3-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1--
yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide; [0941]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyph-
enyl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide; [0942]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl))-2-(3-dimethyl-
amino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)benzamide; [0943]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl))-2-(3-cyanophe-
noxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide; [0944]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1-
,3-benzothiazol-6-yl)oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)am-
ino)phenyl)sulfonyl)benzamide; [0945]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl))-2-((2-methyl--
1,3-benzothiazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitroph-
enyl)sulfonyl)benzamide; [0946]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dime-
thylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-((2-methyl-1,3-benzothiaz-
ol-5-yl)oxy)benzamide; [0947]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimet-
hylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmet-
hyl)amino)phenyl)sulfonyl)benzamide; [0948]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimet-
hylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmeth-
yl)amino)phenyl)sulfonyl)benzamide; [0949]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimeth-
ylamino)propyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [0950]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimeth-
ylamino)ethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide; [0951]
2-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((te-
trahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-di-
methylbenzamide; [0952]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethy-
lamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [0953]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy-
)benzamide; [0954]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dime-
thyl-1,3-thiazol-5-yl)phenyoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-ni-
trophenyl)sulfonyl)benzamide; [0955]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0956]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0957]
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0958]
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-n-
itrophenyl)sulfonyl)benzamide; [0959]
2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3--
nitrophenyl)sulfonyl)benzamide; [0960]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimet-
hylamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)am-
ino)phenyl)sulfonyl)benzamide; [0961]
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-
-nitrophenyl)sulfonyl)benzamide; [0962]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide; [0963]
2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0964]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)p-
iperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide; [0965]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)am-
ino)-3-nitrophenyl)sulfonyl)benzamide; [0966]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0967]
2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0968]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [0969]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin--
4-yl)amino)phenyl)sulfonyl)benzamide; [0970]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylp-
iperidin-4-yl)amino)phenyl)sulfonyl)benzamide; [0971]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide; [0972]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0973]
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-
-nitrophenyl)sulfonyl)benzamide; [0974]
2-(3-chlorophenoxy)-4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biph-
enyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylm-
ethyl)amino)phenyl)sulfonyl)benzamide; [0975]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0976]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)am-
ino)-3-nitrophenyl)sulfonyl)benzamide; [0977]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)p-
iperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide; [0978]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3--
(trifluoromethyl)phenoxy)benzamide; [0979]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahy-
droquinolin-5-yl)oxy)benzamide; [0980]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3((triflu-
oromethyl)sulfonyl)phenyl)sulfonyl)benzamide; [0981]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0982]
2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)--
3-nitrophenyl)sulfonyl)benzamide; [0983]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en--
1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide; [0984]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide; [0985]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4-
-yl)amino)-3-nitrophenyl)sulfonyl)benzamide; [0986]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-ni-
trophenyl)sulfonyl)benzamide; [0987]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide; [0988]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [0989]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1-
H-indol-4-yl)oxy)
-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;
[0990]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-m-
orpholin-4-ylphenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)-
sulfonyl)benzamide; [0991]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3-
-oxopropyl)-1H-indol-5-yl)oxy)benzamide; [0992]
2-(2-benzylxoy)phenoxy)-4-(4-((4'-chloro)-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide; [0993]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [0994]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morph-
olin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-py-
ran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide; [0995]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morph-
olin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4--
ylmethyl)amino)phenyl)sulfonyl)benzamide; [0996]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4((dimethy-
lamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [0997]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imid-
azol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [0998]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophen-
oxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamid-
e; [0999] tert-butyl
4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)benzyl(ethyl)carbamate; [1000] tert-butyl
3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)benzyl(ethyl)carbamate; [1001]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((ethylam-
ino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [1002]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((ethylam-
ino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [1003]
2-(4-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide; [1004] tert-butyl
4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)phenylcarbamate; [1005]
2-(1,1'-biphenyl-2-yloxy)-4-(4-((4
'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahy-
dro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide; [1006]
tert-butyl
3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)phenylcarbamate; [1007]
2-(1,1'-biphenyl-3-yloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide; [1008]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimet-
hylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide; [1009]
2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide; [1010]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-morpholin-
-4-ylphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)benzamide; [1011]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1-
,3-benzothiazol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)a-
mino)phenyl)sulfonyl)benzamide; [1012] tert-butyl
4-(3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3--
nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbo-
nyl)phenoxy)phenyl)piperazine-1-carboxylate; [1013]
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)b-
enzamide; [1014]
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)be-
nzamide; [1015]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpho-
lin-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide; [1016]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4--
((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-((2-oxo-1,2,3,4--
tetrahydroquinolin-5-yl)oxy)benzamide; [1017]
2-(4-benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipera-
zin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)ben-
zamide; [1018] tert-butyl
4-(4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((4--
((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carbonyl)pheno-
xy)phenyl)piperazine-1-caraboxylate; [1019]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)b-
enzamide; [1020]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)b-
enzamide; [1021]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)b-
enzamide; [1022]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimet-
hylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmet-
hyl)amino)phenyl)sulfonyl)benzamide; [1023]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1-
H-benzimidazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophen-
yl)sulfonyl)-benzamide; [1024]
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoy-
l)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamide;
[1025]
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dim-
ethylamino)propylamino)-3-nitrophenylsulfonyl)-2-(3-(methylcarbamoyl)pheno-
xy)benzamide; [1026]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimet-
hylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmet-
hyl)amino)phenyl)sulfonyl)benzamide; [1027]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dime-
thylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-
-ylmethyl)amino)phenyl)sulfonyl)benzamide; [1028]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dime-
thylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)phenox-
y)benzamide; [1029]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-methoxyb-
enzyl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide; [1030]
N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrophenylsulfonyl-
-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzamide; [1031]
4-(4-((4'-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-
-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamid-
e; [1032]
N-{[4-{4-[(4'chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2--
(3,5-dichlorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3--
nitrobenzamide; [1033]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1034]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide; [1035]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1036]
2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperi-
din-4-yl)amino]phenyl}sulfonyl)benzamide; [1037]
2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1038]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [1039]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1040]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [1041]
2-(2-chloro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide; [1042]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2,3-difluorophenoxy)benzamide; [1043]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1044]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2-fluorophenoxy)benzamide; [1045]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide; [1046]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1047]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1048]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]-phenyl}sulfonyl)benzamide; [1049]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1050]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1051]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [1052]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide; [1053]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(3-fluorophenoxy)benzamide; [1054]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2,3-difluorophenoxy)benzamide; [1055]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2-fluorophenoxy)benzamide; [1056]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [1057]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperid-
in-4-yl]amino}phenyl)sulfonyl]benzamide; [1058]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2--
fluorophenoxy)benzamide; [1059]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2--
fluorophenoxy)benzamide; [1060]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4--
fluorophenoxy)benzamide; [1061]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [1062]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1063]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrop-
henyl)sulfonyl]benzamide; [1064]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [1065]
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [1066]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide; [1067]
N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-
-difluorophenoxy)benzamide; [1068]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1069]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1070]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropy-
l)amino]phenyl}sulfonyl)benzamide; [1071]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [1072]
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1073]
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1074]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1075]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-
-nitrophenyl)sulfonyl]benzamide; [1076]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide; [1077]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1078]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[3-(methoxymethoxy)-2-methylphenoxy]-N-({4-[(1-methylpiperidin-4--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1079]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1080]
2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide; [1081]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-n-
itrophenyl}sulfonyl)benzamide; [1082]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [1083]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2-phenylethyl)-piperidin-4-y-
l]amino}phenyl)sulfonyl]benzamide; [1084]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1085]
2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide; [1086]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide; [1087]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide;
[1088]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide; [1089]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1090]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(2-methoxyethoxy)ethyl]piperidin-4-
-yl)}amino]-3-nitrophenyl}sulfonyl)benzamide; [1091]
2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1092]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(3-phenylpropyl)piperidin-4-y-
l]amino}phenyl)sulfonyl]benzamide; [1093]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [1094]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-ethylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1095]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide; [1096]
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [1097]
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1098]
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1099]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-dimethylamino)propyl]amino}-3-nitroph-
enyl)sulfonyl]benzamide; [1100]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide; [1101]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1102]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1103]
2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl-
}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfo-
nyl)benzamide; [1104]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1105]
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [1106]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1107]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [1108]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [1109]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(dimethylamino)-2-oxoethyl]piperid-
in-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide; [1110]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl-
]amino}-3-nitrophenyl)sulfonyl]benzamide; [1111]
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)benzamide; [1112]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methy-
l]amino}-3-nitrophenyl)sulfonyl]benzamide; [1113]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1114]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-n-
itrophenyl)sulfonyl]benzamide; [1115]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-n-
itrophenyl)sulfonyl]benzamide; [1116]
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-[3-(1H-pyrrol-2-yl)phenoxy]benzamide; [1117]
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(3-fluorophenoxy)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)meth-
yl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1118]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-methylpiperazin-1-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [1119]
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl-
)amino]-3-nitrophenyl}sulfonyl)benzamide; [1120]
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2-
H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1121]
tert-butyl
4-(5-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-
amino]carbonyl}phenoxy)-1H-indole-1-carboxylate; [1122]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-ni-
trophenyl)sulfonyl]benzamide; [1123]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nit-
rophenyl)sulfonyl]benzamide; [1124]
Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1125]
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chloroph-
enoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzam-
ide; [1126]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1127]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1128]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1129]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyr-
an-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [1130]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-
-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide; [1131]
2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(-
4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(-
4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1132]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfony-
l]-2-({3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide;
[1133]
2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pi-
perazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarb-
amoyl)pheonxy)-N,N-dimethylbenzamide; [1134]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide;
[1135]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [1136]
(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-
-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide; [1137]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;
[1138]
2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro--
2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1139]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)-
amino]-3-nitrophenyl}sulfonyl)benzamide; [1140]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1141] tert-butyl
4-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)a-
mino]carbonyl}phenoxy)methyl]-1,3-thiazol-2-ylcarbamate; [1142]
2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-nitrophenyl}sulfonyl)benzamide; [1143]
2-[3-(acetylamino)phenoxy]-(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [1144]
2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4--
ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [1145]
2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-y-
lpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [1146]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-py-
ran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [1147]
2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1148]
2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-n-
itrophenyl}sulfonyl)benzamide; [1149] tert-butyl
5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-
amino}carbonyl)phenoxy]-1H-indole-1-carboxylate; [1150]
2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-
-2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide;
[1151]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-
-yl)propyl]amino}phenyl)sulfonyl]benzamide; [1152]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1153]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylc-
yclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide; [1154]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1155]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-[(6,7-difluoro-1H-indol-5-yl)oxy]benzamide; [1156]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1157]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperaz-
in-1-yl)propyl]amino}phenyl)sulfonyl]benzamide; [1158]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-p-
yran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1159]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydr-
o-2H-pyran-4-yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide;
[1160]
2-[(6-chloro-1H-indol-5-yl)oxy]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1161]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1162]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1163]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-yl-
methyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide; [1164]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)-
amino]phenyl}sulfonyl)benzamide;
[1165]
2-(4-amino-3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-py-
ran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1166]
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1167]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3S,4R)-3-hydroxy-1-(1,3-th-
iazol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1168]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H--
pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide; [1169]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran--
4-ylamino)phenyl]sulfonyl}benzamide; [1170]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitro-
phenyl]sulfonyl}benzamide; [1171]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfo-
nyl}benzamide; [1172]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]a-
mino}phenyl)sulfonyl]benzamide; [1173]
2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylp-
iperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1174]
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyra-
n-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1175]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-
-yl)propyl]amino}phenyl)sulfonyl]benzamide; [1176]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H--
pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide; [1177]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3R)-tetrahydro-2H--
pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide; [1178] tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate;
[1179]
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-
-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1180]
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1181]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1182]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran--
4-ylmethyloxy)phenyl]sulfonyl}benzamide; [1183]
2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1184]
2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1185]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]benzamide; [1186]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [1187]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1188] tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [1189]
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino-
]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate;
[1190]
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [1191]
2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1192]
2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [1193]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,-
6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1194]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1195]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1196]
tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate; [1197]
2-[5-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide; [1198] tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [1199]
2-[3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1200]
2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [1201]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-hydroxypyridin-3-yl)oxy]-N-({3-nitro-4-[(2-H-pyran-4-ylmethyl-
)amino]phenyl}sulfonyl)benzamide; [1202]
2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pr-
yan-4ylmethyl)amino]phenyl}sulfonyl)benzamide; [1203]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-
-1H-indol-5-yl)oxy]benzamide; [1204]
2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1205]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-
-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [1206]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-
-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [1207]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide;
[1208]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-ni-
trophenyl]sulfonyl}benzamide; [1209]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino-
]-3-nitrophenyl}sulfonyl)benzamide; [1210]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(6--
fluoro-1H-indol-5-yl)oxy]benzamide; [1211]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1212]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimet-
hyl-5,6-dihydro
2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)a-
mino]-3-nitrophenyl}sulfonyl)benzamide; [1213]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyc-
lohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1214]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-
-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [1215]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro--
2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [1216]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl-
]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1217]
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1218]
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-
-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1219]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1220]
2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2-
H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1221]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1222]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]benzamide;
[1223]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide; [1224]
N-{[5-bromo-6-(1,4-dioxan-2ylmethoxy)pyridino-3-yl]sulfonyl}-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6--
fluoro-1H-indol-5-yl)oxy]benzamide; [1225]
Trans-N-({5-bromo-6-[(4-morpholin-4ylcyclohexyl)amino]pyridin-3-yl}sulfon-
yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1226]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1227]
2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide; [1228]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide; [1229]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)oxy]-3-nitrophenyl}sulfonyl)benzamide; [1230]
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3--
yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1231]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [1232]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-t-
etrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[1233]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-t-
etrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1234]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-
-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1235]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)-
oxy]-3-nitrophenyl}sulfonyl)benzamide; [1236]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1237]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-
-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1238]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfo-
nyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide; [1239]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3-
-dihydro-1H-indol-4-yl)oxy]benzamide;
[1240]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl-
]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1241]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-y-
l]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1242]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-y-
lcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1243]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-yl)oxy]pyridin-3-yl}sulfony-
l)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1244]
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1245]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1246]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(-
6-fluoro-1H-indol-5-yl)oxy]benzamide; [1247]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2-
H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide; [1248]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-
-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [1249]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl-
)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1250]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-y-
lmethyl)amino]phenyl}sulfonyl)benzamide; [1251]
Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1252]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-[(4-{[4-dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)-
sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1253]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-
-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide;
[1254]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-
-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamide;
[1255]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro--
2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1256]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)-
methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1257]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(-
tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[1258]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methyl-
piperazin-1-yl)amino]-3nitrophenyl}sulfonyl)benzamide; [1259]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl-
}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1260]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-{[1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro-
-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[1261]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpipera-
zin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1262]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy-
)-3-nitrophenyl]sulfonyl}benzamide; [1263]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclo-
hexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1264]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl-
)amino]-3-nitrophenyl}sulfonyl)benzamide; [1265]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropy-
l)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[1266]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-
-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamid-
e; [1267]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorot-
etrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[1268]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahy-
dro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1269]
2-amino-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)amino]carbonyl}phenoxy)nicotinamide; [1270]
2-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1271]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroe-
thyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1272]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[1273]
2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1274]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetr-
ahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1275]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amin-
o-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;
[1276]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidi-
n-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1277]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl-
)amino]-3-nitrophenyl}sulfonyl)benzamide; [1278]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [1279]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)-
amino]-3-nitrophenyl}sulfonyl)benzamide; [1280]
2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1281]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2-
H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1282]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-yl-
piperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1283]
2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-di-
methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1284]
2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahyd-
ro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1285]
Trans-2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycycloh-
exyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1286]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-N-({3-nitr-
o-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[1287]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropyl-
morpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1288]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyr-
rolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1289]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro--
1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benza-
mide; [1290] tert-butyl
6bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]ph-
enyl}sulfonyl)amino]carbonyl}phenyoxy)pyridin-2-ylcarbamate; [1291]
tert-butyl
-4-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazi-
n-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methylamino)phenylsulfonylc-
arbamoyl)phenoxy)pyridine-2,6-diyldicarbamate; [1292]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-{[6-(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydr-
o-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1293]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4--
(methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1294]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(t-
etrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[1295]
2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4-
,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetra-
hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1296]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluor-
omethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide-
; [1297]
2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1298]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(2,6-diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyra-
n-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1299]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H--
pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide; [1300]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(f-
luoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide;
[1301] tert-butyl
5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [1302]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tet-
rahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1303]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide; [1304]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)-
methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1305]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimet-
hyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetra-
hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1306]
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]m-
ethyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;
[1307]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofur-
an-3-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1308]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-
-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,-
6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)benzamide;
[1309]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3--
[2-fluoro-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide; [1310]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isoprop-
yl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(t-
etrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[1311]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylgly-
cyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chl-
orophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[1312]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluo-
ro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}ben-
zamide; [1313]
2-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1314]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohex-
yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1315]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4'-chloro-3-[2-(dimethylamin-
o)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1316]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-
-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)b-
enzamide; [1317]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluo-
roethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[1318]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophen-
yl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-
cyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1319]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetr-
ahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;
[1320]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroeth-
yl)-4fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[1321]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotet-
rahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4-
,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[1322]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro--
1-fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3--
yl]sulfonyl}benzamide; [1323]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide; [1324]
2-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-py-
ran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1325]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-)[2-(1H-pyrazol-5-yl)phenoxy]benzamide; [1326]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[4,4-difluorocyclohe-
xyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide; [1327]
N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}suflonyl)-4--
(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1328]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfony-
l]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; and therapeutically
acceptable salts, prodrugs, salts of prodrugs and metabolites
thereof.
[1329] Still another embodiment pertains to
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; and
therapeutically acceptable salts, prodrugs, salts of prodrugs and
metabolites thereof.
[1330] Still another embodiment pertains to
[3-chloro-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)amino]carbonyl}phenoxy)-2-iminopyridin-1(2H)-yl]methyl
dihydrogen phosphate; and therapeutically acceptable salts, and
metabolites thereof.
[1331] In another aspect, the present invention provides compounds
of Formula (II)
##STR00007##
and therapeutically acceptable salts, prodrugs, salts of prodrugs
and metabolites thereof, wherein A.sup.1, B.sup.1, D.sup.1,
E.sup.1, Y.sup.1, Z.sup.2, L.sup.1, and Z.sup.3 are as described
herein for Formula (I), n is 0, 1, 2, or 3; describing the number
of additional substituents on R.sup.26, and R.sup.100 is as
described for substituents on R.sup.26, m is 1, 2, 3, 4, or 5;
describing the number of substituents on R.sup.42, and R.sup.101 is
as described for substituents on R.sup.42.
[1332] In one embodiment of Formula (II), A.sup.1 is N. In another
embodiment of Formula (II), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (II), A.sup.1 is C(A.sup.2); and A.sup.2 is
H.
[1333] In another embodiment of Formula (II), B.sup.1 is OR.sup.1,
or NHR.sup.1. In another embodiment of Formula (II), A.sup.1 is
C(A.sup.2); A.sup.2 is H; and B.sup.1 is NHR.sup.1. In another
embodiment of Formula (II), A.sup.1 is C(A.sup.2); A.sup.2 is H;
and B.sup.1 is OR.sup.1.
[1334] In one embodiment of Formula (II), D.sup.1 is H. In another
embodiment of Formula (II), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; and D.sup.1 is H. In another embodiment of
Formula (II), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
OR.sup.1; and D.sup.1 is H.
[1335] In one embodiment of Formula (II), E.sup.1 is H. In another
embodiment of Formula (II), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; D.sup.1 is H; and E.sup.1 is H. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is OR.sup.1; D.sup.1 is H; and E.sup.1 is H.
[1336] In one embodiment of Formula (II), Y.sup.1 is H, CN,
NO.sub.2, F, Cl, Br, CF.sub.3, R.sup.17 or SO.sub.2R.sup.17. In
another embodiment of Formula (II), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (II), Y.sup.1is Cl. In another embodiment of
Formula (II), Y.sup.1 is SO.sub.2R.sup.17; wherein R.sup.17 is as
defined herein. In another embodiment of Formula (II), Y.sup.1 is
SO.sub.2R.sup.17; wherein R.sup.17 is alkyl. In another embodiment
of Formula (II), Y.sup.1 is R.sup.17; wherein R.sup.17 is alkynyl.
In another embodiment of Formula (II), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is NO.sub.2 or SO.sub.2R.sup.17; wherein R.sup.17 is alkyl
or alkynyl. In another embodiment of Formula (II), A.sup.1 is
C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H;
E.sup.1 is H; and Y.sup.1 is NO.sub.2. In another embodiment of
Formula (II), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and Y.sup.1 is
SO.sub.2R.sup.17, wherein R.sup.17is alkyl substituted with three
F. In another embodiment of Formula (II), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is OR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is Cl.
[1337] In one embodiment of Formula (II), R.sup.1 is R.sup.4 or
R.sup.5. In one embodiment of Formula (II), R.sup.1 is R.sup.4. In
one embodiment of Formula (II), R.sup.1 is R.sup.5. In one
embodiment of Formula (II), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (II),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl. In one embodiment of
Formula (II), R.sup.1 is R.sup.4; and R.sup.4 is
heterocycloalkyl.
[1338] In one embodiment of Formula (II), R.sup.1 is R.sup.4; and
R.sup.4 is cycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(II), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is substituted as defined herein. In another
embodiment of Formula (II), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
R.sup.57, NHR.sup.57, or N(R.sup.57).sub.2. In another embodiment
of Formula (II), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl;
wherein the cycloalkyl ring is cyclohexyl; and wherein the
cyclohexyl ring is substituted with R.sup.57; and R.sup.57 is
R.sup.60. In another embodiment of Formula (II), R.sup.1 is
R.sup.4; R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
R.sup.57; and R.sup.57 is R.sup.60; and R.sup.60 is
heterocycloalkyl. In another embodiment of Formula (II), R.sup.1 is
R.sup.4; R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
R.sup.57; and R.sup.57 is R.sup.60; R.sup.60 is heterocycloalkyl;
wherein the heterocycloalkyl ring is morpholinyl or piperazinyl. In
another embodiment of Formula (II), R.sup.1 is R.sup.4; and R.sup.4
is cycloalkyl; wherein the cycloalkyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (II), R.sup.1
is R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring
is cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (II), R.sup.1
is R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring
is cycloalkyl; and wherein the cycloalkyl ring is substituted with
N(R.sup.57).sub.2, R.sup.57; and R.sup.57 is R.sup.61, and R.sup.61
is alkyl which is unsubstituted. In another embodiment of Formula
(II), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is
substituted with N(R.sup.57).sub.2, R.sup.57 is R.sup.60, and
R.sup.60 is cycloalkyl which is unsubstituted. In another
embodiment of Formula (II), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
NHR.sup.57. In another embodiment of Formula (II), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
NHR.sup.57 In another embodiment of Formula (II), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
NHR.sup.57, R.sup.57 is R.sup.60, and R.sup.60 is heterocycloalkyl
which is unsubstituted.
[1339] In one embodiment of Formula (II), R.sup.1 is R.sup.4; and
R.sup.4 is heterocycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(II), R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein
the heterocycloalkyl ring is substituted as defined herein. In
another embodiment of Formula (II), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
substituted with R.sup.57. In another embodiment of Formula (II),
R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein the
heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or
piperizinyl; and wherein the heterocycloalkyl ring is substituted
with one or two or three or four or five more R.sup.57,
SO.sub.2R.sup.57, or OH, and R.sup.57 is R.sup.60 or R.sup.61. In
another embodiment of Formula (II), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted R.sup.57; and R.sup.57 is R.sup.60or R.sup.61; R.sup.60
is cycloalkyl or heterocycloalkyl; and R.sup.61 is alkyl. In
another embodiment of Formula (II), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl; and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60 is
heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl
or oxetanyl. In another embodiment of Formula (II), R.sup.1 is
R.sup.4; R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl
ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and
wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl;
ring is substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60
is cycloalkyl wherein the cycloalkyl is cyclopropyl or cyclopentyl.
In another embodiment of Formula (II), R.sup.1 is R.sup.4; R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57 is R.sup.61; and R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl. In another
embodiment of Formula (II), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl, and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57 is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl; wherein the
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl are unsubstituted or
substituted.
[1340] In one embodiment of Formula (II), R.sup.1 is R.sup.5; and
R.sup.5 is alkyl which is unsubstituted or substituted. In one
embodiment of Formula (II), R.sup.1 is R.sup.5; and R.sup.5 is
alkyl which is unsubstituted or substituted with R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, or OH.
[1341] In one embodiment a Formula (II), R.sup.7 is R.sup.10 or
R.sup.11 which are unsubstituted or substituted as defined herein.
In another embodiment of Formula (II), R.sup.7 is R.sup.10 which is
unsubstituted or substituted as defined herein. In another
embodiment of Formula (II), R.sup.7 is R.sup.11 which is
unsubstituted or substituted as defined herein.
[1342] In one embodunent ot Formula (II), R.sup.10 is cycloalkyl or
heterocycloalkyl which are unsubstituted or substituted as defined
herein. In another embodiment of Formula (II), R.sup.10 is
heterocycloalkyl which is unsubstituted or substituted as defined
herein. In another embodiment of Formula (II), R.sup.10 is
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,
piperidinyl, piperizinyl, or pyrrolidinyl, which are unsubstituted
or substituted as defined herein. In another embodiment of Formula
(II), R.sup.10 is tetrahydropyranyl, which is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(II), R.sup.10 is morpholinyl, which is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(II), R.sup.10 is cycloalkyl which is unsubstituted or substituted
as defined herein. In another embodiment of Formula (II), R.sup.10
is cyclohexyl which is unsubstituted or substituted as defined
herein.
[1343] In one embodiment of Formula (II), R.sup.11 is alkyl which
is unsubstituted. In another embodiment of Formula (II), R.sup.11
is methyl, which is unsubstituted or substituted as defined herein.
In another embodiment of Formula (II), R.sup.11 is alkyl, which is
substituted as defined herein. In another embodiment of Formula
(II), R.sup.11 is alkyl, which is substituted with OR.sup.12,
R.sup.12 is R.sup.16, and R.sup.16 is alkyl.
[1344] Still another embodiment pertains to compounds having
Formula (II), which are [1345]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethy-
lamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [1346]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylam-
ino)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide; [1347]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-chloro-
phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfo-
nyl)benzamide; [1348]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [1349]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [1350]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide; [1351]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxym-
ethyl)phenoxy-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl-
)benzamide; [1352]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophe-
noxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzami-
de; [1353]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-
-chlorophenoxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfo-
nyl)benzamide; [1354]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzami-
de; [1355]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-
-chlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfon-
yl)benzamide; [1356]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide; [1357]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophe-
noxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzam-
ide; [1358]
2-(3-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide; [1359]
2-(4-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1--
yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide; [1360]
2-(3-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1--
yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide; [1361]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyph-
enyl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide; [1362]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-dimethyla-
mino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide; [1363]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophen-
oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)b-
enzamide; [1364]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimet-
hylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmeth-
yl)amino)phenyl)sulfonyl)benzamide; [1365]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimet-
hylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethy-
l)amino)phenyl)sulfonyl)benzamide; [1366]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimeth-
ylamino)propyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [1367]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimeth-
ylamino)ethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide; [1368]
2-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((te-
trahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-di-
methylbenzamide; [1369]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethy-
lamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [1370]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy-
)benzamide; [1371]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dime-
thyl-1,3-thiazol-5-yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [1372]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [1373]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [1374]
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [1375]
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-n-
itrophenyl)sulfonyl)benzamide; [1376]
2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3--
nitrophenyl)sulfonyl)benzamide; [1377]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimet-
hylamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)am-
ino)phenyl)sulfonyl)benzamide; [1378]
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-
-nitrophenyl)sulfonyl)benzamide; [1379]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide; [1380]
2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [1381]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)p-
iperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide; [1382]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [1383]
2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [1384]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide; [1385]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin--
4-yl)amino)phenyl)sulfonyl)benzamide; [1386]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylp-
iperidin-4-yl)amino)phenyl)sulfonyl)benzamide; [1387]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [1388]
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-
-nitrophenyl)sulfonyl)benzamide; [1389]
2-(3-chlorophenoxy)-4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biph-
enyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylm-
ethyl)amino)phenyl)sulfonyl)benzamide; [1390]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,3-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [1391]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)p-
iperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfony-
l)benzamide; [1392]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3--
(trifluoromethyl)phenoxy)benzamide; [1393]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3((triflu-
oromethyl)sulfonyl)phenyl)sulfonyl)benzamide; [1394]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [1395]
2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)--
3-nitrophenyl)sulfonyl)benzamide; [1396]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en--
1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrop-
henyl)sulfonyl)benzamide; [1397]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4-
-yl)amino)-3-nitrophenyl)sulfonyl)benzamide; [1398]
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-ni-
trophenyl)sulfonyl)benzamide; [1399]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nit-
rophenyl)sulfonyl)benzamide; [1400]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-morpholi-
n-4-ylphenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfony-
l)benzamide; [1401]
2-(3-benzylxoy)phenoxy)-4-(4-((4'-chloro)-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide; [1402]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide; [1403]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4((dimethy-
lamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide; [1404]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imid-
azol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [1405]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophen-
oxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamid-
e; [1406] tert-butyl
4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)benzyl(ethyl)carbamate; [1407] tert-butyl
3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)benzyl(ethyl)carbamate; [1408]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((ethylam-
ino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [1409]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((ethylam-
ino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide; [1410]
2-(4-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pip-
erazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide; [1411] tert-butyl
4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)phenylcarbamate; [1412]
2-(1,1'-biphenyl-2-yloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide; [1413] tert-butyl
3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-nit-
ro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbonyl-
)phenoxy)phenylcarbamate; [1414]
2-(1,1'-biphenyl-3-yloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide; [1415]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimet-
hylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide; [1416]
2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide; [1417]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-morpholin-
-4-ylphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)-
sulfonyl)benzamide; [1418] tert-butyl
4-(3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3--
nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amino)carbo-
nyl)phenoxy)phenyl)piperazine-1-carboxylate; [1419]
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)b-
enzamide; [1420]
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)be-
nzamide; [1421]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpho-
lin-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide; [1422]
2-(4-benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipera-
zin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)ben-
zamide; [1423] tert-butyl
4-(4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((((4--
((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carbonyl)pheno-
xy)phenyl)piperazine-1-caraboxylate; [1424]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)b-
enzamide; [1425]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)b-
enzamide; [1426]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morp-
holin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)b-
enzamide; [1427]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimet-
hylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmet-
hyl)amino)phenyl)sulfonyl)benzamide; [1428]
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoy-
l)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamide;
[1429]
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dim-
ethylamino)propylamino)-3-nitrophenylsulfonyl)-2-(3-(methylcarbamoyl)pheno-
xy)benzamide;
[1430]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-
-(dimethylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran--
4-ylmethyl)amino)phenyl)sulfonyl)benzamide; [1431]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dime-
thylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)phenoxy-
)benzamide; [1432]
N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrophenylsulfonyl-
-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzamide; [1433]
4-(4-((4'-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)-N-
-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamid-
e; [1434]
N-{[4-{4-[(4'chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2--
(3,5-dichlorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3--
nitrobenzamide; [1435]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1436]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide; [1437]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1438]
2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperi-
din-4-yl)amino]phenyl}sulfonyl)benzamide; [1439]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1440]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [1441]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1442]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [1443]
2-(2-chloro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1444]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2,3-difluorophenoxy)benzamide; [1445]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1446]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2-fluorophenoxy)benzamide; [1447]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]phenyl}sulfonyl)benzamide; [1448]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1449]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1450]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiper-
idin-4-yl)amino]-phenyl}sulfonyl)benzamide; [1451]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1452]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1453]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide; [1454]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifl-
uoromethyl)sulfonyl]phenyl}sulfonyl)benzamide; [1455]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(3-fluorophenoxy)benzamide; [1456]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2,3-difluorophenoxy)benzamide; [1457]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-(2-fluorophenoxy)benzamide; [1458]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [1459]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperid-
in-4-yl]amino}phenyl)sulfonyl]benzamide; [1460]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2--
fluorophenoxy)benzamide; [1461]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2--
fluorophenoxy)benzamide; [1462]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4--
fluorophenoxy)benzamide; [1463]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [1464]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1465]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrop-
henyl)sulfonyl]benzamide; [1466]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [1467]
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [1468]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide; [1469]
N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-
-difluorophenoxy)benzamide; [1470]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1471]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1472]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropy-
l)amino]phenyl}sulfonyl)benzamide; [1473]
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [1474]
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1475]
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1476]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-
-nitrophenyl)sulfonyl]benzamide; [1477]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-methylpiperidin-4-yl)methyl]amino-
}-3-nitrophenyl)sulfonyl]benzamide; [1478]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[3-(methoxymethoxy)-2-methylphenoxy]-N-({4-[(1-methylpiperidin-4--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1479]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1480]
2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide; [1481]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-n-
itrophenyl}sulfonyl)benzamide; [1482]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [1483]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2-phenylethyl)-piperidin-4-y-
l]amino}phenyl)sulfonyl]benzamide; [1484]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1485]
2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)ami-
no]-3-nitrophenyl}sulfonyl)benzamide; [1486]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide; [1487]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [1488]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1489]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1490]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(2-methoxyethoxy)ethyl]piperidin-4-
-yl}amino]-3-nitrophenyl}sulfonyl)benzamide; [1491]
2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1492]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(3-phenylpropyl)piperidin-4-y-
l]amino}phenyl)sulfonyl]benzamide; [1493]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-
-3-nitrophenyl)sulfonyl]benzamide; [1494]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-ethylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide; [1495]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide; [1496]
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [1497]
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide; [1498]
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1499]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[3-dimethylamino)propyl]amino}-3-nitroph-
enyl)sulfonyl]benzamide; [1500]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide; [1501]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1502]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1503]
2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl-
}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfo-
nyl)benzamide; [1504]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide; [1505]
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-
-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide; [1506]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1507]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [1508]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]ami-
no}-3-nitrophenyl)sulfonyl]benzamide; [1509]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(dimethylamino)-2-oxoethyl]piperid-
in-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide; [1510]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl-
]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1511]
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophen-
yl)sulfonyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide; [1512]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methy-
l]amino}-3-nitrophenyl)sulfonyl]benzamide; [1513]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-n-
itrophenyl)sulfonyl]benzamide; [1514]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-n-
itrophenyl)sulfonyl]benzamide; [1515]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[3--
(1H-pyrrol-2-yl)phenoxy]benzamide; [1516]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methy-
l]amino}-3-nitrophenyl)sulfonyl]benzamide; [1517]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-methylpiperazin-1-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide; [1518]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1,4-dimethylamino)cyclohexyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide; [1519]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(4-{[1,4-(diethylamino)cyclohexyl]amino}-3-n-
itrophenyl)sulfonyl]benzamide; [1520]
Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1521]
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chloroph-
enoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzam-
ide; [1522]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1523]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide; [1524]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]-
-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide; [1525]
2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-
-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)p-
heonxy)-N,N-dimethylbenzamide; [1526]
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1527]
2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide; [1528]
2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4--
ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1529]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(4-tetrahydro-2H-pyran-4-ylmethy-
l)amino]phenyl}sulfonyl)benzamide; [1530]
2-(4-amino)-3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [1531]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2-H-pyran--
4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide; [1532]
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfo-
nyl}benzamide; [1533]
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)
propyl]amino}phenyl)sulfonyl]benzamide; [1534]
2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide; [1535]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide; [1536]
2-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2-H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl) benzamide; [1537]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-[2-(1H-pyrazol-5-yl)phenoxy]benzamide; and therapeutically
acceptable salts, prodrugs, salts of prodrugs and metabolites
thereof.
[1538] In another aspect, the present invention provides compounds
of Formula (III)
##STR00008##
and therapeutically acceptable salts, prodrugs, salts of prodrugs
and metabolites thereof, wherein A.sup.1, B.sup.1, D.sup.1,
E.sup.1, Y.sup.1, Z.sup.2, L.sup.1, and Z.sup.3 are as described
herein for Formula (I), n is 0, 1, 2, or 3; describing the number
of additional substituents on R.sup.26, and R.sup.100 is as
described for substituents on R.sup.26, and at least one R.sup.102
is a substituent on R.sup.42 and R.sup.42A, and the remainder are
H.
[1539] In one embodiment of Formula (III), A.sup.1 is N. In another
embodiment of Formula (III), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (III), A.sup.1 is C(A.sup.2); and A.sup.2 is
H.
[1540] In another embodiment of Formula (III), B.sup.1 is OR.sup.1,
or NHR.sup.1. In another embodiment of Formula (III), A.sup.1 is
C(A.sup.2); A.sup.2 is H; and B.sup.1 is NHR.sup.1. In another
embodiment of Formula (III), A.sup.1 is C(A.sup.2); A.sup.2 is H;
and B.sup.1 is OR.sup.1.
[1541] In one embodiment of Formula (III), D.sup.1 is H. In another
embodiment of Formula (III), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; and D.sup.1 is H. In another embodiment of
Formula (III), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
OR.sup.1; and D.sup.1 is H.
[1542] In one embodiment of Formula (III), E.sup.1 is H. In another
embodiment of Formula (III), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; D.sup.1 is H; and E.sup.1 is H. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is OR.sup.1; D.sup.1 is H; and E.sup.1 is H.
[1543] In one embodiment of Formula (III), Y.sup.1 is H, CN,
NO.sub.2, F, Cl, Br, CF.sub.3, R.sup.17 or SO.sub.2R.sup.17. In
another embodiment of Formula (III), Y.sup.1 is NO.sub.2. In
another embodiment of Formula (III), Y.sup.1is Cl. In another
embodiment of Formula (III), Y.sup.1 is SO.sub.2R.sup.17; wherein
R.sup.17 is as defined herein. In another embodiment of Formula
(III), Y.sup.1 is SO.sub.2R.sup.17; wherein R.sup.17 is alkyl. In
another embodiment of Formula (III), Y.sup.1 is R.sup.17; wherein
R.sup.17 is alkynyl. In another embodiment of Formula (III),
A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1
is H; E.sup.1 is H; and Y.sup.1 is NO.sub.2 or SO.sub.2R.sup.17;
wherein R.sup.17 is alkyl or alkynyl. In another embodiment of
Formula (II), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and Y.sup.1 is NO.sub.2. In
another embodiment of Formula (III), A.sup.1 is C(A.sup.2); A.sup.2
is H; B.sup.1 is NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and Y.sup.1
is SO.sub.2R.sup.17, wherein R.sup.17is alkyl substituted with
three F. In another embodiment of Formula (III), A.sup.1 is
C(A.sup.2); A.sup.2 is H; B.sup.1 is OR.sup.1; D.sup.1 is H;
E.sup.1 is H; and Y.sup.1 is Cl.
[1544] In one embodiment of Formula (III), R.sup.1 is R.sup.4 or
R.sup.5. In one embodiment of Formula (III), R.sup.1 is R.sup.4. In
one embodiment of Formula (III), R.sup.1 is R.sup.5. In one
embodiment of Formula (III), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl, or heterocycloalkyl. In one embodiment of Formula
(III), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl. In one
embodiment of Formula (III), R.sup.1 is R.sup.4; and R.sup.4 is
heterocycloalkyl.
[1545] In one embodiment of Formula (III), R.sup.1 is R.sup.4; and
R.sup.4 is cycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(III), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is substituted as defined herein. In another
embodiment of Formula (III), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
R.sup.57, NHR.sup.57, or N(R.sup.57).sub.2. In another embodiment
of Formula (III), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl;
wherein the cycloalkyl ring is cyclohexyl; and wherein the
cyclohexyl ring is substituted with R.sup.57; and R.sup.57 is
R.sup.60. In another embodiment of Formula (III), R.sup.1 is
R.sup.4; R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
R.sup.57; and R.sup.57 is R.sup.60; and R.sup.60 is
heterocycloalkyl. In another embodiment of Formula (III), R.sup.1
is R.sup.4; R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
R.sup.57; and R.sup.57 is R.sup.60; R.sup.60 is heterocycloalkyl;
wherein the heterocycloalkyl ring is morpholinyl or piperazinyl. In
another embodiment of Formula (III), R.sup.1 is R.sup.4; and
R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is substituted
with N(R.sup.57).sub.2. In another embodiment of Formula (III),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is
substituted with N(R.sup.57).sub.2. In another embodiment of
Formula (III), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl;
wherein the cycloalkyl ring is cyclohexyl; and wherein the
cyclohexyl ring is substituted with N(R.sup.57).sub.2, R.sup.57 is
R.sup.61, and R.sup.61 is alkyl which is unsubstituted. In another
embodiment of Formula (III), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein
the cyclohexyl ring is substituted with N(R.sup.57).sub.2, R.sup.57
is R.sup.60, and R.sup.60 is cycloalkyl which is unsubstituted. In
another embodiment of Formula (III), R.sup.1 is R.sup.4; and
R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is substituted
with NHR.sup.57. In another embodiment of Formula (III), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
NHR.sup.57. In another embodiment of Formula (III), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
NHR.sup.57, R.sup.57 is R.sup.60, and R.sup.60 is heterocycloalkyl
which is unsubstituted.
[1546] In one embodiment of Formula (III), R.sup.1 is R.sup.4; and
R.sup.4 is heteroeycioalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(III), R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein
the heterocycloalkyl ring is substituted as defined herein. In
another embodiment of Formula (III), R.sup.1 is R.sup.4; and
R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl ring is
substituted with R.sup.57. In another embodiment of Formula (III),
R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein the
heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or
piperizinyl; and wherein the heterocycloalkyl ring is substituted
with one or two or three or four or five more R.sup.57;
SO.sub.2R.sup.57, or OH, and R.sup.57 is R.sup.60 or R.sup.61. In
another embodiment of Formula (III), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl; and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted with R.sup.57; R.sup.57 is R.sup.60 or R.sup.61;
R.sup.60 is cycloalkyl or heterocycloalkyl; and R.sup.61 is alkyl.
Inanother embodiment of Formula (III), R.sup.1 is R.sup.4; R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60 is
heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl
or oxetanyl. In another embodiment of Formula (III), R.sup.1 is
R.sup.4; R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl
ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and
wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl;
ring is substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60
cycloalkyl, wherein the cycloalkyl is cyclopropyl or cyclopentyl.
In another embodiment of Formula (III), heterocycloalkyl; R.sup.1
is R.sup.4; R.sup.4 is heterocycloalkyl; wherein the
heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or
piperizinyl, and wherein the piperidinyl, pyrrolinyl, morpholinyl,
or piperidinyl ring is substituted with one or two or three or four
or five R.sup.57; R.sup.57 is R.sup.61, R.sup.61 is alkyl; and the
alkyl is C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl. In another
embodiment of Formula (II), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl, and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57 is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl; wherein the
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl are unsubstituted or
substituted.
[1547] In one embodiment of Formula (III), R.sup.1 is R.sup.5; and
R.sup.5 is alkyl which is unsubstituted or substituted. In one
embodiment of Formula (II), R.sup.1 is R.sup.5; and R.sup.5 is
alkyl which is unsubstituted or substituted with R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, or OH.
[1548] In one embodiment a Formula (III), R.sup.7 is R.sup.10 or
R.sup.11 which are unsubstituted or substituted as defined herein.
In another embodiment of Formula (III), R.sup.7 is R.sup.10 which
is unsubstituted or substituted as defined herein. In another
embodiment of Formula (III), R.sup.7 is R.sup.11 which is
unsubstituted or substituted as defined herein.
[1549] In one embodunent ot Formula (III), R.sup.10 is cycloalkyl
or heterocycloalkyl which are unsubstituted or substituted as
defined herein. In another embodiment of Formula (III), R.sup.10 is
heterocycloalkyl which is unsubstituted or substituted as defined
herein. In another embodiment of Formula (III), R.sup.10 is
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,
piperidinyl, piperizinyl, or pyrrolidinyl, which are unsubstituted
or substituted as defined herein. In another embodiment of Formula
(III), R.sup.10 is tetrahydropyranyl, which is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(III), R.sup.10 is morpholinyl, which is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(III), R.sup.10 is cycloalkyl which is unsubstituted or substituted
as defined herein. In another embodiment of Formula (III), R.sup.10
is cyclohexyl which is unsubstituted or substituted as defined
herein.
[1550] In one embodiment of Formula (III), R.sup.11 is alkyl which
is unsubstituted. In another embodiment of Formula (III), R.sup.11
is methyl, which is unsubstituted or substituted as defined herein.
In another embodiment of Formula (III), R.sup.11 is alkyl, which is
substituted as defined herein. In another embodiment of Formula
(III), R.sup.11 is alkyl, which is substituted with OR.sup.12,
R.sup.12 is R.sup.16, and R.sup.16 is alkyl.
[1551] Still another embodiment pertains to compounds having
Formula (III), which are [1552]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)ami-
no)-3-nitrophenyl)sulfonyl)benzamide; [1553]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((2methyl-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide; [1554]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide; [1555]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3-
-oxopropyl)-1H-indol-5-yl)oxy)benzamide; [1556]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(morp-
holin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-p-
yran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide; [1557]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(morp-
holin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-
-ylmethyl)amino)phenyl)sulfonyl)benzamide; [1558]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dime-
thylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-
-ylmethyl)amino)phenyl)sulfonyl)benzamide; [1559]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1560]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1561]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyr-
an-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1562]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)-
amino]-3-nitrophenyl}sulfonyl)benzamide; [1563]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-
-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1564]
(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6-
-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide; [1565]
(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-N-({3nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phen-
yl}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide;
[1566]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)-
amino]-3-nitrophenyl}sulfonyl)benzamide; [1567]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1568]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-py-
ran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1569]
tert-butyl
5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-
amino}carbonyl)phenoxy]-1H-indole-1-carboxylate; [1570]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-
-yl)propyl]amino}phenyl)sulfonyl]benzamide; [1571]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1572]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylc-
yclohexyl)amino]-3nitrophenyl}sulfonyl)benzamide; [1573]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1574]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)su-
lfonyl]-2-[(6,7-difluoro-1H-indol-5-yl)oxy]benzamide; [1575]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1576]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperaz-
in-1-yl)propyl]amino}phenyl)sulfonyl]benzamide; [1577]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-p-
yran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1578]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hyd
yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide; [1579]
2-[(6-chloro-1H-indol-5-yl)oxy]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1580]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1581]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1582]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-yl-
methyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide; [1583]
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulf-
onyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1584]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3S,4R)-3-hydroxy-1-(1,3-th-
iazol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1585]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-
-pyran-4-ylamino)phenyl]sulfonyl}benzamide; [1586]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitro-
phenyl]sulfonyl}benzamide; [1587]
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazi-
n-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyra-
n-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1588]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H--
pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide; [1589]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3R)-tetrahydro-2H--
pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide; [1590]
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1591]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1592]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran--
4-ylmethyloxy)phenyl]sulfonyl}benzamide; [1593]
2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1594]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,-
6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1595]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1596]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1597]
2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyr-
an-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1598]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro--
1H-indol-5-yl)oxy]benzamide; [1599]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-ni-
trophenyl]sulfonyl}benzamide; [1600]
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino-
]-3-nitrophenyl}sulfonyl)benzamide; [1601]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(6--
fluoro-1H-indol-5-yl)oxy]benzamide; [1602]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1603]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimet-
hyl-5,6-dihydro
2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)a-
mino]-3-nitrophenyl}sulfonyl)benzamide; [1604]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyc-
lohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1605]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran-
-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [1606]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro--
2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [1607]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl-
]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1608]
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1609]
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-
-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1610]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1611]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfony-
l}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1612]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide; [1613]
N-{[5-bromo-6-(1,4-dioxan-2ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-c-
hlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide; [1614]
Trans-N-({5-bromo-6-[(4-morpholin-4ylcyclohexyl)amino]pyridin-3-yl}sulfon-
yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1615]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-y-
l}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1616]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide; [1617]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcyclo-
hexyl)oxy]-3-nitrophenyl}sulfonyl)benzamide; [1618]
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3--
yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1619]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-t-
etrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[1620]
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-t-
etrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1621]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-
-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1622]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)-
oxy]-3-nitrophenyl}sulfonyl)benzamide; [1623]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-
-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1624]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1625]
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}p-
iperazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-y-
l]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1626]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridi-
n-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;
[1627]
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin--
3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]me-
thyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;
[1628]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)--
2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1629]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(-
6-fluoro-1H-indol-5-yl)oxy]benzamide; [1630]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2-
H-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide; [1631]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl-
)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1632]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-y-
lmethyl)amino]phenyl}sulfonyl)benzamide; [1633]
Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfony-
l)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperaz-
in-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1634]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-N-[(4-{[4-dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)-
sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1635]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro-
-2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide;
[1636]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-tetrahyd-
ro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamide;
[1637]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro--
2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1638]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)-
methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1639]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl-
}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; [1640]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amin-
o-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide;
[1641]
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}su-
lfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]m-
ethyl}piperazin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]benzamide;
[1642]
N-({5-chloro-6-[(4,4-difluorocyclohexyl-methoxy]pyridin-3-yl}sulfonyl)-4--
(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pipe-
razin-1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]benzamide; [1643]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-[(4{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl-
]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide; and therapeutically
acceptable salts, prodrug, salts of prodrugs and metabolites
thereof.
[1644] In another aspect, the present invention provides compounds
of Formula (IV)
##STR00009##
and therapeutically acceptable salts, prodrugs, salts of prodrugs
and metabolites thereof, wherein A.sup.1, B.sup.1, D.sup.1,
E.sup.1, Y.sup.1, Z.sup.2, L.sup.1, and Z.sup.3 are as described
herein for Formula (I), n is 0, 1, 2, or 3; describing the number
of additional substituents on R.sup.26, and R.sup.100 is as
described for substituents on R.sup.26, and at least one R.sup.102
is a substituent as described for substituents on R.sup.42
R.sup.42A, and the remainder are H.
[1645] In one embodiment of Formula (IV), A.sup.1 is N. In another
embodiment of Formula (IV), A.sup.1 is C(A.sup.2). In another
embodiment of Formula (IV), A.sup.1 is C(A.sup.2); and A.sup.2 is
H.
[1646] In one embodiment of Formula (IV), B.sup.1 is OR.sup.1, or
NHR.sup.1. In another embodiment of Formula (IV), A.sup.1 is
C(A.sup.2); A.sup.2 is H; and B.sup.1 is NHR.sup.1. In another
embodiment of Formula (IV), A.sup.1 is C(A.sup.2); A.sup.2 is H;
and B.sup.1 is OR.sup.1.
[1647] In one embodiment of Formula (IV), D.sup.1 is H. In another
embodiment of Formula (IV), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; and D.sup.1 is H. In another embodiment of
Formula (IV), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
OR.sup.1; and D.sup.1 is H.
[1648] In one embodiment of Formula (IV), E.sup.1 is H. In another
embodiment of Formula (IV), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; D.sup.1 is H; and E.sup.1 is H. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is OR.sup.1; D.sup.1 is H; and E.sup.1 is H.
[1649] In one embodiment of Formula (IV), Y.sup.1 is H, CN,
NO.sub.2, F, Cl, Br, CF.sub.3, R.sup.17 or SO.sub.2R.sup.17. In
another embodiment of Formula (IV), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (IV), Y.sup.1is Cl. In another embodiment of
Formula (IV), Y.sup.1 is SO.sub.2R.sup.17; wherein R.sup.17 is as
defined herein. In another embodiment of Formula (IV), Y.sup.1 is
SO.sub.2R.sup.17; wherein R.sup.17 is alkyl. In another embodiment
of Formula (IV), Y.sup.1 is R.sup.17; wherein R.sup.17 is alkynyl.
In another embodiment of Formula (IV), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is NO.sub.2 or SO.sub.2R.sup.17; wherein R.sup.17 is alkyl
or alkynyl. In another embodiment of Formula (IV), A.sup.1 is
C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H;
E.sup.1 is H; and Y.sup.1 is NO.sub.2. In another embodiment of
Formula (IV), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and Y.sup.1 is
SO.sub.2R.sup.17, wherein R.sup.17is alkyl substituted with three
F. In another embodiment of Formula (IV), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is OR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is Cl.
[1650] In one embodiment of Formula (IV), R.sup.1 is R.sup.4 or
R.sup.5. In one embodiment of Formula (IV), R.sup.1 is R.sup.4. In
one embodiment of Formula (IV), R.sup.1 is R.sup.5. In one
embodiment of Formula (IV), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (IV),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl. In one embodiment of
Formula (IV), R.sup.1 is R.sup.4; and R.sup.4 is
heterocycloalkyl.
[1651] In one embodiment of Formula (IV), R.sup.1 is R.sup.4; and
R.sup.4 is cycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(IV), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is substituted as defined herein. In another
embodiment of Formula (IV), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
R.sup.57, NHR.sup.57, or N(R.sup.57).sub.2. In another embodiment
of Formula (IV), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl;
wherein the cycloalkyl ring is cyclohexyl; and wherein the
cyclohexyl ring is substituted with R.sup.57; and R.sup.57 is
R.sup.60. In another embodiment of Formula (IV), R.sup.1 is
R.sup.4; R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
R.sup.57; and R.sup.57 is R.sup.60; and R.sup.60 is
heterocycloalkyl. In another embodiment of Formula (IV), R.sup.1 is
R.sup.4; R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
R.sup.57; and R.sup.57 is R.sup.60; R.sup.60 is heterocycloalkyl;
wherein the heterocycloalkyl ring is morpholinyl or piperazinyl. In
another embodiment of Formula (IV), R.sup.1 is R.sup.4; and R.sup.4
is cycloalkyl; wherein the cycloalkyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (IV), R.sup.1
is R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring
is cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (IV), R.sup.1
is R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring
is cycloalkyl; and wherein the cycloalkyl ring is substituted with
N(R.sup.57).sub.2, R.sup.57; and R.sup.57 is R.sup.61, and R.sup.61
is alkyl which is unsubstituted. In another embodiment of Formula
(IV), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is
substituted with N(R.sup.57).sub.2, R.sup.57 is R.sup.60, and
R.sup.60 is cycloalkyl which is unsubstituted. In another
embodiment of Formula (IV), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
NHR.sup.57. In another embodiment of Formula (IV), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
NHR.sup.57 In another embodiment of Formula (IV), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
NHR.sup.57, R.sup.57 is R.sup.60, and R.sup.60 is heterocycloalkyl
which is unsubstituted.
[1652] In one embodiment of Formula (IV), R.sup.1 is R.sup.4; and
R.sup.4 is heterocycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(IV), R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein
the heterocycloalkyl ring is substituted as defined herein. In
another embodiment of Formula (IV), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
substituted with R.sup.57. In another embodiment of Formula (IV),
R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein the
heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or
piperizinyl; and wherein the heterocycloalkyl ring is substituted
with one or two or three or four or five more R.sup.57,
SO.sub.2R.sup.57, or OH, and R.sup.57 is R.sup.60 or R.sup.61. In
another embodiment of Formula (IV), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted R.sup.57; and R.sup.57 is R.sup.60or R.sup.61; R.sup.60
is cycloalkyl or heterocycloalkyl; and R.sup.61 is alkyl. In
another embodiment of Formula (IV), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl; and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60 is
heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl
or oxetanyl. In another embodiment of Formula (IV), R.sup.1 is
R.sup.4; R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl
ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and
wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl;
ring is substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60
is cycloalkyl wherein the cycloalkyl is cyclopropyl or cyclopentyl.
In another embodiment of Formula (II), R.sup.1 is R.sup.4; R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57 is R.sup.61; and R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl. In another
embodiment of Formula (IV), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl, and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57 is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl; wherein the
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl are unsubstituted or
substituted.
[1653] In one embodiment of Formula (IV), R.sup.1 is R.sup.5; and
R.sup.5 is alkyl which is unsubstituted or substituted. In one
embodiment of Formula (IV), R.sup.1 is R.sup.5; and R.sup.5 is
alkyl which is unsubstituted or substituted with R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, or OH.
[1654] In one embodiment a Formula (IV), R.sup.7 is R.sup.10 or
R.sup.11 which are unsubstituted or substituted as defined herein.
In another embodiment of Formula (IV), R.sup.7 is R.sup.10 which is
unsubstituted or substituted as defined herein. In another
embodiment of Formula (IV), R.sup.7 is R.sup.11 which is
unsubstituted or substituted as defined herein.
[1655] In one embodunent ot Formula (IV), R.sup.10 is cycloalkyl or
heterocycloalkyl which are unsubstituted or substituted as defined
herein. In another embodiment of Formula (IV), R.sup.10 is
heterocycloalkyl which is unsubstituted or substituted as defined
herein. In another embodiment of Formula (IV), R.sup.10 is
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,
piperidinyl, piperizinyl, or pyrrolidinyl, which are unsubstituted
or substituted as defined herein. In another embodiment of Formula
(IV), R.sup.10 is tetrahydropyranyl, which is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(IV), R.sup.10 is morpholinyl, which is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(IV), R.sup.10 is cycloalkyl which is unsubstituted or substituted
as defined herein. In another embodiment of Formula (IV), R.sup.10
is cyclohexyl which is unsubstituted or substituted as defined
herein.
[1656] In one embodiment of Formula (IV), R.sup.11 is alkyl which
is unsubstituted. In another embodiment of Formula (IV), R.sup.11
is methyl, which is unsubstituted or substituted as defined herein.
In another embodiment of Formula (IV), R.sup.11 is alkyl, which is
substituted as defined herein. In another embodiment of Formula
(IV), R.sup.11 is alkyl, which is substituted with OR.sup.12,
R.sup.12 is R.sup.16, and R.sup.16 is alkyl.
[1657] Still another embodiment pertains to compounds having
Formula (IV), which are [1658]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dim-
ethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-y-
l)oxy)benzamide; [1659]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide; [1660]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-
-1-yl)-2-((3methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino-
)-3-nitrophenyl)sulfonyl)benzamide; [1661]
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1-
H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulf-
onyl)benzamide; [1662] tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)a-
mino]carbonyl}phenoxy)-1H-indole-1-carboxylate; [1663]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1664]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyr-
an-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide; [1665]
2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(-
4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(-
4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1666]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfony-
l]-2-({3-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide;
[1667]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)ami-
no]phenyl}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide;
[1668]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopipe-
razin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide; [1669]
2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1670]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nit-
rophenyl}sulfonyl)benzamide; [1671]
2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide; [1672]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(-
tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[1673]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methyl-
piperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; and
therapeutically acceptable salts, prodrugs, salts of prodrugs and
metabolites thereof.
[1674] In another aspect, the present invention provides compounds
of Formula (V)
##STR00010##
and therapeutically acceptable salts, prodrugs, salts of prodrugs
and metabolites thereof, wherein A.sup.1, B.sup.1, D.sup.1,
E.sup.1, Y.sup.1, Z.sup.2, L.sup.1, and Z.sup.3 are as described
herein for Formula (I), n is 0, 1, 2, or 3; describing the number
of additional substituents on R.sup.26, and R.sup.100 is as
described for substituents on R.sup.26, and at least one of
R.sup.103 or R.sup.104 is a substituent as described for
substituents on R.sup.42 and R.sup.42A , and the remainder are
H.
[1675] In one embodiment of Formula (V), R.sup.104 is NH.sub.2. In
another embodiment of Formula (V), R.sup.104 is NH.sub.2.
[1676] In another embodiment of Formula (V), A.sup.1 is N. In
another embodiment of Formula (V), A.sup.1 is C(A.sup.2). In
another embodiment of Formula (V), A.sup.1 is C(A.sup.2); and
A.sup.2 is H.
[1677] In one embodiment of Formula (V), B.sup.1 is OR.sup.1, or
NHR.sup.1. In another embodiment of Formula (V), A.sup.1 is
C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1. In another
embodiment of Formula (V), A.sup.1 is C(A.sup.2); A.sup.2 is H; and
B.sup.1 is OR.sup.1.
[1678] In one embodiment of Formula (V), D.sup.1 is H. In another
embodiment of Formula (V), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; D.sup.1 is H. In another embodiment of
Formula (V), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
OR.sup.1; D.sup.1 is H.
[1679] In one embodiment of Formula (V), E.sup.1 is H. In another
embodiment of Formula (V), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; D.sup.1 is H; and E.sup.1 is H. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is OR.sup.1; D.sup.1 is H; and E.sup.1 is H.
[1680] In one embodiment of Formula (V), Y.sup.1is H, CN, NO.sub.2,
F, Cl, Br, CF.sub.3, R.sup.17, or SO.sub.2R.sup.17. In another
embodiment of Formula (V), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (V), Y.sup.1 is Cl. In another embodiment of
Formula (V), Y.sup.1 is SO.sub.2R.sup.17; wherein R.sup.17 is as
defined herein. In another embodiment of Formula (V), Y.sup.1 is
SO.sub.2R.sup.17; wherein R.sup.17 is alkyl. In another embodiment
of Formula (V), Y.sup.1 is R.sup.17; wherein R.sup.17 is alkynyl.
In another embodiment of Formula (V), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is NO.sub.2 or SO.sub.2R.sup.17; wherein R.sup.17 is alkyl
or alkynyl. In another embodiment of Formula (V), A.sup.1 is
C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H;
E.sup.1 is H; and Y.sup.1 is NO.sub.2. In another embodiment of
Formula (V), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and Y.sup.1 is
SO.sub.2R.sup.17, wherein R.sup.17 is alkyl substituted with three
F. In another embodiment of Formula (V), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is OR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is Cl.
[1681] In one embodiment of Formula (V), R.sup.1 is R.sup.4 or
R.sup.5. In one embodiment of Formula (V), R.sup.1 is R.sup.4. In
one embodiment of Formula (V), R.sup.1 is R.sup.5. In one
embodiment of Formula (V), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (V),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl. In one embodiment of
Formula (V), R.sup.1 is R.sup.4; and R.sup.4 is
heterocycloalkyl.
[1682] In one embodiment of Formula (V), R.sup.1 is R.sup.4; and
R.sup.4 is cycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(V), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is substituted as defined herein. In another
embodiment of Formula (V), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
R.sup.57, NHR.sup.57, or N(R.sup.57).sub.2. In another embodiment
of Formula (V), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl;
wherein the cycloalkyl ring is cyclohexyl; and wherein the
cyclohexyl ring is substituted with R.sup.57; and R.sup.57 is
R.sup.60. In another embodiment of Formula (V), R.sup.1 is R.sup.4;
R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is cyclohexyl;
and wherein the cyclohexyl ring is substituted with R.sup.57; and
R.sup.57 is R.sup.60; and R.sup.60 is heterocycloalkyl. In another
embodiment of Formula (V), R.sup.1 is R.sup.4; R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is cyclohexyl; and wherein
the cyclohexyl ring is substituted with R.sup.57; and R.sup.57 is
R.sup.60; R.sup.60 is heterocycloalkyl; wherein the
heterocycloalkyl ring is morpholinyl or piperazinyl. In another
embodiment of Formula (V), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cyeloalkyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (V), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (V), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cycloalkyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2, R.sup.57 is R.sup.61, and R.sup.61 is alkyl
which is unsubstituted. In another embodiment of Formula (V),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is
substituted with N(R.sup.57).sub.2, R.sup.57 is R.sup.60, and
R.sup.60 is cycloalkyl which is ansubstituted. In another
embodiment of Formula (V), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
NHR.sup.57. In another embodiment of Formula (V), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
NHR.sup.57. In another embodiment of Formula (V), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2, R.sup.57 is R.sup.60, and R.sup.60 is
heterocycloalkyl which is unsubstituted.
[1683] In one embodiment of Formula (V), R.sup.1 is R.sup.4; and
R.sup.4 is heterocycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(V), R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein
the heterocycloalkyl ring is substituted as defined herein. In
another embodiment of Formula (V), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
substituted with R.sup.57. In another embodiment of Formula (V),
R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein the
heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or
piperizinyl; and wherein the heterocycloalkyl ring is substituted
with one or two or three or four or five more R.sup.57,
SO.sub.2R.sup.57, or OH, and R.sup.57 is R.sup.60 or R.sup.61. In
another embodiment of Formula (V), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted R.sup.57; R.sup.57 is R.sup.60or R.sup.61; R.sup.60 is
cycloalkyl or heterocycloalkyl; and R.sup.61 is alkyl. In another
embodiment of Formula (V), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl; and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60 is
heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl
or oxetanyl. In another embodiment of Formula (V), R.sup.1 is
R.sup.4; R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl
ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and
wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl;
ring is substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60
is cycloalkyl, wherein the cycloalkyl is cyclopropyl or
cyclopentyl. In another embodiment of Formula (V), R.sup.1 is
R.sup.4; R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl
ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and
wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl
ring is substituted with one or two or three or four or five
R.sup.57; R.sup.57 is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl. In another
embodiment of Formula (V), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl or piperizinyl, and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57 is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl; wherein the
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl are unsubstituted or
substituted.
[1684] In one embodiment of Formula (V), R.sup.1 is R.sup.5; and
R.sup.5 is alkyl which is unsubstituted or substituted. In one
embodiment of Formula (V), R.sup.1 is R.sup.5; and R.sup.5 is alkyl
which is unsubstituted or substituted with R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, or OH.
[1685] In one embodiment a Formula (V), R.sup.7 is R.sup.10 or
R.sup.11 which are unsubstituted or substituted as defined herein.
In another embodiment of Formula (V), R.sup.7 is R.sup.10 which is
unsubstituted or substituted as defined herein. In another
embodiment of Formula (V), R.sup.7 is R.sup.11 which is
unsubstituted or substituted as defined herein.
[1686] In one embodunent ot Formula (V), R.sup.10 is cycloalkyl or
heterocycloalkyl which are unsubstituted or substituted as defined
herein. In another embodiment of Formula (V), R.sup.10 is
heterocycloalkyl which is unsubstituted or substituted as defined
herein. In another embodiment of Formula (V), R.sup.10 is
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,
piperidinyl, piperizinyl, or pyrrolidinyl, which are unsubstituted
or substituted as defined herein. In another embodiment of Formula
(V), R.sup.10 is tetrahydropyranyl, which is unsubstituted or
substituted as defined herein. In another embootment at Formula
(V), R.sup.10 is morpholinyl, which is unsubstituted or substituted
as defined herein. In another embodiment of Formula (V), R.sup.10
is cycloalkyl which is unsubstituted or substituted as defined
herein. In another embodiment of Formula (V), R.sup.10 is
cyclohexyl which is unsubstituted or substituted as defined
herein.
[1687] In one embodiment of Formula (V), R.sup.11 is aikyl which is
unsubstituted. In another embodiment of Formula (V), R.sup.11 is
methyl, which is unsubstituted or substituted as defined herein. In
another embodiment of Formula (V), R.sup.11 is alkyl, which is
substituted as defined herein. In another embodiment of Formula
(V), R.sup.11 is alkyl, which is substituted with OR.sup.12,
R.sup.12 is R.sup.16, and R.sup.16 is alkyl.
[1688] Still another embodiment pertains to compounds having
Formula (V), which are [1689]
2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylp-
iperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1690]
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1691]
tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [1692]
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-piperidin-4-yl)amino]phe-
nyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [1693]
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [1694]
2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1695]
2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [1696] tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate; [1697]
2-[(5-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [1698] tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}su-
lfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [1699]
2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4--
ylmethyl)amino]phenyl}sulfonyl)benzamide; [1700]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(6-hydroxpyridin-3-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-
-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1701]
2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pr-
yan-4ylmethyl)amino]phenyl}sulfonyl)benzamide; [1702]
2-[(6-amino-5-fluoropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1703]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1704]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-y-
lcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1705]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-
-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [1706]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-y-
l)amino]-3-nitrophenyl}sulfonyl)benzamide; [1707]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy-
)-3-nitrophenyl]sulfonyl}benzamide; [1708]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4methoxycycloh-
exyl)methyl ]amino}-3-nitrophenyl)sulfonyl]benzamide; [1709]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl-
)amino]-3-nitrophenyl}sulfonyl)benzamide; [1710]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropy-
l)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[1711]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-
-pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamid-
e; [1712]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorot-
etrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[1713]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahy-
dro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1714]
2-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-
sulfonyl)amino]carbonyl}phenoxy)nicotinamide; [1715]
2-amino-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahyd-
ro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1716]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroe-
thyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1717]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;
[1718]
2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1719]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetr-
ahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1720]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidi-
n-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide; [1721]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl-
)amino]-3-nitrophenyl}sulfonyl)benzamide; [1722]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide; [1723]
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)-
amino]-3-nitrophenyl}sulfonyl)benzamide; [1724]
2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-
-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1725]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2-
H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1726]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-yl-
piperidin-4-yl)amino]phenyl}sulfonyl)benzamide; [1727]
2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-di-
methylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1728]
2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahyd-
ro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1729]
Trans-2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycycloh-
exyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1730]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorphol-
in-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1731]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyr-
rolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1732]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro--
1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benza-
mide; [1733] tert-butyl
6bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]ph-
enyl}sulfonyl)amino]carbonyl}phenyoxy)pyridin-2-ylcarbamate; [1734]
tert-butyl
-4-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazi-
n-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4yl)methylamino)phenylsulfonylc-
arbamoyl)phenoxy)pyridine-2,6-diyldicarbamate; [1735]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-{[6-(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydr-
o-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1736]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4--
(methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1737]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(t-
etrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[1738]
2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4-
,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetra-
hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1739]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluor-
omethyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide-
; [1740]
2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1741]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-[(2,6-diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyra-
n-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1742]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H--
pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide; [1743]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(f-
luoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide;
[1744] tert-butyl
5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate; [1745]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfony-
l)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide; [1746]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)-
methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1747]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimet-
hyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetra-
hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1748]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofur-
an-3-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1749]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro-
-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,-
6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)benzamide;
[1750]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3--
[2-fluoro-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)pip-
erazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)benzamide; [1751]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isoprop-
yl-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(t-
etrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;
[1752]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylgly-
cyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chl-
orophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[1753]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluo-
ro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}ben-
zamide; [1754]
2-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1755]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohex-
yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide; [1756]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4'-chloro-3-[2-(dimethylamin-
o)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide; [1757]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-
-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{-
[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)b-
enzamide; [1758]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluo-
roethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;
[1759]
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophen-
yl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyano-
cyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;
[1760]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluolro-6-[(4-fl-
uorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;
[1761]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difl-
uoroethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2--
(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benz-
amide; [1762]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro-
-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide; [1763]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[(6-({4-fluoro-1-[2-fluoro-
-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin--
3-yl]sulfonyl}benzamide; [1764]
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4-difluorocycloh-
exyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide; and
therapeutically acceptable salts, prodrugs, salts of prodrugs and
metabolites thereof.
[1765] In another aspect, the present invention provides compounds
of Formula (VI)
##STR00011##
and therapeutically acceptable salts, prodrugs, salts of prodrugs
and metabolites thereof, wherein A.sup.1, B.sup.1, D.sup.1,
E.sup.1, Y.sup.1, Z.sup.2, L.sup.1, and Z.sup.3 are as described
herein for Formula (I), n is 0, 1, 2, or 3; describing the number
of additional substituents on R.sup.26, and R.sup.100 is as
described for substituents on R.sup.26, and at least one R.sup.102
is a substituent as described for substituents on R.sup.42 and
R.sup.42A , and the remainder are H.
[1766] In another embodiment of Formula (VI), A.sup.1 is N. In
another embodiment of Formula (VI), A.sup.1 is C(A.sup.2). In
another embodiment of Formula (VI), A.sup.1 is C(A.sup.2); and
A.sup.2 is H.
[1767] In one embodiment of Formula (VI), B.sup.1 is OR.sup.1, or
NHR.sup.1. In another embodiment of Formula (VI), A.sup.1 is
C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1. In another
embodiment of Formula (VI), A.sup.1 is C(A.sup.2); A.sup.2 is H;
and B.sup.1 is OR.sup.1.
[1768] In one embodiment of Formula (VI), D.sup.1 is H. In another
embodiment of Formula (VI), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; D.sup.1 is H. In another embodiment of
Formula (VI), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
OR.sup.1; D.sup.1 is H.
[1769] In one embodiment of Formula (VI), E.sup.1 is H. In another
embodiment of Formula (VI), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is NHR.sup.1; D.sup.1 is H; and E.sup.1 is H. In another
embodiment of Formula (I), A.sup.1 is C(A.sup.2); A.sup.2 is H;
B.sup.1 is OR.sup.1; D.sup.1 is H; and E.sup.1 is H.
[1770] In one embodiment of Formula (VI), Y.sup.1is H, CN,
NO.sub.2, F, Cl, Br, CF.sub.3, R.sup.17, or SO.sub.2R.sup.17. In
another embodiment of Formula (VI), Y.sup.1 is NO.sub.2. In another
embodiment of Formula (VI), Y.sup.1 is Cl. In another embodiment of
Formula (VI), Y.sup.1 is SO.sub.2R.sup.17; wherein R.sup.17 is as
defined herein. In another embodiment of Formula (VI), Y.sup.1 is
SO.sub.2R.sup.17; wherein R.sup.17 is alkyl. In another embodiment
of Formula (VI), Y.sup.1 is R.sup.17; wherein R.sup.17 is alkynyl.
In another embodiment of Formula (VI), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is NO.sub.2 or SO.sub.2R.sup.17; wherein R.sup.17 is alkyl
or alkynyl. In another embodiment of Formula (VI), A.sup.1 is
C(A.sup.2); A.sup.2 is H; B.sup.1 is NHR.sup.1; D.sup.1 is H;
E.sup.1 is H; and Y.sup.1 is NO.sub.2. In another embodiment of
Formula (VI), A.sup.1 is C(A.sup.2); A.sup.2 is H; B.sup.1 is
NHR.sup.1; D.sup.1 is H; E.sup.1 is H; and Y.sup.1 is
SO.sub.2R.sup.17, wherein R.sup.17is alkyl substituted with three
F. In another embodiment of Formula (VI), A.sup.1 is C(A.sup.2);
A.sup.2 is H; B.sup.1 is OR.sup.1; D.sup.1 is H; E.sup.1 is H; and
Y.sup.1 is Cl.
[1771] In one embodiment of Formula (VI), R.sup.1 is R.sup.4 or
R.sup.5. In one embodiment of Formula (VI), R.sup.1 is R.sup.4. In
one embodiment of Formula (VI), R.sup.1 is R.sup.5. In one
embodiment of Formula (VI), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl, or heterocycloalkyl. In one embodiment of Formula (VI),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl. In one embodiment of
Formula (VI), R.sup.1 is R.sup.4; and R.sup.4 is
heterocycloalkyl.
[1772] In one embodiment of Formula (VI), R.sup.1 is R.sup.4; and
R.sup.4 is cycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(VI), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is substituted as defined herein. In another
embodiment of Formula (VI), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
R.sup.57, NHR.sup.57, or N(R.sup.57).sub.2. In another embodiment
of Formula (VI), R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl;
wherein the cycloalkyl ring is cyclohexyl; and wherein the
cyclohexyl ring is substituted with R.sup.57; and R.sup.57 is
R.sup.60. In another embodiment of Formula (VI), R.sup.1 is
R.sup.4; R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
R.sup.57; and R.sup.57 is R.sup.60; and R.sup.60 is
heterocycloalkyl. In another embodiment of Formula (VI), R.sup.1 is
R.sup.4; R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
R.sup.57; and R.sup.57 is R.sup.60; R.sup.60 is heterocycloalkyl;
wherein the heterocycloalkyl ring is morpholinyl or piperazinyl. In
another embodiment of Formula (VI), R.sup.1 is R.sup.4; and R.sup.4
is cycloalkyl; wherein the cyeloalkyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (VI), R.sup.1
is R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring
is cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2. In another embodiment of Formula (VI), R.sup.1
is R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring
is cycloalkyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2, R.sup.57 is R.sup.61, and R.sup.61 is alkyl
which is unsubstituted. In another embodiment of Formula (VI),
R.sup.1 is R.sup.4; and R.sup.4 is cycloalkyl; wherein the
cycloalkyl ring is cyclohexyl; and wherein the cyclohexyl ring is
substituted with N(R.sup.57).sub.2, R.sup.57 is R.sup.60, and
R.sup.60 is cycloalkyl which is unsubstituted. In another
embodiment of Formula (VI), R.sup.1 is R.sup.4; and R.sup.4 is
cycloalkyl; wherein the cycloalkyl ring is substituted with
NHR.sup.57. In another embodiment of Formula (VI), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
NHR.sup.57. In another embodiment of Formula (VI), R.sup.1 is
R.sup.4; and R.sup.4 is cycloalkyl; wherein the cycloalkyl ring is
cyclohexyl; and wherein the cyclohexyl ring is substituted with
N(R.sup.57).sub.2, R.sup.57 is R.sup.60, and R.sup.60 is
heterocycloalkyl which is unsubstituted.
[1773] In one embodiment of Formula (VI), R.sup.1 is R.sup.4; and
R.sup.4 is heterocycloalkyl; wherein R.sup.4 is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(VI), R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein
the heterocycloalkyl ring is substituted as defined herein. In
another embodiment of Formula (VI), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
substituted with R.sup.57. In another embodiment of Formula (VI),
R.sup.1 is R.sup.4; and R.sup.4 is heterocycloalkyl; wherein the
heterocycloalkyl ring is piperidinyl, pyrrolinyl, morpholinyl, or
piperizinyl; and wherein the heterocycloalkyl ring is substituted
with one or two or three or four or five more R.sup.57,
SO.sub.2R.sup.57, or OH, and R.sup.57 is R.sup.60 or R.sup.61. In
another embodiment of Formula (VI), R.sup.1 is R.sup.4; and R.sup.4
is heterocycloalkyl; wherein the heterocycloalkyl ring is
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and wherein
the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted R.sup.57; R.sup.57 is R.sup.60or R.sup.61; R.sup.60 is
cycloalkyl or heterocycloalkyl; and R.sup.61 is alkyl. In another
embodiment of Formula (VI), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl, or piperizinyl; and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; ring is
substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60 is
heterocycloalkyl, wherein the heterocycloalkyl is tetrahydropyranyl
or oxetanyl. In another embodiment of Formula (VI), R.sup.1 is
R.sup.4; R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl
ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl; and
wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl;
ring is substituted with R.sup.57; R.sup.57 is R.sup.60; R.sup.60
is cycloalkyl, wherein the cycloalkyl is cyclopropyl or
cyclopentyl. In another embodiment of Formula (VI), R.sup.1 is
R.sup.4; R.sup.4 is heterocycloalkyl; wherein the heterocycloalkyl
ring is piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl, and
wherein the piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl
ring is substituted with one or two or three or four or five
R.sup.57; R.sup.57 is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl. In another
embodiment of Formula (VI), R.sup.1 is R.sup.4; R.sup.4 is
heterocycloalkyl; wherein the heterocycloalkyl ring is piperidinyl,
pyrrolinyl, morpholinyl or piperizinyl, and wherein the
piperidinyl, pyrrolinyl, morpholinyl, or piperizinyl ring is
substituted with one or two or three or four or five R.sup.57;
R.sup.57 is R.sup.61; R.sup.61 is alkyl; and the alkyl is
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl; wherein the
C.sub.1-alkyl, C.sub.2-alkyl, or C.sub.3-alkyl are unsubstituted or
substituted.
[1774] In one embodiment of Formula (VI), R.sup.1 is R.sup.5; and
R.sup.5 is alkyl which is unsubstituted or substituted. In one
embodiment of Formula (VI), R.sup.1 is R.sup.5; and R.sup.5 is
alkyl which is unsubstituted or substituted with R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, or OH.
[1775] In one embodiment a Formula (VI), R.sup.7 is R.sup.10 or
R.sup.11 which are unsubstituted or substituted as defined herein.
In another embodiment of Formula (VI), R.sup.7 is R.sup.10 which is
unsubstituted or substituted as defined herein. In another
embodiment of Formula (VI), R.sup.7 is R.sup.11 which is
unsubstituted or substituted as defined herein.
[1776] In one embodunent ot Formula (VI), R.sup.10 is cycloalkyl or
heterocycloalkyl which are unsubstituted or substituted as defined
herein. In another embodiment of Formula (VI), R.sup.10 is
heterocycloalkyl which is unsubstituted or substituted as defined
herein. In another embodiment of Formula (VI), R.sup.10 is
tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, dioxanyl,
piperidinyl, piperizinyl, or pyrrolidinyl, which are unsubstituted
or substituted as defined herein. In another embodiment of Formula
(VI), R.sup.10 is tetrahydropyranyl, which is unsubstituted or
substituted as defined herein. In another embootment at Formula
(VI), R.sup.10 is morpholinyl, which is unsubstituted or
substituted as defined herein. In another embodiment of Formula
(VI), R.sup.10 is cycloalkyl which is unsubstituted or substituted
as defined herein. In another embodiment of Formula (VI), R.sup.10
is cyclohexyl which is unsubstituted or substituted as defined
herein.
[1777] In one embodiment of Formula (VI), R.sup.11 is alkyl which
is unsubstituted. In another embodiment of Formula (VI), R.sup.11
is methyl, which is unsubstituted or substituted as defined herein.
In another embodiment of Formula (VI), R.sup.11 is alkyl, which is
substituted as defined herein. In another embodiment of Formula
(VI), R.sup.11 is alkyl, which is substituted with OR.sup.12,
R.sup.12 is R.sup.16, and R.sup.16 is alkyl.
[1778] Still another embodiment pertains to compounds having
Formula (VI), which are
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nit-
ro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide.
and therapeutically acceptable salts, prodrugs, salts of prodrugs
and metabolites thereof.
Pharmaceutical Compositions, Combination Therapies, Methods of
Treatment, and Administration
[1779] Another embodiment comprises pharmaceutical compositions
comprising a compound having Formula (I) and an excipient.
[1780] Still another embodiment comprises methods of treating
cancer in a mammal comprising administering thereto a
therapeutically acceptable amount of a compound having Formula
(I).
[1781] Still another embodiment comprises methods of treating
autoimmune disease in a mammal comprising administering thereto a
therapeutically acceptable amount of a compound having Formula
(I).
[1782] Still another embodiment pertains to compositions for
treating diseases during which antiapoptotic Bcl-2 proteins are
expressed, said compositions comprising an excipient and a
therapeutically effective amount of the compound having Formula
(I).
[1783] Still another embodiment pertains to methods of treating
disease in a patient during which antiapoptotic Bcl-2 proteins are
expressed, said methods comprising administering to the patient a
therapeutically effective amount of a compound having Formula
(I).
[1784] Still another embodiment pertains to compositions for
treating bladder cancer, brain cancer, breast cancer, bone marrow
cancer, cervical cancer, chronic lymphocytic leukemia, colorectal
cancer, esophageal cancer, hepatocellular cancer, lymphoblastic
leukemia, follicular lymphoma, lymphoid malignancies of T-cell or
B-cell origin, melanoma, myelogenous leukemia, myeloma, oral
cancer, ovarian cancer, non-small cell lung cancer, prostate
cancer, small cell lung cancer or spleen cancer, said compositions
comprising an excipient and a therapeutically effective amount of
the compound having Formula (I).
[1785] Still another embodiment pertains to methods of treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic lymphocytic leukemia, colorectal cancer,
esophageal cancer, hepatocellular cancer, lymphoblastic leukemia,
follicular lymphoma, lymphoid malignancies of T-cell or B-cell
origin, melanoma, myelogenous leukemia, myeloma, oral cancer,
ovarian cancer, non-small cell lung cancer, prostate cancer, small
cell lung cancer or spleen cancer in a patient, said methods
comprising administering to the patient a therapeutically effective
amount of a compound having Formula (I).
[1786] Still another embodiment pertains to compositions for
treating diseases during which are expressed anti-apoptotic Bcl-2
proteins, said compositions comprising an excipient and a
therapeutically effective amount of the compound having Formula (I)
and a therapeutically effective amount of one additional
therapeutic agent or more than one additional therapeutic
agent.
[1787] Still another embodiment pertains to methods of treating
disease in a patient during which are expressed anti-apoptotic
Bcl-2 proteins, said methods comprising administering to the
patient a therapeutically efftctive amount of a compound having
Formula (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
[1788] Still another embodiment pertains to compositions for
treating bladder cancer, brain cancer, brent cancer, bone marrow
cancer, cervical cancer, chronic lymphocytic leukemia, colorectal
cancer, esophageal cancer, hepatocellular cancer, lymphoblastic
leukemia, follicular lymphoma, lymphoid malignancies of T-cell or
B-cell origin, melanoma, myelogenous leukemia, myeloma, oral
cancer, ovarian cancer, non-small cell lung cancer, chronic
lymphocytic leukemia, myeloma, prostate cancer, small cell lung
cancer or spleen cancer, said compositions comprising an excipient
and a therapeutically effective amount of the compound having
Formula (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
[1789] Still another embodiment pertains to methods of treating
bladder cancer, brain cancer, breast cancer, bone marrow cancer,
cervical cancer, chronic lymphocytic leukemia, colorectal cancer,
esophageal cancer, hepatocellular cancer, lyruphoblastic leukemia,
follicular lymphoma, lymphoid malignancies of T-cell or B-cell
origin, melanoma, myelogenous leukemia, myeloma, oral cancer,
ovarian cancer, nonsmall cell lung cancer, chronic lymphocytic
leukemia, myeloma, prostate cancer, small cell lung cancer or
spleen cancer in a patient, said methods comprising administering
to the patient a therapeutically effective amount of the compound
having Formula (I) and a therapeutically effective amount of one
additional therapeutic agent or more than one additional
therapeutic agent.
[1790] Metabolites of compounds having Formula (I), produced by in
vitro or in vivo metabolic processes, may also have utility for
treating diseases associated with anti-apoptotic Bcl-2
proteins.
[1791] Certain precursor compounds which may be metabolized in
vitro or in vivo to form compounds having Formula (I) may also have
utility for treating diseases associated with expression of
anti-apoptotic Bcl-2 proteins.
[1792] Compounds having Formula (I) may exist as acid addition
salts, basic addition salts or zwitterions. Salts of the compounds
are prepared during isolation or following purification of the
compounds. Acid addition salts of the compounds are those derived
from the reaction of the compounds with an acid. For example, the
acetate, adipate, alginate, bicarbonate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsufonate, digluconate, formate, fumarate, glyccrophosphate,
glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, lactobionate, lactate, maleate,
mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,
nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate,
picrate, propionate, succinate, tartrate, thiocyannate,
trichloroacetic, trifluoroacetic, para-toluenesulfonate, and
undecanoate salts of the compounds and prodrugs thereof are
contemplated as being embraced by this invention. Basic addition
salts of the compounds are those derived from the reaction of the
compounds with the hydroxide, carbonate or bicarbonate of cations
such as lithium, sodium, potassium, calcium, and magnesium.
[1793] The compounds having Formula (I) may be administered, for
example, bucally, ophthalmically, orally, osmotically, parenterally
(intramuscularly, intraperitoneally intrasternally, intravenously,
subcutaneously), rectally, topically, transdermally or
vaginally.
[1794] Therapeutically effective amounts of compounds having
Formula (I) depend on the recipient of the treatment, the disorder
being treated and the severity thereof, the composition containing
the compound, the time of administration, the route of
administration, the duration of treatment, the compound potcncy,
its rate of clearance and whether or not another drug is
co-administered. The amount of a compound of this invention having
Formula (I) used to make a composition to be administered daily to
a patient in a single dose or in divided doses is from about 0.03
to about 200 mg/kg body weight. Single dose compositions contain
these amounts or a combination of submultiples thereof.
[1795] Compounds having Formula (I) may be administered with or
without an excipient. Excipients include, for example,
encapsulating materials or additives such as absorption
accelerators, antioxidants, binders, buffers, coating agents,
coloring agents, diluents, disintegrating agents, emulsifiers,
extenders, fillers, flavoring agents, humectants, lubricants,
perfumes, preservatIves, propellants, releasing agents, sterilizing
agents, sweeteners, solubilizers, wetting agents and mixtures
thereof.
[1796] Excipients for preparation of compositions comprising a
compound having Formula (I) to be administered orally in solid
dosage form include, for example, agar, alginic acid, aluminum
hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol,
carbomers, castor oil, cellulose, cellulose acetate, cocoa butter,
corn starch, corn oil, cottonseed oil, cross-povidone,
diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl
oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,
groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonic
saline, lactose, magnesium hydroxide, magnesium stearate, malt,
mannitol, monoglycerides, olive oil, peanut oil, potassium
phosphate salts, potato starch, povidone, propylene glycol,
Ringer's solution, safflower oil, sesame oil, sodium carboxymethyl
cellulose, sodium phosphate salts, sodium lauryl sulfate, sodium
sorbitol, soybean oil, stearic acids, steayl fumarate, sucrose,
surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol,
triglycerides, water, and mixtures thereof. Excipients for
preparation of compositions comprising a compound of this invention
having Formula (I) to be administered ophthalmically or orally in
liquid dosage forms include, for example, 1,3-butylene glycol,
castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of
sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive
oil, polyethylene glycols, propylene glycol, sesame oil, water and
mixtures thereof. Exciepients for preparation of compositions
comprising a compound of this invention having Formula (I) to be
administered osmotically include, for example,
chlorofluorohydrocarbons, ethanol, water and mixtures thereof.
Excipients for preparation of compositions comprising a compound of
this invention having Formula (I) to be administered parenterally
include, for example, 1,3-butanediol, castor oil, corn oil,
cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic
acid, olive oil, peanut oil, Ringer's solution, safflower oil,
sesame oil, soybean oil, U.S.P. or isotonic sodium chloride
solution, water and mixtures thereof. Excipients for preparation of
compositions comprising a compoand of this invention having Formula
(I) to be administered rectally or vaginally include, for example,
cocoa butter, polyethylene glycol, wax and mixtures thereof.
[1797] Compounds having Formula (I) are expected to be useful when
used with alkylating agents, angiogenesis inhibitors, antibodies,
antimetabolites, antimitotics, antiproliferatives, antivirals,
aurora kinase inhibitors, other apoptosis promoters (for example,
Bcl-xL, Bcl-w and Bfl-l) inhibitors, activators of death receptor
pathway, Bcr-Abl kinase ininbitors, BiTE (Bi-Specific T cell
Engager) antibodies, antibody drug conjugates, biologic response
modifiers, cyclin-dependent kinase inhibitors, cell cycle
inhibitors, cyclooxygenase-2 inhibitors, DVDs, 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, 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 knoase (Plk)
inhibitors, phosphoinositide-3 kinase (PI3K) inhibitors, proteosome
inhibitors, purine analogs, pyrimidine analogs, receptor tyrosine
kinase inhibirors, etinoids deltodis, plant alkaloids, small
inhibitory ribonucleic acids (siRNAs), topoisomerase inhibitors,
ubiqutin ligase inhibitors, and the like, and in combination with
one or more of these agents. BiTE antibodies are bi-specific
antibodies that direct T-cells to attack cancer cells by
simultaneously binding the two cells. The T-cells 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).
[1798] 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'-OCH3-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, us well as present on the 5'
and/or the 3'-ends of a given strand. For example, siRNAs targeting
MCl-1 have been shown to enhance the activity of ABT-263, (i.e.,
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) or
ABT-737 (i.e.,
N-(4-(4-(((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)ben-
zoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-
-nitrobenzenesulfonamide) in multiple tumor cell lines (Tse et. al,
Cancer Research 2008, 68(9), 3421 and references therein).
[1799] 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 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.
[1800] Alkylating agents include altretamine, AMD-473, AP-5280,
apaziquone, bendamustine, brostallicin, busulfan, carboquone,
carmustine (BCNU), chlorambucil, CLORETAZTINE.RTM. (laromustine,
VNP 40101M),l cyclophossphamide, decarbazine, estramustine,
foternustine, glufosfamide, ifosfamide, KW-2170, lormustine (CCNU),
mafosfamide, melphalan, mitobronitol, mitolactol, nimustine,
nitrogen mustard N-oxide, ranimustine, termozolormide, thiotepa,
TREANDA.RTM. (bendamustine), treosulfan, rofosfamide and the
like.
[1801] 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) inbibitors, thrombospondin analogs,
vascular endothelial growth factor receptor tyrosine kinase (VEGFR)
inhibitors and the like.
[1802] Anitmetabolites include ALIMTA.RTM. (pemetrexed disodium,
LY231514, MTA), 5-azacitidine, XELODA.RTM. (capecitabine)l armofur,
LEUSTAT.RTM. (cladribine), clofarabine, cytarabine, cytarabine
ocfosfate, cytosine arabinoside, decitabine, deferoxamine,
doxifluridine, eflornithine, EICAR
(5-ethynyl-1-.beta.-D-riboruranosylimidazole-4-carboxamide),
enocitabine, ethnylcytidien, 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.
[1803] Antivirals include ritonavir, hydroxychloroquine and the
like.
[1804] Aurora kinase inhibitors include ABT-348, AZD-1152,
MLN-8054, VX-680, Aurora A-specific kinase inhibitors, Auroroa
B-specific kinase inhibitors and pan-Aurora kinase inhibitors and
the like.
[1805] Bcl-2 protein inhibitors include AT-101 ((-)gossypol),
GENASENSE.RTM. (G3139 or oblimersen (Bcl-2 targeting antisense
oligonucieotide)), 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-nitrobenz-
enesulfonamide) (ABT-737),
N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)pip-
erazine-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methy-
l)propyl)amino)-3-((trifluoromethyl)sulfonyl0benzenesulfonamide
(ABT-263), GX-070 (obatoclax) and the like.
[1806] Bcr-Abl kinase inhibitors include DASATINIB.RTM.
(BMS-354825), GLEEVEC.RTM. (imatinib) and the like.
[1807] CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387,
CVT-2584, flabopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509,
seliciclib (CYC-202), R-roscovitine) ZK-304709 and the like.
[1808] COX2 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-2O16, S-2474, T-614, VIOXX.RTM. (rofecoxib) and the
like.
[1809] EGFR inhibitors include 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.
[1810] 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/2ncu bispecific antibody,
B7.her2IgG3, AS HER2 trifunctional bispecific antibodies, mAB
AR-209, mAB 2B-1 and the like.
[1811] Histone deacetylase inhibitors include depsipeptide,
LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA),
TSA, valproic acid and the like.
[1812] HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-10I,
CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953,
MYCOGRAB.RTM. (human recombinant antibody to HSP-90), NCS-683664,
PU24FC1, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the
like.
[1813] Inhibitors of inhibitors of apoptosis proteins include
HGS1029, GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.
[1814] Antibody drug conjugates include anti-CD22-MC-MMAF,
anti-CD22-MC-MMAE, anti-CD-22-MCC-DM1, CR-011-veMMAE, PSMA-ADC,
MEDI-547, SGN-19Am SGN-35, SGN-75 and the like.
[1815] Activators of death receptor pathway include TRAIL,
antibodies or other agents that target TRAIL or death neeptors
(e.g., DR4 and DR5) such us Apomab, conatumumab. ETR1-ST01,
GDC0145, (lexatumumab), HGS-1029, LBY-135. PRO-1762 and
trastuzumab.
[1816] Kinesin inhibitors include EG5 inhibitors such as AZD4877,
ARRY-520; CENPE inhibitors such as GSK923295A and the like.
[1817] JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and
INCB018424 and the like.
[1818] MEK inhibitors include; ARRY-142886, ARRY-438162 PD-325901,
PD-914059 and the like.
[1819] 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.
[1820] Non-steroidal antiinflammatory drugs include AMIGESIC
(salsalate), DOLOBID.RTM. (diflunisal), MOTRIN.RTM. (ibuprofen),
ORUDIS.RTM. (ketoprofen), RELAFEN.RTM. (nabumetone). FELDENE.RTM.
(piroxicam), ibuprofin cream, ALEVE.RTM. (naproxen) and
NAPROSYN.RTM. (naproxen), VOLTAREN (diclofenac), INDOCIN.RTM.
(indomethacin), CLINORIL.RTM. (sulindac), TOLECTIN.RTM. (tolmetin),
LODINE.RTM. (etodolac), TORADOL.RTM. (ketorolac), DAYPRO
(oxaprozin) and the like.
[1821] PDGFR inhibitors include C-451, CP-673, CP-838596 and the
like.
[1822] Platinum chemotherapeutics include cisplatin, ELOXATIN.RTM.
(oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN.RTM.
(carboplatin), satraplatin, picoplatin and the like.
[1823] Polo-like kinase inhibitors include BI-2536 and the
like.
[1824] Phosphoinositide-3 kinase (PI3K) inhibitors include
wortmannin, LY294002, XL-147, CAL-120, ONC-21, AEZS-127, EPT-45658,
PX-866, GDC-0941, BGT226, BEZ235, XL765 and the like.
[1825] Thrombospondin analogs include ABT-510, ABT-567, ABT-898,
TSP-1 and the like.
[1826] 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), and the like.
[1827] Antibiotics include intercalating antibiotics aclarubicin,
actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE.RTM.
(bleomycin), daunorabicin, CAELYX.RTM. or MYOCET.RTM. (liposomal
doxorubicin), elsamitracin, epirbucin, glarbuicin, ZAVEDOS.RTM.
(idarnbicin), mitomycin C, nemorubicin, neocarzinostatin,
peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin,
VALSTAR.RTM. (valrubicin), zinostatin and the like.
[1828] Topoisomerase inhibitors include aclarubicin,
9-aminocaraptothecin, 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.
[1829] Antibodies include AVASTIN.RTM. (bevacizumab), CD40-specific
antibodies, chTNT-1/B, denosumab, ERBITUX.RTM. (cetuximab),
HUMAX-CD4.RTM. (zanolimumab), IGFIR-specsfic antibodies,
lintuzumab, PANOREX.RTM. (edrecolomab), RENCAREX.RTM. (WX G250),
RITUXAN.RTM. (rituximab), ticilimumab, trastuzimab, CD.sup.20
antibodies types I and II, GA101, ofatumumab, ABT-806 (mAb-806),
ErbB3 specific antibodies, BSG2 specific antibodies, DLL4 specific
antibodies and C-met specific antibodies, and the like.
[1830] Hormonal therapies include ARIMIDEX.RTM. (anastrozole),
AROMASIN.RTM. (exemestane), arzoxifene, CASODEX.RTM.
(bicalutamide), CETROTIDE.RTM. (cetrorelix), degareix, 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. (sevelasmer carbonate),
lasofoxifene, leuprolide acetate, MEGACE.RTM. (megesterol),
MIFEPREX.RTM. (mifepristone), NILANDRON.TM. (nilutamide),
NOLVADEX.RTM. (tamoxifen citrate), PLENAXIS.TM. (abarelix),
prednisone, PROPECIA.RTM. (finasteride), ribostane, 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.
[1831] Deltoids and reinoids include seocalcitol (EB1089, CB1093),
lexacalcitrol (KH1060), fenretinide, PANRETIN.RTM. (aliretinoin,
ATGRAGEN.RTM. (liposomal tretinoin), TARGRETIN.RTM. (bexarotene),
LGD-1550 and the like.
[1832] PARP inhibitors include ABT-888 (veliparib), olaparib,
KU-59436, AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231
and the like.
[1833] Plant alkaloids include, but are not limited to, incristine,
vinglastine, vindesine, vinorelbine and the like.
[1834] Proteasome inhibitors include VELCADE.RTM. (bortezomib),
MG132, NPI-0052, PR-171, and the like.
[1835] Examples of immunologicals include interfeons and other
immune-enhancing agents. Interferons include interferon alpha,
interferon alpha-2a, interferon alpha-2b, interferon beta,
interferon gamm-1a, ACTIMMUNE.RTM. (interferon gamma-1b) or
interferon gamma-n1, combinations thereof and the like. Other
agents include ALFAFERONE.RTM. , INF-.alpha.), BAM-002 (oxidized
glutathione), BEROMUN.RTM. (tasonermin), BEXXAR.RTM. (tositumomab),
CAMPATH.RTM. (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4),
decarbazine, deniluekin, epratuzumab, GRANOCYTE.RTM. (lenograstim),
lentinan, leukocyte alpha interferon, imiquimod, MDX-010
(anti-CTLA-4), melanoma vaccine, miturnomab, molgramostim,
MYLOTARG.TM. (gemtuzumab ozogamicin), NEUPOGEN.RTM. (filgrastim),
Onco VAC-CL, OVAREX.RTM. (oregovomab), pemtumomab (Y-muHMFG1),
PROVENGE.RTM. (sipulcucci-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), ZAVALIN.RTM. (90Y-ibritumomab tiuxetan)
and the like.
[1836] 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.
[1837] 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.
[1838] Purine analogs include LANVIS.RTM. (thioguanine) and
PURI-NETHOL.RTM. (mercaptopurine).
[1839] 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.
[1840] Ubiqutin ligase inhibitors include MDM2 inhibitor, such as
nutlins, NEDD.sup.8 inhibitors such as MLN4924 and the like.
[1841] 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.
[1842] Additionally, compounds having Formula (I) may be combined
wit other chemotherapeutic agents such as ABRAXANE.RTM. (ABI-007),
ABT-100 (farnesyl transferase inhibitor), ADVEXIN.RTM. (Ad5CMV-p53
vaccine), ALTOCOR.RTM. or MEVACOR.RTM. (lovastatin), AMPLIGEN.RTM.
(poly I:poly C12U, a synthetic RNA), APTOSYN.RTM. (exisulind),
AREDIA.RTM. (pamidronic acid), arglabin, L-asparaginase, atamestane
(1-methyl-3,17-dione-androsta-1,4-diene), AVAGE.RTM. (tazarotene),
AVE-8062 (combreastatin derivative) BEC2 (mitumomab), cachectin or
cachexin (tumor necrosis factor), canvaxin (vaccine), CEAVAC.RTM.
(cancer vaccine), CELEUK.RTM. (celmoleukin), CEPLENE.RTM.
(histamine dihydrochloride), CERVARIX.RTM. (human papilloma virus
vaccine), CHOP.RTM. (C:CYTOXAN.RTM. (cyclophosphamide; H:
ADRIAMYCIN.RTM. (hydroxydoxorubicin); O: Vincristine
(ONCOVIN.RTM.); P: prednisone), CYPAT.TM. (cyproterone acetate),
combrestatin A.sup.4P, 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, dactinomycm, 5,6-dimethylxanthenone-4-acetic acid
(DMXAA), eniluracil, EVIZON.TM. (squalamine lactate),
DIMERICINE.RTM. (T4N5 liposome lotion), discodermolide, DX-8951f
(exatecan mesylate), cazastaurin, EPO906 (epithilone B),
GARDASIL.RTM. (quadrivalent human papilloma virus (Types 6, 11, 16,
18) recombinant vaccine), GASTRIMMUNE.RTM., GENASENSE.RTM., GMK
(ganglioside conjugatevaccine), GVAX.RTM. (prostate cancer
vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic
acid, IGM-101, IL-13-PE.sup.38, IL-13-PE38QQR (cintredekin
besudotox), IL-13-pseudomonas exotoxin, interferon-.alpha.,
interferon-.gamma., JUNOVAN.TM. or MEPACT.TM. (mifamurtide),
lonafamib, 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, ribimastat, 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.
(temozolormide), 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. (besentan), tretinoin (Retin-A), tetrandrine,
TRISENOX.RTM. (arsenic trioxide), VIRULIZIN.RTM., ukrain
(derivative of alkaloids from the greater celandine plant), vitaxin
(anti-alphavbeta3 anitbody), 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.
Data
[1843] Determination of the utility of compounds having Formula (I)
as binders to and inhibitors of anti-apoptotic Bcl-2 proteins was
performed using the Time-Resolved-Fluorescence Resonance Energy
Transfer (TR-FRET) Assay. Tb-anti-GST antibody was purchased from
Invitrogen (Catalog No. PV4216.
Probe Synthesis
[1844] All reagents were used as obtained from the vendor unless
otherwise specified. Peptide synthesis reagents including
diisopropylethylamine (DIEA), dichloromethane (DCM),
N-methylpyrrolidone (NMP),
2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate (HBTU), N-hydroxybenzotriazole (HOBt) and
piperidine were obtained from Applied Biosystems, Inc. (ABI),
Foster City, Calif. or American Bioanalytical, Natick, Mass.
Preloaded 9-Fluorenylmethyloxycarbonyl (Fmoc) amino acid cartridges
(Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH,
Fmoc-Phe-OH, Fmoc-Gly-OH, Fmoc-His(Trt)-OH, Fmoc-Ile-OH,
Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Asn(Trt)-OH,
Fmoc-Pro-OH, Fmoc-Gln(Trt)-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH,
Fmoc-Thr(tBu)-OH, Fmoc-Val-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH
were obtained from ABI or Anaspec, San Jose, Calif. The peptide
sysnthesis resin (Fmoc-Rink amide MBHA resin) and Fmoc-Lys(Mtt)-OH,
were obtained from Novabiochem, San Diego, Calif. Single-isomer
6-carboxyfluorescein succinimidyl ester (6-FAM-NHS) was obtained
from Anaspec. Trifluoroacetic acid (TFA) was obtained from Oakwood
Products, West Columbia, S.C. Thioanisole, phenol
triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) and
isopropanol were obtained from Aldrich Chemical Co., Milwaukee,
Wis., Matrix-assisted laser desorption ionization mass-spectra
(MALDI-MS) were recorded on an Applied Biosystems Voyager DE-PRO
MS). Electrospray Mass-spectra (ESI-MS) were recorded on Finnigan
SSQ7000 (Finnigan Corp., San Jose, Calif.) in both positive and
negative ion mode.
General Procedure for Solid-Phase Peptide Synthesis (SPPS)
[1845] peptides were synthesize with, at most 250 .mu.mol preloaded
Wang resin/vessel on an ABI 433A peptide synthesizer using 20
.mu.mol scale Fastmoc.TM. coupling cycles. Preloaded cartridges
containing 1 mmol standard Fmoc-amino acids, except for the
position of attachment of the fluorophore, where 1 mmol
Fmoc-Lys(Mtt)-OH was placed in the cartridge, were used with
conductivity feedback monitoring. N-terminal acetylation was
accomplished by using 1 mmol acetic acid in a cartridge under
standard coupling conditions.
Removal of 4-methyltrityl (Mtt) from Lysine
[1846] The resin from the syntesizer was washed thrice with
dichloromethane and kept wet. 150 mL of 95:4:1
dichloromethane:triisopropylsilane:trifluoroacetic acid was flowed
through the resin bed over 30 minutes. The mixture turned deep
yellow then faded to pale yellow. 100 mL of N,N-dimethylformamide
was flowed through the bed over 15 minutes. The resin was then
washed thrice with N,N-dimethylformamide and filtered. Ninhydrin
tests showed a strong signal for primary amine.
Resin Labeling with 6-Carboxyfluorescein-NHS (6-FAM-NHS)
[1847] The resin was treated with 2 equivalents 6-FAM-NHS in 1%
DIEA/N,N-dimethylformamide and stirred or shaken at ambient
temperature overnight. When complete, the resin was drained, washed
thrice with N, N-dimethylformamide, thrice with (1.times.DCM and
1.times.methanol) and dried to provide an orange resin that was
negative by ninhydrin test.
General Procedure for Cleavage and Deprotection of Resin-Bound
Peptide
[1848] Peptides were cleavfed from the resin by shaking for 3 hours
at ambient temperature in a cleavage cocktail consisting of 80%
TFA, 5% water, 5% thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1
mL/0.1 g resin). The resin was removed by filtration and rinsing
twice with TFA. The TFA was evaporated from the filtrates, and
product was precipitated with ether (10 mL/0.1 g resin), recovered
by centrifugation, washed twice with ether (10 mL/0.1 g resin) and
dried to give the crude peptide.
General Procedure for Purification of Peptides
[1849] The crude peptides were purified on a Gilson preparative
HPLC system running Unipoint.RTM. analysis software (Gilson, Inc.,
Middleton, Wis.) on a radial compression column containing two
25.times.100 mm segments packed with Delta-Pak.TM. C18 15 .mu.m
particles with 100 .ANG. pore size and eluted with one of the
gradient methods listed below. One to two milliliters of crude
peptide solution (10 mg/mL in 90% DMSO/water) was purified per
injection. The peaks containing the product(s) from each run were
pooled and lyophilized. All preparative runs were run at 20 mL/min
with eluents as buffer A: 0.1% TFA-water and bufferB:
acetonitrile.
General Procedure for Analytical HPLC
[1850] Analytical HPLC was performed on a Hewlett-Packard 1200
series system with a diode-array detector and a Hewlett-Packard
1046A fluorescence detector running HPLC 3D ChemStation software
version A.03.04 (Hewlett-Packard, Palo Alto, Calif.) on a
4.6.times.25 mm YMC column packed with ODS-AQ 5 .mu.m particles
with a 120 .ANG. pore size and eluted with one of the gradient
metnhods listed below after preequilibrating at the starting
conditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water and
buffer B: acetonitrile. The flow rate for all gradients was 1
mL/min.
F-Bak: Peptide Probe Acetyl-(SEQ ID NO: 1)GQVGRQLAIIGDK(6-FAM)-(SEQ
ID NO: 2)INR-NH.sub.2
[1851] Fmoc-Rink amide MBHA resin was extended using the general
peptide synthesis procedure to provide the protected resin-bound
peptide (1.020 g). The Mtt group was removed, labeled with
6-FAM-NHS and cleaved and deprotected as described hereinabove to
provide the crdue product as an orange solid (0.37 g). This product
was purified by RP-HPLC. Fractions across the main peak were tested
bgy analytical RP-HPLC, and the pure fractions were isolated and
lyophilized, with the major peak providing the title compound
(0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1
[(M+H).sup.+].
Alternative Synthesis of Peptide Probe F-Bak: Acetyl-(SEQ ID NO:
1)GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO:2)INR-NH.sub.2
[1852] The protected peptide was assembled on 0.25 mmol fmoc-Rink
amide MBHA resin (Novabiochem) on an Applied Biosystems 433A
automated peptide synthesizer running Fastmoc.TM. coupling cycles
using pre-loaded 1 mmol amino acid cartridges, except for the
fluorescein(6FAM)-labeled lysine, where 1 mmol
Fmoc-Lys(4-methyltrityl) was weighed into the cartridge. The
N-terminal acetyl group was incorporated by putting 1 mmol acetic
acid in a cartridge and coupling as described hereinabove.
Selective removal of the 4 -methyltrityl group was accomplished
with a solution of 95:4:1 DCM:TIS:TFA (v/v/v) flowed through the
resin over 15 minutes, followed by quenching with a flow of
dimethylformamide. Single-isomer 6-carboxyfluorescein-NHS was
reacted with the lysine side-chain in 1% DIEA in
N,N-dimethylformamide and confirmed complete by ninhydrin testing.
The peptide was cleaved from the resin and side-chains deprotected
by treating with 80:5:5:5:2.5:2.5
TFA/water/phenol/thioanisole/triisopropylsilane:
3,6/dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide
was recovered by precipitation with diethyl ether. The crude
peptide was purified by reverse-phase high perforntance liquid
chromatography, and its purity and identity were confirmed by
analytical reverse-phase high/performance liquid chromatography and
matrix.assisted laser-desorption mass spectrometry (m/z 2137.1
((M+H).sup.+)).
Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)
Assay
[1853] Representative compounds were serially diluted in dimethyl
sulfoxide (DM5O) starting at 50 .mu.M (2.times. starting
concentration; 10% DMSO) and 10 .mu.L were transferred into a
384-well plate. Then 10 .mu.L of a protein/probe/antibody mix was
added to each well at final concentrations listed in TABLE 1. The
samples are then mixed on a shaker for 1 minute and incubated for
an additional 3 hours at room temperature. For each assay, the
probe antibody and protein/probe/antibody were included on each
assay plate as negative and positive controls, respectively.
Fluorescence was measured on the Envision (Perkin Elmer) using a
340/35 nm excitation filter and 520/525 (F-Bak peptide) and 495/510
nm (Tb-labeled anti-Histidine antibody) emission filtes. Inhibition
constants (Ki) are shown in TABLE 2 below and were determined using
Wang's equation (Wang Z.-X An Exact Mathematical Expression For
Describing Competitive Binding Of Two Different Ligands To A
Protein Molecule, FEBS Lett. 1995, 360:111-4).
TABLE-US-00001 TABLE 1 Protein, Probe And Antibody Used For TR-FRET
Assays Pro- Anti- Pro- tein Probe Anti- body tein Probe (nM) (nM)
body (nM) GST- F-Bak Peptide 1 100 Tb- 1 Bcl-2 Probe Acetyl-(SEQ
anti- ID NO: 1 GST GQVGRQLAIIGDK(6- FAM) SEQ ID NO: 2 INR-amide)
6-FAM = 6-carboxyfluorescein.; Tb = terbium; GST = glutathione
S-transferase
[1854] The samples were then mixed on a shaker for 1 minute and
incubated for an additional 3 hours at room temperature. For each
assay, the probe/antibody and protein/probe/antibody were included
on each assay plate as negative and positive controls,
respectively. Fluorescence was measured on the Envision (Perkin
Elmer) using a 340/35 nm excitation filter and 520/525 (F-Bak
peptide) and 495/510 nm (Tb-labeled anti-Histidine antibody)
emission filters.
[1855] Inhibition constants (K.sub.i) for compounds according to
the invention are shown in TABLE 2 below. Where the K.sub.i for a
compound is represented as ">" (greater than) a certain
numerical value, it is intended to mean that the binding affinity
value is greater than the limits of detection of the assay used.
Where the K.sub.i for a compound is represented as "<" (less
than) a certain numerical value, it is intended to mean that the
binding affinity value is lower than the limit of detection of the
assay used.
TABLE-US-00002 TABLE 2 TR-FRET Bcl-2 Binding Ki (.mu.M) TR-FRET
Example Binding: Bcl-2 No. Ki (.mu.M) 1 0.008354 2 0.031467 3
0.000827 4 0.002474 5 0.000746 6 0.000787 7 0.002592 8 0.003451 9
0.000754 10 0.00072 11 0.000171 12 0.000331 13 0.001621 14 0.000079
15 0.000586 16 0.003039 17 0.005578 18 0.002487 19 0.001679 20
0.003965 21 0.014054 22 0.005455 23 0.00827 24 0.014984 25 0.001501
26 0.000511 27 0.002212 28 0.001326 29 0.000903 30 0.000071 31
0.002007 32 0.001584 33 0.007173 34 0.000049 35 0.000022 36 0.00007
37 0.000005 38 0.000013 39 0.000019 40 0.000019 41 0.000027 42
0.00003 43 0.000034 44 0.000036 45 0.000047 46 0.000047 47 0.00005
48 0.000053 49 0.000062 50 0.000062 51 0.000066 52 0.000072 53
0.000077 54 0.000082 55 0.00009 56 0.000106 57 0.000147 58 0.000155
59 0.000184 60 0.000187 61 0.00022 62 0.000227 63 0.000438 64
0.000458 65 0.00052 66 0.000592 67 0.000807 68 0.005934 69 0.008246
70 0.020421 71 0.031597 72 0.031666 73 0.03226 74 0.18943 75
0.076832 76 0.2395 77 0.45052 78 >1.195000 79 0.099826 80
0.14872 81 0.031048 82 0.51156 83 >1.195000 84 0.013654 85
0.005626 86 0.005263 87 0.26427 88 >1.195000 89 0.006111 90
0.010626 91 >1.195000 92 0.002569 93 0.01683 94 0.56121 95
0.000428 96 >1.195000 97 0.14659 98 0.000959 99 0.071364 100
0.11299 101 0.6695 102 0.043518 103 0.006755 104 0.002321 105
0.003567 106 0.21452 107 0.000331 108 nd 109 0.000237 110 0.000039
111 0.01744 112 0.000042 113 0.000032 114 0.000036 115 0.000042 116
0.000123 117 0.000072 118 0.000151 119 0.000156 120 0.000214 121
0.000081 122 <0.000001 123 0.00011 124 0.000033 125 0.000075 126
0.000068 127 0.00003 128 0.000064 129 0.000107 130 0.000067 131
0.000066 132 0.000211 133 0.000055 134 0.000181 135 0.000068 136
0.000177 137 0.000021 138 0.000016 139 0.000125 140 0.000223 141
0.000482 142 0.000071 143 0.000053 144 0.000028 145 0.000057 146
0.00004 147 0.000127 148 0.000106 149 0.00003 150 0.000759 151
0.006935 152 0.018589 154 0.000012 155 0.000062 156 0.000035 157
0.00072 158 0.000619 159 0.000526 160 0.000028 161 0.000031 162
0.000048 163 0.000686 164 0.000056 165 0.00012 166 0.000082 167
0.001345 168 0.028343 169 0.000498 170 0.000036 171 0.000066 172
0.000549 173 0.000019 174 0.000037 175 0.000046 176 0.00024 177
0.000037 178 0.000175 179 0.000036 180 0.000112 181 0.000119 182
0.000172 183 0.00253 184 0.000155 185 0.000083 186 0.000035 187
0.000054 188 0.000073 189 0.000036 190 0.000077 191 0.000552 192
0.000024 193 0.000064 194 0.000317 195 0.000684 197 0.00022 198
<0.000010 199 0.000244 200 0.000081 201 0.000001 202 0.020043
203 0.000084 204 0.000075 205 0.000153 206 0.000037 207 0.000074
208 0.000261 209 <0.000010 210 0.00002 211 0.001338 212 0.000375
213 0.000031 214 0.000221 215 0.002954 216 0.000027 217 0.000174
218 0.000175 219 0.014857 220 0.000127 221 0.000227 222
>1.195000 223 0.010911 224 0.005603 225 0.003283 226 0.007586
227 0.000174 229 0.001085 230 0.002833 231 0.036946 232 0.001047
233 0.000037 234 0.000099 235 0.000039 236 0.000071 237 0.000197
238 0.000124 239 0.000105 240 0.000912 241 0.000141 242 0.000092
243 0.000069 244 0.001734 245 0.00048 246 0.000065
247 0.000039 248 0.000051 249 0.000168 250 0.000672 251 0.000435
252 0.001147 253 0.00005 254 0.000119 255 0.007013 256 0.000105 257
0.000097 258 0.000083 259 0.000165 260 0.011834 261 0.000186 262
0.000276 263 0.00011 264 0.000068 265 0.000363 266 0.00081 267
0.028426 268 0.000042 269 0.000469 270 >1.195000 271 0.001908
272 0.00124 273 0.000516 274 0.000936 275 0.000081 276 0.000199 277
0.000017 278 0.039967 279 0.001703 280 0.00755 281 0.000111 282
0.001012 283 0.01721 284 0.079348 285 0.000037 286 0.003181 287
0.000131 288 0.000017 289 <0.000010 290 0.000251 291 0.000273
292 0.000191 293 0.000233 294 0.000127 295 0.000077 296
<0.000010 297 <0.000010 298 0.000054 299 0.051687 300
0.013659 301 0.000113 302 <0.000010 303 0.000092 304 0.000822
305 0.000146 306 0.000671 307 0.000524 308 0.00004 309 0.00069 310
0.000155 311 0.000185 312 0.000531 313 <0.000010 314 0.003094
315 0.004555 316 0.000058 317 0.000205 318 <0.000010 319
0.000198 320 0.000028 321 0.000029 322 0.00453 323 0.003484 324
<0.000010 325 0.000183 326 0.000037 327 0.000212 328 0.000068
329 0.000108 330 <0.000010 331 0.000238 332 0.000034 333
0.000107 334 0.000197 335 <0.000010 336 <0.000010 337
0.000049 338 <0.000010 339 0.000057 340 0.000385 341 0.000017
342 0.003340 343 0.000009 344 0.000042 345 0.000005 346
<0.000010 347 0.000377 348 0.003779 349 0.000019 350
<0.000010 351 0.002843 352 0.000079 353 0.000016 354 0.000114
355 0.009567 356 0.002822 357 0.000177 358 0.000062 359 0.000110
360 0.000050 361 0.000015 362 0.000033 363 <0.000010 364
0.000014 365 0.004551 366 0.006052 367 0.000012 368 <0.000010
369 0.000014 370 <0.000010 371 <0.000010 372 0.014978 373
1.195000 374 0.005337 375 0.327810 376 0.057705 377 0.002323 378
<0.000010 379 0.017948 380 0.008274 381 0.000020 382 0.000114
383 0.427490 384 0.006233 385 0.049293 386 <0.000010 387
<0.000010 388 0.000020 389 <0.000010 390 <0.000010 391
<0.000010 392 <0.000010 393 <0.000010 394 0.000018 395
0.000077 396 <0.000010 397 0.000137 398 0.000175 399
<0.000010 400 0.000082 401 0.000035 402 0.000039 403 0.002136
404 0.000069 405 0.000354 406 0.000166 407 0.000946 408 0.001160
409 0.000686 410 <0.000010 411 0.021291
[1856] The inhibition at constant (K.sub.i) is the dissociation
constant at an enzyme-inhibitor complex or a protein/small molecule
complex, wherein the snanil molecule is inhibiting binding of one
protein to another protein. So a large K.sub.i value indicates a
low binding affinity and a small K.sub.i value indicates a high
binding affinity.
[1857] The data in TABLE 2 shows inhibition constants for the
inhibition of a Bak BH3 peptide probe to Bcl-2 and indicate that
compounds according to the invention have high binding affinities
for anti-apoptotic Bcl-2 protein. The compounds are therefore
expected to have utility in treatment of diseases during which
anti-apoptotic Bcl-2 protein is expressed.
[1858] It is expected that, because compounds having Formula I bind
to Bcl-2, they would also have utility as binders to anti-apoptotic
proteins having close structural homology to Bcl-2, such as, for
example, anti-apoptotic Bcl-2 , Bcl-X.sub.L, Mcl-1 and BFl-1/A1
proteins.
[1859] Involvement of Bcl-2 proteins in bladder cancer, brain
cancer, breast cancer, bone marrow cancer, cervical cancer, chronic
lymphocytic leukemia, colorectal cancer, esophageal cancer,
hepatocellular cancer, lymphoblastic leukemia, follicualr lymphoma,
lymphoid malignancies of T-cell or B-cell origin, melanoma,
myelogenous leukemia, myeloma, oral cancer, ovarian cancer,
non-small cell lung cancer, prostate cancer, small cell lung
cancer, chronic lymphocytic leukemia, myeloma, prostate cancer
splee cancer, and the like is described in commonly-owned PCT US
2004/36770, published as WO 2005/049593, and PCT US 2004/37911,
published as WO 2005/024636.
[1860] Involvement of Bcl-2 proteins in immune and autoimmune
diseases is described in Current Allergy and Asthma Reports 2003,
3, 378-384; British Journal of Haematology 2000, 110 (3), 584-90;
Blood 2000, 95 (4), 1283-92; and New England Journal of Medicine
2004, 351(14), 1409-1418.
[1861] Involvement of Bcl-2 proteins in arthritis is disclosed in
commonly-owned U.S. Provisional Patent Application Ser. No.
60/988,479.
[1862] Involvement of Bcl-2 proteins in bone marrow transplant
rejection is disclosed in commonly-owned U.S. patent application
Ser. No. 11/941,196.
[1863] Overexpression of Bcl-2 proteins correlates with resistance
to chemotherapy, clinical outcome, disease progression, overall
prognosis or a combination thereof in various cancers and disorders
of the immune system. Cancers include, but are not limited to,
hematologic and solid tumor types such as acoustic neuroma, acute
leukemia, acute lymphoblastic leukemia, acute myelogenous 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 (including estrogen-receptor
positive breast cancer), bronchogenic carcinoma, Burkitt's
lymphoma, cervical cancer, chondrosarcoma, chordoma,
choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia,
chronic myelocytic (granulocytic) leukemia, chronic myelogenous
leukemia, colon cancer, colorectal cancer, craniopharyngioma,
cystadenocarcinoma, 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, gastric carcinoma, germ cell testicular cancer,
gestational trophobalstic disease, glioblastoma, head and neck
cancer, heavy chain disease, hemangioblastoma, hepatoma,
hepatocellular cancer, hormone insensitive prostate cancer,
leiomyosarcoma, liposarcoma, lung cancer (including small cell lung
cancer and non-small cell lung cancer),
lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic
leukemia, lymphoma (lymphoma, including diffuse large B-cell
lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's
lymphoma), 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,
medullary carcinoma, medulloblastoma, melanoma, meningioma,
mesothelioma, multiple myeloma, myelogenous leukemia, myeloma,
myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer,
osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary
adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma,
pinealoma, polyeythemia vera, prostate cancer (including
hormone-insensitive (refectory) protstate cancer), rectal cancer,
renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma,
sebaceous gland carcinoma, seminoma, skin cancer, small cell lung
carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,
squamous cell carcinoma, synovioma, sweat gland carcinoma,
testicular cancer (including germ cell testicular cancer), thyroid
cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine
cancer, Wilms' tumor and the like.
[1864] It is also expected that compounds having Formula (I) would
inhibit growth of cells expressing Bcl-2 proteins derived from a
pediatric cancer or neoplasm including embryonal rhabdomyosarcoma,
pediatric acute lymphoblastic leukemia, pediatric acute myelogenons
leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic
ependymoma, pediatric anaplastic large cell lymphoma, pediatric
anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid
tumor of the central nervous system, pediatric biphenotypic acute
leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's
family of tumors such as primitive neuroectodermal rumors,
pediatric diffuse anaplastic Wilm's tumor, pediatric favorable
histology Wilm's tumor, pediatric glioblastoma, pediatric
medulloblastoma, pediatric neuroblastoma, pediatric
neuroblastoma-derived myelocytomatosis, pediatric pre-B-cell
cancers (such as leukemia), pediatric psteosarcoma, pediatric
rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric
T-cell cancers such as lymphoma and skin cancer and the like.
[1865] Autoimmune disorders include acquired immunodeficiency
disease syndrome (AIDS), autoimmune lymphoproliferativc syndrome,
hemolytic anemia, inflammatory diseases, and thrornbocytopcnia,
acute or chronic immune disease associated with organ
transplantation, Addison's disease, allergic diseases, alopecia,
alopecia areata, atheromatous disease/arteriosclerosis,
atherosclerosis, arthritis (including osteoarthritis, juvenile
chronic arthritis, septic arthritis, Lyme arthritis, psoriatic
arthritis and reactive arthritis), autoimmune bullous disease,
abetalipoprotemia, acquired immunodeficiency-related diseases,
acute immune disease associated with organ transplantation,
acquired acrocyanosis, acute and chronic parasitic or infectious
processes, acute pancreatitis, acute renal failure, acute rheumatic
fever, acute transverse myelitis, adenocarcinomas, aerial ectopic
beats, adult (acute) respiratory distress syndrome, AIDS dementia
complex, alcoholic cirrhosis, alcohol-induced liver injury,
alcohol-induced hepatitis, allergic conjunctivitis, allergic
contact dermatitis, allergic rhinitis, allergy and asthma,
allograft rejection, alpha-1-antitrypsin deficiency, Alzheimer's
disease, amyotrophic lateral sclerosis, anemia, angina pectoris,
ankylosing spondylitis associated lung disease, anterior horn cell
degeneration, antibody mediated cytotoxicity, antiphospholipid
syndrome, anti-receptor hypersensitivity reactions, aortic and
peripheral aneurysms, aortic dissection, arterial hypertension,
arteriosclerosis, arteriovenous fistula, arthropathy, asthma,
asthma, ataxia, atopic allergy, atrial fibrillation (sustained or
paroxysmal), atrial flutter, atrioventricular block, atrophic
autoimmune hypothyroidism, autoimmune haemolytic anaemia,
autoimmune hepatitis, type-1 autoimmune hepatitis (classical
autoimmune or lupoid hepatitis), autoimmune mediated hypoglyecemia,
autoimmune neutropaenia, autoimmune thrombocytopaenia, autoimnmune
thyroid disease, B cell lymphoma, bone graft rejection, bone marrow
transplant (BMT) rejection, bronchiolitis obliterans, bundle branch
block, burns, cachexia, cardiac arrhythmias, cardiac stun syndrome,
cardiac tumors, cardiomyopathy, cardiopulmonary bypass inflammation
response, cartilage transplant rejection, cerebellar cortical
degenerations, cerebellar disorders, chaotic or multifocal atrial
tachycardia, chemotherapy associated disorders, chlamydia,
choleosatatis, chronic alcoholism, chronic active hepatitis,
chronic fatigue syndrome, chronic immune disease associated with
organ transpianration, chronic eosinophilic pneumonia, chronic
inflammatory pathologies, chronic mucocutaneous candidiasis.
chronic obstructive pulmonary disease (COPD), chronic salicylate
intoxication, colorectal common varied immunodeficieney (common
variable hypogammaglobulinaemia), conjunctivitis, connective tissue
disease associated interstitial lung disease, contact dermatitis,
Coombs positive haemolytic anaemia, cor pulmonale,
Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis,
cryptogenic fibrosing alveolitis, culgture negative sepsis, cystic
fibrosis, cytokine therapy associated disorders, Crohn's disease,
dementia pugilistica, demyelinating diseases, dengue hemorrhagic
fever, dermatitis scleroderma, dermatologic conditions,
dermatomyositis/polymyositis associated lung disease, diabetes,
diabetic arteriosclerotic disease, diabetes mellitus, Diffuse Lewy
body disease, dilated cardiomyopathy, dilated congestive
cardiomyopathy, discoid lupus erythematosus, disorders of the basal
ganglia, disseminated intravascular coagulation, Down's Syndrome in
middle age, drug-induced interstitial lung disease, drug-induced
hepatitis, drug-induced movement disorders induced by drugs which
block CNS dopamine, receptors, drug sensitivity, eczema
encephalomyelitis, endocarditis, endocrinopathy, enteropathic
synovitis, epiglottitis, Epstein-Barr virus infection,
erythromelalgia, extrapyramidal and cerebellar disorders, familial
hematophagocytic lymphohistiocytosis, fetal thymus implant
rejection, Friedreich's ataxia, functional peripheral arterial
disorders, femal infertility, fibrosis, fibrotic lung disease,
fungal sepsis, gas gangrene, gastric ulcer, giant cell arteritis,
glomerular nephritis, glomerulonephritides, Goodpasture's syndrome,
goitrous autoimmune hypothroidism (Hashimoto's disease), gouty
arthritis, graft rejection of any organ or tissue, graft versus
host disease, gram negative sepsis, gram positive sepsis,
granulomas due to intracellular organisms, group B streptocci (GBS)
infection, Grave's disease, heaemosiderosis associated lung
disease, hairy cell leukemia, hairy cell leukemia,
Hallerrorden-Spatz disease, Hashimoto's throiditis, hay fever,
heart transplant rejection, hemachromatosis, hematopoietic
malignancies (leukemia and lymphoma), hemolytic anemia, hemolytic
uremic syndrome/thrombolytic thrombocytopenic purpura, hemorrhage,
Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C,
HIV infection/HIV neuropathy, Hodgkin's disease hypoparathyroidism,
Huntington's chorea, hyperkinetic movement disorders,
hypersensitivity reactions, hypersensitivity pneumonitis,
hyperthyroidism, hypokinetic movement disorders,
hypothalamic-pituitary-adrenal axis evaluation, idiopathic
Addison's disease, idiopathic leucopaenia, idiopathic pulmonary
fibrosis, idiopathic thrombocytopaenia, idiosyncratic liver
disease, infantile spinal muscular atrophy, infection diseases,
inflammation of the aorta, inflammatory bowel disease, insulin
dependent diabetes mellitus, interstitial pneumonitis,
iridocyclitis/uveitis/optic neuritis, ischemia-reperfusion injury,
ischemic stroke, juvenile pernicious anaemia, juvenile rheumatoid
arthritis, juvenile spinal muscular atrophy, Kaposi's sarcoma,
Kawasaki's disease, kidney transplant rejection, legionella,
leishmaniasis, leprosy, lesions of the corticospinal system, linear
IgA disease, lipidema, liver transplant rejection, Lyme disease,
lymphederma, lymphocytic infiltrative lung disease, malaria, male
infertility idiopathic or NOS, malignant histiocytosis, malignant
melanoma, meningitis, meningococcemia, microscopic vasculitis of
the kidneys, migraine headache, mitochondrial multisystem disorder,
mixed connective tissue disease, mixed connective tissue disease
associated lung disease, monoclonal gammopathy, multiple mycloma,
multiple systems degenerations (Mencel Dejerine-Thomas Shi-Drager
and Machado-Joseph), myalgic encephalitis/Royal Free Disease,
myasthenia gravis, microscopic vasculitis of the kidneys,
mycobacterium avium intracellulare, mycobacterium tuberculosis,
myelodyplastic syndrome, myocardial infarction, myoeardial ischemic
disorders, nasopharyngeal carcinoma, neonatal chronic lung disease,
nephritis, nephrosis, nephrotic syndrome, neurodegenerative
diseases, neurogenic I muscular atrophies, neutropenic fever,
Non-alcoholic Steatohepatitis, occlusion of the abdominal aorta and
its branches, occlusive arterial disorders, organ transplant
rejection, orchitis/epidydimitis, orchitis/vasectomy reversal
procedures, organomegaly, osteoarthrosis, osteoporosis, ovarian
failure, pancreas transplant rejection, parasitic diseases,
panthyroid transplant rejection, Parkinson's disease, pelvic
inflammatory disease, pemphigus vulgaris, pemphigus foliaccus,
pemphigoid, perennial rhinitis, pericardial disease, peripheral
atherlosclerotic disease, peripheral vascular disorders,
peritonitis, pernicious anemia, phacogenic uveitis, pneumocystis
carinii pneumonia, pneumonia, POEMS syndrome (polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin
changes syndrome), post perfusion syndrome, post pump syndrome,
post-MI cardiotomy syndrome, postinfectious interstitial lung
disease, premature ovarian failure, primary biliary cirrhosis,
primary sclerosing hepatitis, primary myxoedema, primary pulmonary
hypertension, primary sclerosing cholangitis, primary vasculitis,
Progressive supranucleo Palsy, psoriasis, psoriasis type 1,
psoriasis type 2, psoriatic arthropathy, pulmonary hypertension
secondary to connective tissue disease, pulmonary manifestation of
polyarteritis nodosa, post-inflammatory interstitial lung disease,
radiation fibrosis, mdiation therapy, Raynaud's phenomenon and
disease, Raynoud's disease, Refsum's disease, regular narrow QRS
tachycardia, Reiter's disease, renal disease NOS, renovascular
hypertension, reperfusion injury, restrictive cardiomyopathy,
rheumatoid arthritis associated interstitial lung disease,
rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,
seleroderma, senile chorea, Senile Dementia of Lewy body type,
sepsis syndrome, septic shock, seronegative arthropathies, shock,
sickle cell anemia, Sjogren's disease associated lung disease,
Sjorgren's syndrome, skin allograft rejection, skin changes
syndrome, small bowel transplant rejection, sperm autoimmunity,
multiple sclerosis (all subtypes), spinal ataxia, spinocerebellar
degenerations, spondyloarthropathy, spondyloarthopathy, sporadic,
polyglandular deficiency type I sporadic, polyglandular deficiency
type II, Still's disease, streptococcal myositis, stroke,
structural lesions of the cerebellum, Subacute sclerosing
panencephalitis, sympathetic ophthalmai, Syncope, syphilis of the
cardiovascular system, systemic anaphylasis, systemic inflammatory
response syndrome, systemic onset juvenile rheumatoid arthritis,
systemic lupus erythematosus, systemic lupus
erythematosus-associated lung disease, system sclerosis, systemic
sclerosis-associated interstitial lung disease, T-cell or FALL ALL,
Takayasu's disease.arteritis, Telangiectasia, Th2 Type and Th1 Type
mediated diseases, thromboangitis obliterans, thrombocytopenia,
thyroiditis, toxicity, toxic shock syndrome, transplants,
trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibody
hepatitis), type B insulin resistance with acanthosis nigricans,
type III hypersensitivity reactions, type IV hypersensitivity,
ulcerative colitic arthropathy, ulcerative colitis, unstable
angina, uremia, urosepsis, urticaria, uveitis, valvular heart
diseases, varicose veins, vasculitis, vasculitic diffuse lung
disease, venous diseases, venous thrombosis, ventricular
fibrillation, vitiligo acute liver disease, viral and funal
infections, vital encephalitis/aseptic meningitis, vital-associated
hemaphagocytic syndrome, Wegener's granulomatosis,
Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection
of any organ or tissue, yersinia and salmonella-associated
arthropathy and the like.
Schemes and Experimentals
[1866] The following abbreviations have the meaings indicated. ADDP
means 1,1'-(azodicarbonyl)dipiperidine; AD-mix-.beta. means a
mixture of (DHQD).sub.2PHAL, K.sub.3Fe(CN).sub.6, K.sub.2CO.sub.3,
and K.sub.2SO.sub.4; 9-BBN means 9-borabicyclo(3.3.1)nonane; Boc
means tert-butoxycarbonyl; (DHQD).sub.2PHAL means hydroquinidine
1,4-phthalazinediyl diethyl ether, DBU means
1,8-diazabicyclo[5.4.0]undec-7-ene; DIBAL means diisobutylaluminum
hydride; DIEA means diisopropylethylamine; DMAP means
N,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe
means 1,2-bis(dimethylphosphino)ethane; DMSO means
dimethylsulfoxide; dppb means 1,4-bis(diphenylphosphino)-butane;
dppe means 1,2-bis(diphenylphosphino)ethane; dppf means
1,1'-bis(diphenylphosphino)ferrocene; dppm means
1,1-bis(diphenylphosphino)methane; EDAC-HCl means
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc
means fluorenylmethoxycarbonyl; HATU means
O-(7-azabenzotriazol-1-yl)N,N', N'N'-tetramethyluronium
hexafluorophosphate; HMPA means hexamethylphosphoramide; IPA means
isopropyl alcohol; MP-BH.sub.3 means macroporous triethylammonium
methylpolystyrene cyanoborohydride; TEA means triethylamine; TFA
means trifluoroacetic acid; THF means tetrahydrofuran; NCS means
N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means
N-methylmorpholine; PPh.sub.3 means triphenylphosphine.
[1867] The following schemes are presented to provide what is
believed to be the most useful and readily understood description
of procedures and conceptual aspects of this invention. Compounds
of this invendon may be made by synthetic chemical processes,
examples of which are shown herein. It is meant to be understood
that the order of the steps in the processes may be varied, that
reagents, solvents and reaction conditions may be substituted for
those specifically mentioned, and that vulnerable moieties may be
protected and deprotected, as necessary.
##STR00012##
[1868] Compounds of Formula (4) can be prepared as shown in SCHEME
I, and can be used as described in SCHEME 8 to prepare compounds of
Formula (I), which are representative of the compounds of the
present invention, Compounds of Formula (I) wherein R is alkyl, can
be converted to compounds of Formula (2) using
Z.sup.3L.sup.1MgX.sup.1, wherein X.sup.1 is a halide, in a solvent
such as but not limited to ether or tetrahydrofuran. Compounds of
Formula (3) can be prepared from compounds of Formula (2) using a
strong base such as NaH and R.sup.57X.sup.2, wherein X.sup.2is a
halide and R.sup.57 is as described herein. Compounds of Formula
(3), when treated with aqueous Na0H or LiOH, will provide compounds
of Formula (4).
##STR00013##
[1869] As shown in SCHEME 2, compounds of Formula (5) can be
reacted with compounds of Formula (6) and a reducing agent to
provide compounds of Formula (7). Examples of reducing agents
include sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride, polymer supported cyanoborohydride, and the
like. The reaction is typically performed in a solvent such as but
not limited to methanol, tetrahydrofuran, and dichloromethane or
mixtures thereof. Compounds of Formula (8) can be prepared from
compounds of Formula (7) as described in SCHEME 1, and can be used
as described in SCHEME 8 to prepare compounds of Formula (I).
##STR00014##
[1870] Compounds of Formula (9), when reaction with a compound a
Formula (10) wherein X is a halide or triflate, and a base will
provide a compound of Formula (11). Bases useful in the reaciton
include triethylamine, diisopropylethylamine and the like.
Compounds of Formula (13), wherein Y is as described herein for
substituents on Z.sup.3, can be prepared from compounds of Formula
(11) and compounds of Formula (12) using Suzuki coupling conditions
known to those skilled in the art and readily available in the
literature. Compounds of Formula (14) can be prepared from
compounds of Formula (13) as described in SCHEME 1, and can be used
as described in SCHEME 8 to prepare compounds of Formula (I).
##STR00015##
[1871] As shown in SCHEME 4, compounds of Formula (17) can be
prepared from compounds of Formula (15) and compounds of Formula
(16), wherein R is alkyl and R.sup.38 is as described herein, using
Suzuki coupling conditions known to those skilled in the art and
readily available in the literature. Compounds of Formula (17) can
be reduced to compounds of Formula (18) using a reducing agent such
as LiAlH.sub.4 in a solvent such as but not limited to diethyl
ether or THF. Compounds of Formula (19) can be prepared from
compounds of Formula (18) using Dess-Martin periodinane or Swern
oxidation conditions known to those skilled in the art and readily
available in the literature. Compounds of Formula (19) can be
reacted with a compound of Formula (5) and a reducing agent to
provide compounds of Formula (20). Examples of reducing agents
include sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride, polymer supported cyanoborohydride, and the
like. The reaction is typically performed in a solvent such as but
not limited to methanol, tetrahydrofuran, 1,2-dichloroethane, and
dichloromethane or mixtures thereof. Compounds of Formula (21) can
he prepared from compounds of Formula (20) as described in SCHEME
1, and can be used as described in SCHEME B to prepare compounds of
Formula (I).
##STR00016##
[1872] As shown in SCHEME 5, compounds of Formula (22), wherein R
is alkyl, may be converted to compounds of Formula (23) by reacting
the former, wherein X.sup.1 is Cl, Br, I, or CF.sub.3SO.sub.3--,
and compounds of Formula R.sup.41--OH and a catalyst, with or
without a first base. Examples of catalysts include copper(I)
trifluoromethanesulfonate toluene complex, PDCl.sub.2,
Pd(OAc).sub.2, and Pd.sub.2(dba).sub.3. Examples of first bases
include triethylamine, N,N-diisopropylethylamine, Cs.sub.2CO.sub.3,
Na.sub.2CO.sub.3, K.sub.3PO.sub.4, and mixtures thereof.
[1873] Compounds of Formula (22) may also be converted to compounds
of Formula (23) by reacting the former, when X.sup.1 is Cl, F, or
NO.sub.2, and compounds of Formula R.sup.41--OH with a first base.
Examples of first bases include triethylamine,
N,N-diisopropylethylamine, Cs.sub.2CO.sub.3, Na.sub.2CO.sub.3,
K.sub.3PO.sub.4, and mixtures thereof.
##STR00017##
[1874] Compounds of Formula (18) can be reacted with mesyl chloride
and a base such as but not limited to triethylamine, followed by
N-t-butoxycarbonylpiperazine, to provide compoundes of Formula
(24). Compounds of Formula (25) can be prepared by reacting
compounds of Formula (24) with triethylsilane and trifluoroacetic
acid. Compounds of Formula (25) can be reacted with compounds of
Formula (26) and HK.sub.2PO.sub.4 to provide compounds of Formula
(27) in a solvent such as but not limited to dimethylsulfoxide.
Compounds of Formula (28) can be prepared from compounds of Formula
(27) as described in SCHEME 1, and can be used as described in
SCHEME 8 to prepare compounds of Formula (I).
##STR00018##
[1875] As shown in SCHEME 7, compounds of Formula (I) can be
reacted with an appropriate triphenylphosphonium bromide of Formula
(29) and a base such as but not limited to sodium hydride or
n-butyllithium to provide compounds of Formula (30). The reaction
is typically performed in a solvent such as THF or DMSO. Compounds
of Formula (31) can be prepared from compounds of Formula (30) as
described in SCHEME 1, and can be used as described in SCHEME 8 to
prepare compounds of Formula (I).
##STR00019##
[1876] As shown in SCHEME 8, compounds of Formula (32), which can
be prepared as described herein, may be converted to compounds of
Formula (33) by reacting the former with ammonia. Compounds of
Formula (33) may be converted to compounds of Formula (I) by
reacting the former and compounds of Formula (4), (8), (14), (21),
(28), (31), or (38) and a coupling agent, with or without a first
base. Examples of coupling agents include
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride.
1,1'-carbonyldiimidazole, and
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.
Examples of first bases include triethylamine,
N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixtures
thereof.
##STR00020##
[1877] Compounds of Formula (33), prepared as described in SCHEME
(8), may also be convened to compounds of Formula (I) by reacting
the former and compounds of Formula (34) and a first base. Examples
of first bases include but are not limited to sodium hydride,
triethylamine, N,N-diisopropylethylamine,
4-(dimethylamino)pyridine, and mixtures thereof.
##STR00021##
[1878] As shown m SCHEME 10, compounds of Formula (35), wherein L
is a bond, alkyl, O, S, S(O), S(O).sub.2, NH, etc., can be reacted
with compounds or Formula (36), to provide compounds of Formula
(37). The reaction is typically performed at elevated temeratures
in a solvent such as but not limited to dimethylsulfoxide, and may
require the use of a base such as but not limited to potassium
phosphate, potassium carbonate, and the like. Compounds of Formula
(38) can be prepared from compounds of Formula (37) as described in
SCHEME 1, and can be used as described in SCHEME 8 to prepare
compounds of Formula (I).
##STR00022##
[1879] Compounds of Formula (39), wherein Y is as described herein
for substituents on Z.sup.3, can be prepared from compounds of
Formula (39A) wherein X is a halide or triflate, and Y-B(OH).sub.2
using Suzuki coupling conditions known to those skilled in the art
and readily available in the literature. Compounds of Formula (39)
can be reacted with tert-butyl piperazine-1-carboxylate and a
reducing agent such as sodium triacetoxyborohydride to provide
compounds of Formula (40). The reaction is typically performed in a
solvent such as but not limited to methylene chloride. Compounds of
Formula (41) can be prepared from compounds of Formula (40) by
reacting the latter with R.sup.57X, wherein X is a halide, and NaH
in a solvent such as N,N-dimethylformamide, and then the resulting
material can be treated with triethylsilane and trifluoroacetic
acid in dichloromethane. Compounds of Fonnula (41) can be used as
described in Scheme 10 wherein L.sup.1-Z.sup.3 is as shown in
Formula (41).
##STR00023##
[1880] As shown in SCHEME 12, substituted piperazin-2-ones wherein
R.sup.57 is alkyl, can be reacted with compounds of Formula (6) and
a reducing agent such as sodium triacetoxyborohydride in
dichloromethane to provide compounds of Formula (42). Compounds of
Formula (42) can be reduced to compounds of Formula (43) using a
reducing agent such as but not limited to lithium aluminum hydride
in a solvent such as but not limited to tetrahydrofuran. Compounds
of Formula (43) can be used as described in Scheme 10 wherein
L.sup.1-Z.sup.3 is as shown in Formula (43).
[1881] The following examples are presented to provide what is
believed to be the most useful and readily understood description
of procedures and conceptual aspects of this invention. The
exemplified compounds were named using ACO/ChemSketch Version 5.06
(5 Jun. 2001, Advanced Chemistry Development Inc., Toronto,
Ontario), or ChemDraw.RTM. Vet 9.0.5 (CambridgeSoft, Cambridge,
Mass.). Intermediates were named using ChemDraw.RTM. Vet. 9.0.5
(CambridgeSoft, Cambridge, Mass.).
EXAMPLE 1
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethyl-
amino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide
EXAMPLE 1A
tert-butyl
4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-carboxylate
[1882] 4'-Chlorobiphenyl-2-carboxaldehyde (4.1 g), tert-butyl
piperazine-1-carboxylate (4.23 g) and sodium triacetoxyborohydride
(5.61 g) in CH.sub.2Cl.sub.2 (60 mL) were stirred for 24 hours. The
mixture was treated with methanol and poured into ether. The
extract was washed with water and brine and concentrated. The
concentrate was chromatographed on silica gel with 2-25% ethyl
acetate/hexanes.
EXAMPLE 1B
1-((4'-chlorobiphenyl-2-yl)methyl)piperazine
[1883] EXAMPLE 1A (3.0 g) and triethylsilane (1 mL) were stirred in
dichloromethane (30 mL) and trifluoroacetic acid (30 mL) for 2
hours. The mixture was concentrated, taken up in ether and
concentrated again.
EXAMPLE 1C
methyl
2-bromo-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoat-
e
[1884] Methyl 2-bromo-4-fluorobenzoate (3 g), EXAMPLE 1B (4.43 g),
and K.sub.2CO.sub.3 (3.56 g) were stirred in DMSO (35 mL) at
125.degree. C. for 24 hours. The mixture was cooled, taken up in
ethyl acetate (500 mL), washed with water and brine, dried over
Na.sub.2SO.sub.4, filtered and concentrated. The concentrate was
chromatographed on sibca gel with 5-25% ethyl acetate hexanes.
EXAMPLE 1D
3-((dimethylamino)methyl)phenol
[1885] 3-Hydroxybenzaldehyde (1.0 g), 2M dimethylamine in THF (5
mL), and sodium triacetoxyborohydride (2 g) in CH.sub.2Cl.sub.2 (10
mL) were stirred for 24 hours. The mixture was treated with
methanol and chromatographed on silica gel with 2-25% ethyl
acetate/hexanes.
EXAMPLE 1E
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethy-
lamino)methyl)phenoxy)benzoate
[1886] EXAMPLE 1C (400 mg), EXAMPLE 1D (260 mg), Cs.sub.2CO.sub.3
(570 mg), 1-naphtoic acid (2.96 g), copper (1) triflate-toluene
complex (245 mg), ethyl acetate (9 .mu.L), and 4 .ANG. sieves (30
mg) in toluene (2 mL) was stirred at 105.degree. C. for 24 hours.
The mixture was cooled and taken up in ethyl acetate (100 mL) and
water (40 mL). The layers were separated and the extract was washed
twice with Na.sub.2CO.sub.3 solution and brine, dried, and
concentrated. The concentrate was chromatographed on silica gel
with 25-50% ethyl acetate/hexanes.
EXAMPLE 1F
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((dimethylamino)-
methyl)phenoxy)benzoic acid
[1887] EXAMPLE 1E (750 mg) was stirred in 25 mL 2:1 dioxane/1 M
NaOH at 80.degree. C. for 4 hours. The solution was cooled and
adjusted to pH 4 with NaH.sub.2PO.sub.4 solution and concentrated
HCl, and extracted with ethyl acetate. The extract was washed with
brine, dried (Na.sub.2SO.sub.4), and concentrated.
EXAMPLE 1G
3-nitro-4-((tetrahydro-2H-pyran-4-yl)methyiamino)benzenesulfonamide
[1888] 4-Fluoro-3-nitrobenzenesulfonamide (2.18 g),
(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g)
were stirred in THF (30 mL) for 24 hours. The solution was diluted
with ethyl acetate, washed with NaH.sub.2PO.sub.4 solution and
brine, and dried (Na.sub.2SO.sub.4), filtered and concentrated. The
product was triturated from ethyl acetate.
EXAMPLE 1H
4-(4-((4
'-chloro-1-biphenyl-2-yl)methyl)piperszin-1-yl)-2-(3-((dimethylam-
ino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)p-
henyl)sulfonyl)benzamide
[1889] EXAMPLE 1F (128 mg), EXAMPLE 1G (73 mg),
1-ethyl-3-(3-(dimethylamino)propyl)-carbodiimide hydrochloride (88
mg), and 4-dimethylaminopyridine (28 mg) were stirred in
CH.sub.2Cl.sub.2 (3 mL) for 24 hours. The mixture was cooled and
chromatographed on silica gel with 0-10% methanol/ethyl acetate.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.15 (br s, 1H), 8.63
(dd, 1H), 8.49 (d, 1H), 7.80 (dd, 1H), 7.44-7.53 (m, 5H), 107.36
(m, 3H), 7.22 (m, 3 H), 7.01 (s, 1H), 6.92 (d, 1H), 6.78 (d, 1H),
6.44 (s, 1H), 4.17 (m, 2H), 3.86 (dd, 2H), 3.33 (m, 6H), 3.16 (m,
4H), 2.66 (s, 6H), 2.37 (br s, 4H), 1.91 (m, 1H), 1.63 (d, 2H),
1.29 (m, 2H).
EXAMPLE 2
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylami-
no)methyl)phenoxy)-N((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phe-
nyl)sulfonyl)benzamide
EXAMPLE 2A
3-(methylamino)phenol
[1890] Ethylamine was bubbled into a solution of
4-hydroxybenzaldehyde (2.0 g) and sodium triacetoxyborohydride (5.2
g) in CH.sub.2Cl.sub.2 (60 mL) for 12 hour, and the mixture was
stoppered and stirred for 24 hours. 1M NaOH solution was added (10
mL), and di-tert-butyl dicarbonate (3.57 g) and triethylamine (2.28
mL) were then added and the mixture was stirred for 24 hours. The
solution was cooled and adjusted to pH 4 with NaH.sub.2PO.sub.4
solution and concentrated HCl, and extracted with ethyl acetate.
The extract was washed with brine, dried (Na.sub.2SO.sub.4), and
concentrated. The concentrate was chromatographed on silica gel
with 20% ethyl acetate/hexanes.
EXAMPLE 2B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylam-
ino)phenoxy)benzoate
[1891] EXAMPLE 1C (457 mg), EXAMPLE 2A (225 mg), cesium carbonate
(595 mg), copper(1) triflate toluene complex (41 mg), and ethyl
acetate (0.016 mL) in toluene (5 mL) were stirred at 110.degree. C.
for 72 hours. The mixture was cooled and chromatographed on silica
gel with 5-25% ethyl acetate/hexanes.
EXAMPLE 2 C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylamino)phe-
noxy)benzoic acid
[1892] This EXAMPLE was prepared by substituting EXAMPLE 2B for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 2D
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylami-
no)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide
[1893] This EXAMPLE was prepared by substituting EXAMPLE 2C for
EXAMPLE 1F in EXAMPLE 1G. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.60 (br s, 1H), 8.37 (s, 1H), 7.69 (d, 1H), 7.58 (d, 1H),
7.47 (m, 5H). 7.38 (m, 3 H), 7.24 (m, 1H) 6.95 (d, 1H), 6.89 (dd,
1H), 6.61 (d, 1H), 6.26 (s, 1H), 6.13 (d, 1H), 5.97 (s, 1H), 5.92
(d, 1H), 5.59 (br s, 1H), 3.84 (dd, 2H), 3.37 (m, 6H), 3.03 (m,
4H), 2.89 (m, 2H), 2.59 (br s, 3 H), 2.36 (br s, 4H), 1.91 (m, 1H),
1.62 (d, 2H), 1.24 (m, 2H).
EXAMPLE 3
[1894]
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)p-
iperazin-1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-(methylpiperidin-
-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide
EXAMPLE 3A
ethyl 4-fluoro-2-(2-methyl-1H-indol-5-yloxy)benzoate
[1895] Ethyl 2,4-difluorobenzoate (1.14 g), K.sub.3PO.sub.4 (1.30
g) and 2-methyl-5-indolol (0.90 g) were stirred at 110.degree. C.
in diglyme (12 mL) for 24 hours. The mixture was cooled and poured
into ether. The solution was washed three times with 1M NaOH
solution, and with brine, and dried. The solution was then
concentrated. The concentrate was chromatographed on silica gel
with 10% ethyl acetate/hexanes.
EXAMPLE 3B
methyl
4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylat-
e
[1896] to a suspension of hexane-washed NaH (17 g) in
dichloromethane (700 mL) was added
5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwise at
0.degree. C. After stirring for 30 minutes, the mixutre was cooled
to -78.degree. C. and trifluoroacetic anhydride (40 mL) was added.
The mixture was warmed to room temperature and stirred for 24
hours. The extract was washed with brine, dried and
concentrated.
EXAMPLE 3C
methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate
[1897] EXAMPLE 3B (62.15 g) 4-chlorophenylboronic acid (32.24 g),
CsF (64 g) and tetrakis(triphenylphosphine)palladium(0) (2 g) in
2:1 dimethoxyethane/mehanol (600 mL) were heated to 70.degree. C.
for 24 hours. The mixture was concentrated. Ether was added, and
the mixture was filtered and concentrated.
EXAMPLE 3D
(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol
[1898] To a mixture of LiBH.sub.4 (13 g), EXAMPLE 3C (53.8 g) and
ether (400 mL), methanol (25 mL) was added slowly by syringe. The
mixture was stirred at room temperature for 24 hours. The mixture
was quenched with 1N HCl with ice-cooling. The mixture was diluted
with water and extracted by ether (3.times.100 mL). The extracts
were dried, and concentrated. The concentrate was chromatographed
on silica gel with 0-30% ethyl acetate/hexanes.
EXAMPLE 3E
tert-butyl
4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piper-
azine-1-carboxylate
[1899] Mesyl chloride (7.5 mL) was added via syringe to EXAMPLE 3D
(29.3 g) and triethylamine (30 mL) in CH.sub.2Cl.sub.2 (500 mL) at
0.degree. C., and the mixture was stirred for 1 minute.
N-t-butoxycarbonylpiperazine (25 g) was added and the mixture was
stirred at room temperature for 24 hours. The suspension was washed
with brine, dried, and concentrated. The concentrate was
chromatographed on silic gel with 10-20% ethyl acetate/hexanes.
EXAMPLE 3F
1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine
[1900] This EXAMPLE was prepared by substituting EXAMPLE 3E for
EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 3G
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
ine-1-yl)-2-(2-methyl-1H-indol-5-yloxy)benzoate
[1901] EXAMPLE 3F (1008 mg), EXAMPLE 3 A (900 mg), and
HK.sub.2PO.sub.4 (550 mg) were stirred in DMSO (7 mL) at
140.degree. C. for 24 hours. The mixture was diluted with ethyl
acetate, washed three times with water, washed with brine, dried,
and concentrated. The concentrate was chromatographed on silica gel
wtih 30% ethyl acetate/hexanes.
EXAMPLE 3H
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-((2-methyl)-1H-indol-5-yloxy)benzoic acid
[1902] This EXAMPLE was prepared by substituting EXAMPLE 3G for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 3I
4-(1-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
[1903] This EXAMPLE was prepared by substituting
4-amino-N-methylpiperidine for 3-(N-morpholinyl)-1-propylamine in
EXAMPLE 4A.
EXAMPLE 3J
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((1-(methylpiperidin-4-yl)ami-
no)-3-nitrophenyl)sulfonyl)benzamide
[1904] This EXAMPLE was prepared by substituting EXAMPLE 3H for
EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H, .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 10.98 (s, 1H), 10.50 (br s, 1H),
8.55 (dd, 1H), 8.17 (d, 1H), 7.88 (dd, 1H), 7.51 (d, 1H), 7.34 (d,
2H), 7.24 (d, 1H), 7.14 (d, 1H), 7.05 (d, 2H), 7.00 (d, 1H), 6.72
(d, 1H), 6.55 (d, 1H), 6.08 (d, 2H), 3.85 (m, 1H), 3.45 (m, 4H),
2.98 (br s, 4H), 2.85 (m, 2H), 2.71 (br s, 2H), 2.63 (s, 2H), 2.38
(s, 2H), 2.15 (m, 6H), 1.95 (m, 4H), 1.80 (m, 2H), 1.38 (m, 2H),
0.92 (s, 6H).
EXAMPLE 4
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide
EXAMPLE 4A
4-(3-morpholinopropylamino)-3-nitrobenzenesulfonamide
[1905] 4-Fluoro-3-nitrobenzenesulfonamide (550 mg),
3-(N-morpholinyl)-1-propylamine (1.00 g), and triethylamine (1 g
)were stirred in THF (30 mL) for 24 hours. The mixture was diluted
with ethyl acetate, washed with NaH.sub.2PO.sub.4 solution and
brine, and dried (Na.sub.2SO.sub.4), filtered and concentrated. The
product was triturated from ethyl acetate.
EXAMPLE 4B
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((2-methyl)-1H-indol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide
[1906] This EXAMPLE was prepared by substituting EXAMPLE 4A for
EXAMPLE 1F and EXAMPLE 3H for EXAMPLE 2G in EXAMPLE 1H. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 10.98 (m, 2H), 8.80 (dd, 1H), 8.58
(d, 1H), 7.82 (dd, 1H), 7.50 (d, 1H), 7.34 (d, 2H), 7.27 (d, 1H),
7.05 (m, 4H), 6.75 (d, 1H), 6.62 (d, 1H), 6.10 (d, 1H), 3.60 (m,
4H), 3.45 (m, 2H), 3.01 (br s, 4H), 2.71 (br s, 3H), 2.38 (m, 8H),
2.14 (br s, 6H), 1.95 (m, 2H), 1.81 (m, 2H), 1.38 (m, 2H), 0.92 (s,
6H).
EXAMPLE 5
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(chlorophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide
EXAMPLE 5A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophe-
noxy)benzoate
[1907] This EXAMPLE was prepared by substituting 2-chlorophenol for
EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 5B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophenoxy)be-
nzoic acid
[1908] This EXAMPLE was prepared by substituting EXAMPLE 5A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 5C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide
[1909] This EXAMPLE was prepared by substituting EXAMPLE 5B for
EXAMPLE 1F is EXAMPLE 1H. The crude product was purified by
preparative HPLC using a 250.times.50 mm C18 column and eluing with
20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving
the product as a trifluoroacetate salt. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 11.77 (br s, 1H), 9.58 (v br s, 1H), 8.63 (t,
1H), 8.46 (d, 1H), 7.79 (dd, 1H), 7.71 (br s, 1H), 7.52 (m, 5H),
7.33 (m, 4H), 7.15 (d, 1H), 7.13 (m, 1H), 6.99 (m, 1H), 6.78 (dd,
1H), 6.65 (d, 1H), 6.40 (s, 1H), 4.35 (v br s, 1H), 3.90 (m, 2H),
3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m, 1H),
1.63 (m, 2H), 1.28 (m, 2H).
EXAMPLE 6
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide
EXAMPLE 6A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophe-
noxy)benzoate
[1910] This EXAMPLE was prepared by substituting 3-chlorophenol for
EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 6B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophenoxy)be-
nzoate
[1911] This EXAMPLE was prepared by substituting EXAMPLE 6A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 6C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide
[1912] This EXAMPLE was prepared by substituting EXAMPLE 6B for
EXAMPLE 5B in EXAMPLE 5C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11. 85 (br s, 1H), 9.60 (v br s, 1H), 8.63 (t, 1H), 8.43
(d, 1H), 7.72 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 5H), 7.40 (d,
2H), 7.35 (m, 1H), 7.19 (dd, 1H), 7.14 (d, 1H), 6.95 (m, 1H), 6.80
(dd, 1H), 6.72 (m, 1H), 6.70 (m, 1H), 6.56 (d, 1H), 4.35 (v br s,
1H), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m,
2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).
EXAMPLE 7
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(chlorophe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide
EXAMPLE 7A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophe-
noxy)benzoate
[1913] This EXAMPLE was prepared by substituting 4-chlorophenol for
EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 7B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophenoxy)be-
nzoic acid
[1914] This EXAMPLE was prepared by substituting EXAMPLE 7A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 7C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-chlorophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide
[1915] This EXAMPLE was prepared by substituting EXAMPLE 7B for
EXAMPLE 5B in EXAMPLE 5C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.81 (br s, 1H), 9.58 (v br s, 1H), 8.63 (t, 1H), 8.46 (d,
1H), 7.73 (dd, 1H), 7.71 (br s, 1H), 7.50 (m, 5H), 7.38 (d, 2H),
7.33 (m, 1H), 7.25 (m, 2H), 7.15 (d, 1H), 6.79 (m, 3H), 6.50 (d,
1H), 4.35 (v br s, 1H), 3.90 (m, 2H), 3.80-2.80 (v br m, 7H), 3.36
(m, 4H), 3.27 (m, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.28 (m,
2H).
EXAMPLE 8
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitropheno-
xy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)b-
enzamide
EXAMPLE 8A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophen-
oxy)benzoate
[1916] This EXAMPLE was prepared by substituting 3-nitrophenol for
EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 8B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitrophenoxy)ben-
zoic acid
[1917] This EXAMPLE was prepared by substituting EXAMPLE 8A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 8C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(nitrophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide
[1918] This EXAMPLE was prepared by substituting EXAMPLE 8B for
EXAMPLE 5B in EXAMPLE 5C. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.81 (br s, 1H), 9.59 (v br s, 1H), 8.60 (t, 1H), 8.39 (d,
1H), 7.70 (m, 3H), 7.50 (m, 6H), 7.38 (m, 4H), 7.23 (m, 1H), 7.10
(d, 1H), 6.85 (dd, 1H), 6.63 (d, 1H), 4.35 (v br s, 1H), 3.90 (m,
2H), 3.80-2.80 (v br m, 7H), 3.36 (m, 4H), 3.27 (m, 2H), 1.90 (m,
1H), 1.63 (m, 2H), 1.28 (m, 2H).
EXAMPLE 9
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxyme-
thyl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)-
benzamide
EXAMPLE 9A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxyme-
thyl)phenoxy)benzoate
[1919] This EXAMPLE was prepared by substituting
3-(hydroxymethyl)phenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 9B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxymethyl)p-
henoxy)benzoic acid
[1920] This EXAMPLE was prepared by substituting EXAMPLE 9 A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 9C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(hydroxyme-
thyl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)-
benzamide
[1921] This EXAMPLE was prepared by substituting EXAMPLE 9B for
EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that
the purification was performed by HPLC according to EXAMPLE 5C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.63 (br s, 1H), 9.60
(v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.80 (dd, 1H), 7.67 (br
s, 1H), 7.50 (m, 5H), 7.40 (m, 2H), 7.35 (br s, 1H), 7.20 (m, 2H),
6.95 (d, 1H), 6.75 (m, 3H), 6.40 (s, 1H), 4.40 (s, 2H), 4.35-2.80
(m, 22 H),1.98 (m, 2H).
EXAMPLE 10
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophen-
oxy)-N-((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)benzamide
[1922] This EXAMPLE was prepared by substituting EXAMPLE 5B for
EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that
the purification was performed by HPLC according to EXAMPLE 5C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.77 (br s, 1H), 9.62
(v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.71 (br
s, 1H), 7.52 (m, 5H), 7.40 (m, 3H), 7.33 (br s, 1H), 7.16 (m, 2H),
7.02 (m, 1H), 6.79 (dd, 1H), 6.70 (d, 1H), 6.40 (s, 1H), 4.35-2.80
(m, 22 H), 1.98 (m, 2H).
EXAMPLE 11
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophen-
oxy)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)benzamid-
e
EXAMPLE 11A
4-(3-(dimethylamino)propylamino)-3-nitrobenzenesulfonamide
[1923] This EXAMPLE was prepared by substituting
3-(dimethylamino)-1-propylamine for 3-(N-morpholinyl)-1-propylamine
in EXAMPLE 4A,
EXAMPLE 11B
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophen-
oxy)-N-((4-((3-(dimethylamino)propyl)amino-3-nitrophenyl)sulfonyl)benzamid-
e
[1924] This EXAMPLE was prepared by substituting EXAMPLE 5B for
EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G and EXAMPLE 1H, except
that the purification was performed by HPLC according to EXAMPLE
5C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.77 (br s, 1H),
9.38 (v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.65
(br s, 1H), 7.52 (m, 5H), 7.40 (m, 3H), 7.33 (br s, 1H), 7.16 (m,
2H), 7.02 (m, 1H), 6.79 (dd, 1H), 6.70 (d, 1H), 6.40 (s, 1H),
4.35-2.80 (m, 12 H), 2.80 (s, 3H), 2.78 (s, 3H), 1.98 (m, 2H).
EXAMPLE 12
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-chlorophen-
oxy-N-((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)benzamide
[1925] This EXAMPLE was prepared by substituting EXAMPLE 6B for
EXAMPLE 1F and EXAMPLE 4 A for EXAMPLE 1G is EXAMPLE 1H, except
that the purification was performed by HPLC according to EXAMPLE
5C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.85 (br s, 1H),
9.63 (v br s, 2H), 8.66 (t, 1H), 8.43 (d, 1H), 7.78 (dd, 1H), 7.67
(br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.20 (dd,
1H), 7.14 (d, 1H), 6.95 (m, 1H), 6.80 (dd, 1H), 6.72 (m, 1H), 6.70
(m, 1H), 6.53 (s, 1H), 4.35-2.80 (m, 22 H), 1.98 (m, 2H).
EXAMPLE 13
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophen-
oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamid-
e
[1926] This EXAMPLE was prepared by substituting EXAMPLE 7B for
EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H, except that
the purification was performed by HPLC according to EXAMPLE 5C.
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.81 (br s, 1H), 9.63
(v br s, 2H), 8.70 (t, 1H), 8.50 (d, 1H), 7.80 (dd, 1H), 7.69 (br
s, 1H), 7.50 (m, 5H), 7.38 (d, 2H), 7.33 (m, 1H), 7.25 (m, 2H),
7.15 (d, 1H), 6.79 (m, 3H), 6.50 (d, 1H), 4.35-2.80 (m, 22 H), 1.98
(m, 2H).
EXAMPLE 14
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophen-
oxy)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzami-
de
[1927] This EXAMPLE was prepared by substituting EXAMPLE 6B for
EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G is EXAMPLE 1H, except
that the purification was performed by HPLC according to EXAMPLE
5C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.85 (br s, 1H),
9.63 (v br s, 2H), 8.70 (t, 1H), 8.45 (d, 1H), 7.78 (dd, 1H), 7.70
(br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m, 1H), 7.20 (dd,
1H), 7.14 (d, 1H), 6.95 (m, 1H), 6.80 (dd, 1H), 6.72 (m, 1H), 6.70
(m, 1H), 6.56 (s, 1H), 4.35-2.80 (m, 12 H), 2.52 (s, 3H), 2.50 (s,
3H), 2.00 (m, 2H).
EXAMPLE 15
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-chlorophen-
oxy)-N-((4-((3-dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)benzamid-
e
[1928] This EXAMPLE was prepared by substituting EXAMPLE 7B for
EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H, except
that the purification was performed by HPLC according to EXAMPLE
5C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.81 (br s, 1H),
9.38 (v br s, 1H), 8.68 (t, 1H), 8.50 (d, 1H), 7.80 (dd, 1H), 7.69
(br s, 1H), 7.50 (m, 5H), 7.40 (d, 2H), 7.33 (m, 1H), 7.25 (m, 2H),
7.15 (d, 1H), 6.80 (m, 3H), 6.46 (s, 1H), 4.35-2.80 (m, 12 H), 2.81
(s, 3H), 2.79 (s, 3H), 1.98 (m, 2H).
EXAMPLE 16
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-)y-
l)oxy)benzamide
EXAMPLE 16A
1-(triisopropylsilyl)-1H-indol-4-ol
[1929] 4-Benzyloxyindole (1 g) was treated with 60% oily NaH (135
mg) and triisopropylsilyl chloride (1 g) in THF, purified by flash
chromatography (98/2 ethyl acetate/hexanes), then debenzylated in
ethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogen
balloon.
EXAMPLE 16B
methyl
2-(1H-indol-4-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-
-1-yl)benzoate
[1930] This EXAMPLE was prepared by substituting EXAMPLE 16A for
EXAMPLE 1D in EXAMPLE 1E. The crude material from the ether
formation was desilylated using tetrabutyl ammonium fluoride in
THF/water 95/5 for 1 hour prior to purification.
EXAMPLE 16C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-methyl-1H-
-indol-4-yloxy)benzoate
[1931] EXAMPLE 16B (148 mg), 60% oily NaH (9 mg) and methyliodide
(57 mg) in THF (1 mL) were stirred at room temperature overnight.
The mixture was chromatographed on silica gel with 20% ethyl
acetate in hexanes.
EXAMPLE 16D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-methyl-1H-indol--
4-yloxy)benzoic acid
[1932] This EXAMPLE was prepared by substituting EXAMPLE 16C for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 16E
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((1-methyl-1H-indol-4-)y-
l)oxy)benzamide
[1933] This EXAMPLE was prepared by substituting EXAMPLE 11A for
EXAMPLE 1G and EXAMPLE 16D for EXAMPLE 1E in EXAMPLE 1H, except
that the purification was performed by HPLC according to EXAMPLE
5C. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.58 (br s, 1H),
9.42 (br s, 2H), 8.64 (t, 1H), 8.44 (d, 1H), 7.77 (dd, 1H), 7.66
(br s, 1H), 7.50 (m, 5H), 7.37 (d, 2H), 7.30 (m, 1H), 7.25 (d, 1H),
7.19 (d, 1H), 7.06 (d, 1H), 7.00 (dd, 1H), 6.75 (dd, 1H), 6.40 (d,
1H), 6.38 (s, 1H), 6.23 (d, 1H), 4.35-2.80 (m, 12 H), 3.80 (s, 3H),
2.79 (s, (3H), 2.77 (s, 3H), 1.96 (m, 2H).
EXAMPLE 17
2-(3-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide
EXAMPLE 17A
2-(3-(acetamindophenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1--
yl)benzoate
[1934] This EXAMPLE was prepared by substituting 3-acetamidophenol
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 17B
2-(3-(acetamindophenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1--
yl)benzoic acid
[1935] This EXAMPLE was prepared by substituting EXAMPLE 17A for
EXAMPLE 1E in EXAMPLE 1F.
EXMAPLE 17C
2-(3-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide
[1936] This EXAMPLE was prepared by substituting EXAMPLE 17B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.48 (s, 1H), 9.89 (s, 1H), 8.59 (m, 1H), 8.50 (d, 1H),
7.71 (dd, 1H), 7.47 (m, 6H), 7.36 (m, 2H), 7.24 (m, 2H), 7.14 (m,
3H), 6.75 (dd, 1H), 6.30 (dd, 1H), 6.39 (d, 1H), 3.86 (dd, 2H),
3.37 (m, 2H), 3.30 (m, 6H), 3.10 (m, 4H), 2.35 (s, 4H), 2.00 (s,
3H), 1.89 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).
EXAMPLE 18
2-(4-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-y-
l)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide
EXAMPLE 18A
methyl
2-(4-(tert-butoxycarbonylamino)phenoxy)-4-(4-((4'-chlorobiphenyl-2--
yl)methyl)piperazin-1-yl)benzoate
[1937] This EXAMPLE was prepared by substituting
N-tert-butoxycarbonyl-4-aminophenol for EXAMPLE 1D in EXAMPLE
1E.
EXAMPLE 18B
2-(4-(tert-butoxycarbonylamino)phenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)meth-
yl)piperazin-1-yl)benzoic acid
[1938] This EXAMPLE was prepared by substituting EXAMPLE 18A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 18C
tert-butyl
4-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-ni-
tro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)pheno-
xy)phenylcarbamate
[1939] This EXAMPLE was prepaid by substituting EXAMPLE 18B for
EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 18D
2-(4-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-y-
l)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide
[1940] This EXAMPLE was prepaid by substituting EXAMPLE 18C for
EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.41 (s, 1H), 9.54 (s, 1H), 8.66 (t, 1H), 8.59 (d, 1H),
7.86 (dd, 1H), 7.67 (m, 1H), 7.51 (dd, 5H), 7.38 (d, 2H), 7.31 (m,
1H), 7.25 (d, 1H), 6.82 (m, 4H), 6.69 (dd, 1H), 6.24 (m, 1H), 4.26
(s, 2H), 3.85 (dd, 2H), 3.35 (m, 4H), 3.26 (td, 4H), 3.04 (m, 4H),
2.81 (m, 2H), 1.91 (m, 1H), 1.62 (dd, 2H), 1.26 (m, 2H).
EXAMPLE 19
2-(3-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-y-
l)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)ben-
zamide
EXAMPLE 19A
methyl
2-(3-(tert-butoxycarbonylamino)phenoxy)-4-(4-((4'-chlorobiphenyl-2--
yl)methyl)piperazin-1-yl)benzoate
[1941] This EXAMPLE was prepared by substituting
N-tert-butoxycarbonyl-3-aminophenol for EXAMPLE 1D in EXAMPLE
1E.
EXAMPLE 19B
2-(3-tert-butoxycarbonylamino)phenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methy-
l)piperazin-1-yl)benzoic acid
[1942] This EXAMPLE was prepared by substituting EXAMPLE 19A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 19C
tert-butyl
3-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-ni-
tro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)pheno-
xy)phenylcarbamate
[1943] This EXAMPLE was prepared by substituting EXAMPLE 19B for
EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 19D
2-(3-aminophenoxy-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-y-
l)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide
[1944] This EXAMPLE was prepared by substituting EXAMPLE 19C for
EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 11.39 (s, 1H), 9.50 (s, 1H), 8.64 (t, 1H), 8.54 (d, 1H),
7.75 (dd, 2H), 7.51 (d, 5H), 7.38 (m, 2H), 7.31 (m, 1H), 7.16 (d,
1H), 6.92 (t, 1H), 6.73 (dd, 1H), 6.38 (d, 1H), 6.28 (m, 1H), 6.09
(m, 1H), 6.02 (d, 1H), 5.24 (m, 1H), 4.36 (m, 1H), 3.86 (dd, 2H),
3.72 (m, 1H), 3.28 (m, 8H), 3.20 (m, 1H), 3.04 (m, 3H), 2.85 (m,
1H), 1.90 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).
EXAMPLE 20
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphe-
noxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide
EXAMPLE 20A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyph-
enoxy)benzoate
[1945] This EXAMPLE was prepared by substituting 3-methoxyphenol
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 20B
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphe-
noxy)benzoic acid
[1946] This EXAMPLE was prepared by substituting EXAMPLE 20A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 20C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-methoxyphe-
noxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl-
)benzamide
[1947] This EXAMPLE was prepared by substituting EXAMPLE 20B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 11.57 (s, 1H), 8.63 (t, 1H), 8.47 (d, 1H), 7.76 (dd,
1H), 7.47 (m, 6H), 7.36 (m, 2H), 7.24 (m, 1H), 7.11 (m, 2H), 6.76
(dd, 1H), 6.53 (ddd, 1H), 6.35 (m, 3H), 3.86 (m, 2H), 3.66 (s, 3H),
3.32 (m, 6H), 3.17 (m, 4H), 2.36 (m, 4H), 1.92 (m, 1H), 1.64 (dd,
2H), 1.27 (m, 2H).
EXAMPLE 21
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-dimethylam-
ino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide
EXAMPLE 21A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(dimethyl-
amino)phenoxy)benzoate
[1948] This EXAMPLE was prepared by substituting
3-(dimethylamino)phenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 21B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(dimethylamino)p-
henoxy)benzoic acid
[1949] This EXAMPLE was prepared by substituting EXAMPLE 21A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 21C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-dimethylam-
ino)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide
[1950] This EXAMPLE was prepared by substituting EXAMPLE 21B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 11.36 (s, 1H), 8.63 (t, 1H), 8.51 (d, 1H), 7.79 (dd,
1H), 7.46 (m, 6H), 7.36 (m, 2H), 7.24 (m, 1H), 7.15 (d, 1H), 7.04
(t, 1H), 6.72 (dd, 1H), 6.39 (dd, 1H), 6.33 (d, 1H), 6.24 (t, 1H),
6.10 (dd, 1H), 3.86 (dd, 2H), 3.32 (m, 6H), 3.13 (m, 4H), 2.83 (s,
6H), 2.34 (m, 4H), 1.90 (m, 1H), 1.63 (dd, 2H), 1.27 (m, 2H).
EXAMPLE 22
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanopheno-
xy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide
EXAMPLE 22A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophen-
oxy)benzoate
[1951] This EXAMPLE was prepared by substituting 3-cyanophenol for
EXAMPLE 1D is EXAMPLE 1E.
EXAMPLE 22B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanophenoxy)ben-
zoic acid
[1952] A mixture of EXAMPLE 22A (0.081 g) in pyridine (2 mL) in a
10 mL microwave vial equipped with a magnetic stir bar was treated
with LiI (0.402 g), flushed with nitrogen and heated in a CEM
microwave reactor at 120.degree. C. for 30 minutes. The mixture was
concentrated, acidified with 1N HCl, extracted with ethyl acetate
and dried (MgSO.sub.4), filtered and concentrated. The concentrate
was purified by column chromatography on silica gel, eluting with a
gradient of 0-10% methanol in dichloromethane.
EXAMPLE 22C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-cyanopheno-
xy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)be-
nzamide
[1953] This EXAMPLE was prepared by substituting EXAMPLE 22B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 11.78 (s, 1H), 8.62 (t, 1H), 8.41 (d, 1H), 7.72 (dd,
1H), 7.48 (m, 6H), 7.34 (m, 4H), 7.25 (m, 1H), 7.08 (m, 3H), 6.82
(dd, 1H), 6.54 (d, 1H), 3.87 (dd, 2H), 3.33 (m, 6H), 3.22 (m, 4H),
2.38 (m, 4H), 1.93 (m, 1H), 1.65 (dd, 2H), 1.29 (m, 2H).
EXAMPLE 23
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,-
3-benzothiazol-6-yl)oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide
EXAMPLE 23A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(methylbe-
nzo[d]thiazol-6-yloxy)benzoate
[1954] This EXAMPLE was prepared by substituting
2-methylbenzothiazol-6-ol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 23B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(methylbenzo[d]t-
hiazol-6-yloxy)benzoate
[1955] This EXAMPLE was prepared by substituting EXAMPLE 23A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 23C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,-
3-benzothiazol-6-yl)oxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide
[1956] This EXAMPLE was prepared by substituting EXAMPLE 23B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. ppm 11.78 (s, 1H), 8.56 (t, 1H), 8.40 (d, 1H), 7.71 (d,
2H), 7.64 (dd, 1H), 7.51 (m, 5H), 7.37 (d, 2H), 7.32 (m, 1H), 7.28
(d, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.51 (m, 1H), 4.33 (br s,
1H), 3.87 (dd, 2H), 3.69 (br s, 2H), 3.28 (m, 4H), 3.04 (br s, 2H),
2.84 (br s, 1H), 2.74 (s, 3H), 2.49 (m, 4H), 1.90 (br s, 1H), 1.63
(dd, 2H), 1.28 (m, 3H).
EXAMPLE 24
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,-
3-benzothiazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
EXAMPLE 24A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(methylbe-
nzo[d]thiazol-5-yloxy)benzoate
[1957] This EXAMPLE was prepared by substituting
2-methylbenzothiazol-5-ol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 24B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(methylbenzo[d]t-
hiazol-5-yloxy)benzoic acid
[1958] This EXAMPLE was prepared by substituting EXAMPLE 24A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 24C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((2-methyl-1,-
3-benzothiazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
[1959] This EXAMPLE was prepared by substituting EXAMPLE 24B and
EXAMPLE 4A for EXAMPLE 1F and EXAMPLE 1G respectively, in EXAMPLE
1H. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.83 (s, 1H), 9.48
(br s, 1H), 8.64 (t, 1H), 8.45 (d, 1H), 7.88 (d, 1H), 7.76 (dd,
1H), 7.50 (m, 5H), 7.37 (m, 2H), 7.30 (m, 1H), 7.18 (m, 1H), 7.04
(d, 1H), 6.97 (dd, 1H), 6.78 (dd, 1H), 6.48 (br s, 1H), 4.35 (br s,
1H), 3.98 (m, 3H), 3.77 (br s, 2H), 3.60 (t, 4H), 3.49 (m, 2H),
3.15 (m, 4H), 3.04 (m, 4H), 2.75 (s, 3H), 2.56 (m, 2H), 1.94 (m,
2H).
EXAMPLE 25
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-dimet-
hylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-((2-methyl-1,3-benzothiazo-
l-5-yl)oxy)benzamide
[1960] This EXAMPLE was prepared by substituting EXAMPLE 24B
andEXAMPLE 11A for EXAMPLE 1F and EXAMPLE 1G respectively, in
EXAMPLE 1H. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 11.86 (s,
1H), 9.23 (br s, 1H), 8.63 (t, 1H), 8.46 (d, 1H), 7.88 (d, 1H),
7.77 (dd, 2H), 7.51 (m, 6H), 7.39 (m, 3H), 7.32 (br s, 1H), 7.19
(m, 1H), 7.04 (d, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.49 (br s,
1H), 4.37 (br s, 1H), 3.76 (br s, 2H), 3.49 (m, 4H). 3.11 (m, 4H),
2.79 (s, 3H), 2.77 (s, 3H), 2.76 (s, 3H), 1.94 (m, 2H).
EXAMPLE 26
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimeth-
ylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmeth-
yl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 26A
3-(2-hydroxyphenyl)-N,N-dimethylpropanamide
[1961] A solution of chroman-2-one (444 mg) in THF (1 mL) was
treated with dimethylamine (7.5 mL) and stirred at room temperature
for 5 hours. The solution was concentrated. The concentrate was
filtered through a small pad of silica gel.
EXAMPLE 26B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethyl-
amino)-3-oxopropyl)phenoxy)benzoate
[1962] This EXAMPLE was prepared by substituting EXAMPLE 26A for
EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 26C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamin-
o)-3-oxopropyl)phenoxy)benzoic acid
[1963] This EXAMPLE was prepared by substituting EXAMPLE 26B for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 26D
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimeth-
ylamino)-3-oxopropyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethy-
l)amino)phenyl)sulfonyl)benzamide
[1964] This EXAMPLE was prepared by substituting EXAMPLE 26C for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 11.74 (s, 1H), 8.65 (t, 1H), 8.44 (d, 1H), 7.73 (dd, 2H),
7.52 (m, 5H), 7.35 (d, 3H), 7.13 (dd, 2H), 6.96 (t, 1H), 6.87 (t,
1H), 6.75 (dd, 1H), 6.44 (d, 1H), 6.39 (d, 1H), 3.87 (dd, 2H), 3.67
(br, 8H), 3.34 (t, 2H), 3.28 (t, 2H), 3.00 (br, 2H), 2.91 (s, 3H),
2.79 (s, 3H), 2.74 (t, 2H), 2.55 (t, 2H), 1.91 (m, 1H), 1.64 (d,
2H), 1.29 (m, 2H).
EXAMPLE 27
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimeth-
ylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl-
)amino)phenyl)sulfonyl)benzamide
EXAMPLE 27A
2-(2-hydroxyphenyl)-N,N-dimethylacetamide
[1965] This EXAMPLE was prepared by substituting
benzofuran-2(3H)-one for chroman-2-one in EXAMPLE 26A.
EXAMPLE 27B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimet-
hylamino)-2-oxoethyl)phenoxy)benzoate
[1966] This EXAMPLE was prepared by substituting EXAMPLE 27A for
EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 27C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimethylamin-
o)-2-oxoethyl)phenoxy)benzoic acid
[1967] This EXAMPLE was prepared by substituting EXAMPLE 27B for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 27D
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimeth-
ylamino)-2-oxoethyl)phenoxy)-N-((3-nitro-4-(tetrahydro-2H-pyran-4-ylmethyl-
)amino)phenyl)sulfonyl)benzamide
[1968] This EXAMPLE was prepared by substituting EXAMPLE 27C for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.64 (t, 1H), 8.52 (d, 1H), 7.82 (dd, 1H), 7.70 (s, 1H),
7.52 (dd, 5H), 7.37 (d, 2H), 7.33 (s, 1H), 7.19 (m, 2H), 7.14 (t,
1H), 7.03 (t, 1H), 6.70 (m, 2H), 6.23 (s, 1H), 3.86 (dd, 2H), 3.64
(s, 2H), 3.40 (br, 12H), 3.25 (t, 2H), 2.92 (s, 3H), 2.72 (s, 3H),
1.91 (s, 1H), 1.63 (d, 2H), 1.28 (m, 2H).
EXAMPLE 28
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimethy-
lamino)propyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide
EXAMPLE 28A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimet-
hylamino)propyl)phenoxy)benzoate
[1969] A solution of EXAMPLE 26B (211 mg) in THF (1.7 mL) at room
temperature was treated with borane (689 .mu.L) and stirred for 24
hours. The mixture was quenched with 1N HCl and heated at
50.degree. C. overnight. The solution was concentrated. The
concentrate was purified by flash chromatography (0-5% 7N NH.sub.3
in 10% methanol/dichloromethane).
EXAMPLE 28B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-(dimethylamin-
o)propyl)phenoxy)benzoic acid
[1970] This EXAMPLE was prepared by substituting EXAMPLE 28A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 28C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(3-dimethy-
lamino)propyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide
[1971] This EXAMPLE was prepared by substituting EXAMPLE 28B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.65 (t, 1H), 8.44 (d, 1H), 7.75 (dd, 1H), 7.51 (m, 6H),
7.39 (d, 2H), 7.32 (s, 1H), 7.16 (m, 2H), 6.98 (m, 1H), 6.90 (t,
1H), 6.76 (d, 1H), 6.48 (d, 1H), 6.37 (s, 1H), 3.87 (d, 2H), 3.35
(m, 2H), 3.29 (m, 2H), 3.07 (s, 2H), 2.79 (s, 6H), 2.61 (t, 2H),
1.94 (s, 2H), 1.64 (d, 2H), 1.30 (m, 2H).
EXAMPLE 29
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimethy-
lamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide
EXAMPLE 29A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimet-
hylamino)propyl)phenoxy)benzoate
[1972] This EXAMPLE was prepared by substituting EXAMPLE 27B for
EXAMPLE 26B in EXAMPLE 28 A.
EXAMPLE 29B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-(dimet-
hylamino)propyl)phenoxy)benzoic acid
[1973] This EXAMPLE was prepared by substituting EXAMPLE 29A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 29C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(2-dimethy-
lamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide
[1974] This EXAMPLE was prepared by substituting EXAMPLE 29B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.64 (t, 1H), 8.44 (d, 1H), 7.72 (m, 2H), 7.53 (m, 5H),
7.38 (d, 2H), 7.32 (m, 1H), 7.19 (dd, 1H), 7.15 (d, 1H), 7.01 (td,
1H), 6.90 (t, 1H), 6.79 (dd, 1H), 6.49 (d, 1H), 6.42 (d, 1H), 3.88
(m, 2H), 3.60 (br, 10H), 3.35 (t, 2H), 3.29 (t, 4H), 2.97 (m, 2H),
2.81 (m, 6H), 1.92 (s, 1H), 1.65 (m, 2H), 1.30 (m, 2H).
EXAMPLE 30
2-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tet-
rahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-dim-
ethylbenzamide
EXAMPLE 30A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethyl-
carbamoyl)phenoxy)benzoate
[1975] This EXAMPLE was prepared by substituting
2-hydroxy-N,N-dimethylbenzamide for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 30B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethylcarbamo-
yl)phenoxy)benzoic acid
[1976] This EXAMPLE was prepared by substituting EXAMPLE 30A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 30C
2-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitro-4-((tet-
rahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)phenoxy)-N,N-dim-
ethylbenzamide
[1977] This EXAMPLE was prepared by substituting EXAMPLE 30B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 8.63 (t, 1H), 8.52 (d, 1H), 7.83 (dd, 1H), 7.71 (s, 1H),
7.51 (m, 5H), 7.30 (m, 5H), 7.20 (d, 1H), 7.13 (t, 1H), 6.82 (d,
1H), 6.74 (m, 1H), 6.24 (d, 1H), 4.30 (s, 1H), 3.80 (br, 11H), 3.34
(t, 2H), 3.27 (t, 2H), 2.79 (s, 3H), 2.66 (s, 3H), 1.90 (s, 1H),
1.62 (d, 2H), 1.27 (ddd, 2H).
EXAMPLE 31
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethyl-
amino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide
EXAMPLE 31A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethyl-
amino)methyl)phenoxy)benzoate
[1978] This EXAMPLE was prepared by substituting EXAMPLE 30A for
EXAMPLE 26B in EXAMPLE 28A.
EXAMPLE 31B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-(dimethylamino)m-
ethyl)phenoxy)benzoate
[1979] This EXAMPLE was prepared by substituting EXAMPLE 31A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 31C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-((dimethyl-
amino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide
[1980] This EXAMPLE was prepared by substituting EXAMPLE 31B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. 8.62 (m, 1H), 8.38 (d, 1H), 7.70 (dd, 1H), 7.61 (d, 1H),
7.51 (d, 4H), 7.39 (m, 4H), 7.33 (s, 1H), 7.15 (m, 2H), 6.97 (t,
1H), 6.84 (d, 1H), 6.61 (s, 1H), 6.43 (d, 1H), 4.33 (s, 2H), 3.88
(d, 2H), 3.55 (br, 10H), 3.35 (m, 2H), 3.29 (m, 2H), 2.78 (s, 6H),
1.92 (s, 1H), 1.64 (d, 2H), 1.31 (m, 2H).
EXAMPLE 32
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy)-
benzamide
EXAMPLE 32A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(morpholi-
nophenoxy)benzoate
[1981] This EXAMPLE was prepared by substituting 3-morpholinophenol
for EXAMPLE 1D to EXAMPLE 1E.
EXAMPLE 32B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(morpholinopheno-
xy)benzoic acid
[1982] This EXAMPLE was prepared by substituting EXAMPLE 32A for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 32C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-morpholin-4-ylphenoxy)-
benzamide
[1983] This EXAMPLE was prepared by substituting EXAMPLE 32B for
EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 11.61 (br s, 1H), 9.50 (br s,
1H), 8.69 (t, 1H), 8.51 (d, 1H), 7.83 (dd, 1H), 7.68 (m, 1H), 7.50
(m, 5H), 7.39 (m, 2H), 7.31 (m, 1H), 7.15 (d, 3H), 7.08 (m. 1H),
6.75 (dd, 1H), 6.59 (dd, 1H), 6.40 (m, 2H), 6.23 (m, 1H), 3.71 (m,
4H), 3.52 (m, 4H), 3.40 (m, 4H), 3.13 (m, 4H), 3.00 (m, 6H), 2.78
(s, 6H), 1.96 (m, 2H).
EXAMPLE 33
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimet-
hyl-1,3-thiazol-5-yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
EXAMPLE 33A
methyl
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piper-
azin-1-yl)benzoate
[1984] This EXAMPLE was prepared by substituting
3-(benzyloxy)phenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 33B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-hydroxyph-
enoxy)benzoate
[1985] EXAMPLE 33 A (510 mg) in CH.sub.2Cl.sub.2 (5 mL) was cooled
to 0.degree. C., treated with 1M BBr.sub.3 CH.sub.2Cl.sub.2 (4 mL),
and stirred at room temperature for 2 hours. The mixture was
quenched with saturated NaHCO.sub.3 solution and extracted with
ethyl acetate. The extract was washed with water and brine, dried
over Na.sub.2SO.sub.4 and concentrated. The concentrate was
purified by flash column chromatography on silica gel with 0-30%
ethyl acetate in hexane.
EXAMPLE 33C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3(trifluoro-
methylsulfonyloxy)phenoxy)benzoate
[1986] EXAMPLE 33B (180 mg) in THF (5 mL) was cooled to -78.degree.
C., and 0.5 mL of 1M lithium hexamethyldisilazide in THF was added.
The mixture was stirred for 15 minutes then treated with 1,1
1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide
(146 mg). The mixture was warmed to room temperature overnight,
quenched with saturated NH.sub.4Cl solution and extracted with
ethyl acetate. The extract was washed with water and brine, dried
over Na.sub.2SO.sub.4 and concentrated.
EXAMPLE 33D
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dime-
thylthiazol-5-yl)phenoxy)benzoate
[1987] EXAMPLE 33C (60 mg),
2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2,-dioxaborolan-2-yl)thiazole
(36 mg) and dichlorobis(triphenylphosphine) palladium(II) (2 mg)
were dissolved in 5 mL of a dimethoxyethane:ethanol:2M
Na.sub.2CO.sub.3 solution (7:2:2). The mixture was heated at
130.degree. C. for 15 minutes in a microwave reactor and
concentrated. The concentrate was purified by flash column
chromatography with 0-30% ethyl acetate/hexanes.
EXAMPLE 33E
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dime-
thylthiazol-5-yl)phenoxy)benzoic acid
[1988] This EXAMPLE was prepared by substituting EXAMPLE 33D for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 33F
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2,4-dimet-
hyl-1,3-thiazol-5-yl)phenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
[1989] This EXAMPLE was prepared by substituting EXAMPLE 33E for
EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.80 (br s, 1H), 9.67 (br s, 1H),
8.63 (t, 1H), 8.47 (d, 1H), 7.78 (dd, 1H), 7.68 (m, 1H), 7.52 (m,
5H), 7.35 (m, 4H), 7.10 (d, 1H), 7.05 (d, 1H), 6.77 (m, 3H), 6.57
(m, 1H), 3.95 (m, 2H), 3.60 (m, 6H), 3.45 (m, 6H), 3.16 (m, 4H),
3.07 (m, 4H), 2.31 (s, 3H)S 2.26 (s, 3H), 1.95 (m, 2H).
EXAMPLE 34
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
EXAMPLE 34A
ethyl 2-(2-chlorophenoxy)-4-fluorobenzoate
[1990] This EXAMPLE was prepared by substituting 2-chlorophenol
2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 34B
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)-
methyl)piperazin-1-yl)benzoate
[1991] This EXAMPLE was prepared by substituting EXAMPLE 34A for
EXAMPLE 3A is EXAMPLE 3G.
EXAMPLE 34C
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)-
methyl)piperazin-1-yl)benzoic acid
[1992] This EXAMPLE was prepared by substituting EXAMPLE 34B for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 34D
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide
[1993] This EXAMPLE was prepared by substituting EXAMPLE 34C for
EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H NMR
(500 MHz, pyridine-d.sub.5) .delta. 8.37 (d, 1H), 8.08 (d, 1H),
7.76 (dd, 1H), 7.62 (d, 1H), 7.36 (d, 2H), 7.35 (d, 1H), 7.07 (d,
2H), 7.07-7.03 (m, 2H), 6.90 (td, 1H), 6.71 (dd, 1H), 6.55 (dd,
1H), 6.26 (d, 1H), 3.81 (m, 1H), 3.21 (m, 2H), 3.08 (m, 4H), 2.86
(m, 2H), 2.76 (s, 2H), 2.63 (s, 3H), 2.28-2.04 (m, 8H), 1.97 (s,
2H), 1.76 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 35
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
EXAMPLE 35A
ethyl 2-(3,5-dichlorophenoxy)-4-fluorobenzoate
[1994] This EXAMPLE was prepared by substituting 3,5-dichlorophenol
for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 35B
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3,5-dichlorophenoxy)benzoate
[1995] This EXAMPLE was prepared by substituting EXAMPLE 35A for
EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 35C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3,5-dichlorophenoxy)benzoic acid
[1996] This EXAMPLE was prepared by substituting EXAMPLE 35B for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 35D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(3,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
[1997] This EXAMPLE was prepared by substituting EXAMPLE 35C for
EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H NMR
(400 MHz, pyridine-d.sub.5) .delta. 9.14 (d, 1H), 8.53 (m, 1H),
8.32 (m, 1H), 7.95 (d, 1H), 7.46 (d, 2H), 7.11 (d, 2H), 6.99 (m,
3H), 6.81 (m, 2H), 3.73 (m, 1H), 3.22 (m, 4H), 3.05 (m, 2H), 2.85
(s, 2H), 2.56 (m, 2H), 2.46 (s, 3H), 2.30 (m, 6H), 2.14 (m, 2H),
1.95 (m, 4H), 1.42 (m, 2H), 0.97 (s, 6H).
EXAMPLE 36
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophe-
nyl)sulfonyl)benzamide
EXAMPLE 36A
ethyl 2-(3-chlorophenoxy)-4-fluorobenzoate
[1998] This EXAMPLE was prepared by substituting 2-chlorophenol for
2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 36B
ethyl
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-enyl)methyl)piperazin-1-yl)benzoate
[1999] This EXAMPLE was prepared by substituting EXAMPLE 36A for
EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 36C
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)-
methyl)piperazin-1-yl)benzoic acid
[2000] This EXAMPLE was prepared by substituting EXAMPLE 36B for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 36D
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
[2001] This EXAMPLE was prepared by substituting EXAMPLE 36C for
EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H NMR
(400 MHz, pyridine-d.sub.5) .delta. 9.12 (d, 1H), 8.51 (d, 1H),
8.31 (dd, 1H), 7.99 (d, 1H), 7.45 (d, 1H), 7.11 (m, 3H), 7.02 (m,
2H), 6.91 (dd, 1H), 6.82 (dd, 1H), 6.68 (d, 2H), 4.05 (br s, 1H),
3.55 (br s, 2H), 3.31 (s, 6H), 2.99 (s, 2H), 2.85 (s, 3H), 2.51 (br
s, 3H), 2.41 (s, 6H), 1.99 (s, 2H), 1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 37
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-ni-
trophenyl)sulfonyl)benzamide
EXAMPLE 37A
4'-chloro-4-hydroxybiphenyl-2-carbaldhyde
[2002] 2-bromo-5-hydroxybenzaldehyde (20 g), 4-chlorophenylboronic
acid (17.1 g) and dichlorobis)triphenylphosphine) palladium(II)
(1.75 g) were dissolved in 475 mL of a dimethoxyethane:ethanol:2M
Na.sub.2CO.sub.3 solution (7:2:2). The mixture was heated to reflux
for 1 hour. The reaction mixture was then diluted with ethyl
acetate, washed thoroughly with water and with brine, dried over
MgSO.sub.4, filtered and concentrated. The resulting solid was
slurried in 500 mL of hexane:ether mixture (2:1). The title
compound was collected by filtration.
EXAMPLE 37B
tert-butyl
4-((4'-chloro-4-hydroxybiphenol-2-yl)methyl)piperazine-1-carbox-
ylate
[2003] The title compound was prepared by substituting EXAMPLE 37A
for 4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 37C
tert-butyl
(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)-
piperazine-1-carboxylate
[2004] EXAMPLE 37B (2 g), 2-chloro-N,N-dimethylethanamine
hydrochloric acid salt (2.15 g), and cesium carbonate (9.70 g) were
combined in 10 mL of N,N-dimethylformamide. The resulting mixutre
was heated to 80.degree. C. overnight. The reaction was cooled to
room temperature, diluted with ethyl acetate and poured into water.
The aqueous layer was xtracted with ethyl acetate, and the combined
organic layers were washed thoroughly with water and with brine,
dried over MgSO.sub.4, filtered and concentrated. The crude
material was slurried in 100 mL of ether and the product was
obtained by filtration.
EXAMPLE 37D
2-(4
'-chloro-2-(piperazin-1-ylmethyl)biphenyl-4-yloxy)-N,N-dimethylethana-
mine
[2005] The title compound was prepared by substituting EXAMPLE 37C
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 37E
ethyl
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)pip-
erazin-1-yl)-2-(3-chlorophenoxy)benzoate
[2006] The title compound was prepared by substituting EXAMPLE 36A
for EXAMPLE 3A and EXAMPLE 37D for EXAMPLE 3F in EXAMPLE 3G.
EXAMPLE 37F
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-
-1-yl)-2-(3-chlorophenoxy)benzoic acid
[2007] The title compound was prepared by substituting EXAMPLE 37E
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 37G
4-(4-((4'-chloro-4-(2-(dimethylamino)ethoxy-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-2-(3-chlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-ni-
trophenyl)sulfonyl)benzamide
[2008] The title compound was prepared by substituting EXAMPLE 37F
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.88 (br s, 1H),
9.52 (br s, 1H), 9.30 (br s, 1H), 8.45 (m, 1H), 8.21 (d, 1H), 7.78
(dd, 1H), 7.50 (m, 3H), 7.38 (m, 2H), 7.1B(in, 3H), 6.95 (m, 1H),
6.81 (dd, 1H), 6.72 (dd, 1H), 6.6 H(m, 1H), 6.53 (m, 1H), 4, 35 (m,
2H), 3.53 fro, 2B), 3.28 fro, 2H), 3.21 (m, 4H), 3.08 (m, 2H), 2.88
(s, 6H), 2, 73 (m, 2H), 2.64 (m, 1H), 2.43 (s, 3H), 2.27 (m, 4H),
1.83 (m, 2H).
EXAMPLE 38
2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3-n-
itrophenyl)sulfonyl)benzamide
EXAMPLE 38A
methyl 6,6-dimethyl-4-oxotetrahydro-2H-pyran-3-carboxylate
[2009] To a suspension of hexane-washed NaH (0.72 g, 60%) in
tetrahydrofuran (30 mL) was added a solution of
2,2-dimethyldihydro-2H-pyran-4(3H)-one (2.0 g) in tetrahydrofuran
(20 mL). The suspension was stirred at room temperature for 30
minutes. Dimethylcarbonate (6.31 mL) was added dropwise by syringe.
The mixture was heated to reflux for 4 hours. The mixture was
acidified with 5% aqueous HCl and extracted with dichloromethane
(100 mL.times.3) and washed with water and brine, and dried over
Na.sub.2SO.sub.4. After filtration and concentration, the crude
product was loaded on a column and eluted with 10% ethyl acetate in
hexane to give the product
EXAMPLE 38B
[2010] methyl
6,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydro-2H-pyran-3-carbox-
ylate
[2011] To a cooled (0.degree. C.) stirring suspension of NaH (0.983
g 60% in mineral oil, washed with hexane three times) in ether (50
mL) was added EXAMPLE 38A (3.2 g). The mixture was stirred at
0.degree. C. for 30 minutes before the addition of triflic
anhydride (4.2 mL). The mixture was then stirred at room
temperature overnight. The mixture wa diluted with ether (200 mL)
and washed with 5% HCl, water and brine. After drying over
Na.sub.2SO.sub.4, evaporation of solvent gave the crude product
which was used without further purification.
EXAMPLE 38C
methyl
4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylate
[2012] To a solution of EXAMPLE 38B (2.88 g), 4-chlorophenylboronic
acid (1.88 g) and tetrakis(triphenylphosphine)palladium(0) (0.578
g) in toluene (40 mL) and ethanol (10 mL) was added 2N aqueous
Na.sub.2CO.sub.3 (10 mL). The mixture was stirred at reflux
overnight. The mixture was diluted with ether (300 mL) and washed
with water, grine and dried over Na.sub.2SO.sub.4. After filtration
and evaporation of solvent, the residue was loaded on a column and
eluted with 3% ethyl acetate in hexane to give the product.
EXAMPLE 38D
4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methanol
[2013] To a solution of EXAMPLE 38C (1.6 g) in ether (20 mL) was
added LiAlH.sub.4 (1.2 g). The mixture was stirred at room
temperature for 4 hours. The mixxture was acidified carefully with
5% aqueous HCl and extracted with ethyl acetate (100 mL.times.3)
and the combined organic layers were washed with water, brine and
dried over Na.sub.2SO.sub.4. After filtration and evaporation of
solvent, the crude product was loaded on a column and eluted with
10% ethyl acetate in hexane to give the product.
EXAMPLE 38E
4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carbaldehyde
[2014] To a solution of oxalyl chloride (1.1 g) in dichloromethane
(30 mL) at -78.degree. C. for 30 minutes, and then a solution of
EXAMPLE 38D (1.2 g) in dichloromethane (10 mL) was added. The
mixture was stirred at -78.degree. C. for 2 hours before the
addition of triethylamine (10 mL). The mixture was stirred
overnight and the temperature was allowed to rise to room
temperature. The mixture was diluted with ether (300 mL) and washed
with water, brine and dried over Na.sub.2SO.sub.4. After filtration
and evaporation of solvent, the crude product was loaded on a
column and eluted with 5% ethyl acetate in hexane to give the
product.
EXAMPLE 38F
methyl 2-(2-chlorophenoxy)-4-(piperazin-1-yl)benzoate
[2015] This example was prepared by substituting piperazine for
EXAMPLE 3F and EXAMPLE 34A for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 38G
methyl
2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihy-
dro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
[2016] To a solution of EXAMPLE 38E (100 mg) and EXAMPLE 38F (177
mg) in dichloromethane (10 mL) was added sodium
triacetoxyborohydride (154 mg). The mixture was stirred at room
temperature overnight. The mixture was diluted with ethyl acetate
(200 mL) and washed with 2 wt % aqueous NaOH, water and brine.
After drying over Na.sub.2SO.sub.4 and filtration, the solvent was
evaporated under vacuum and the residue was loaded on a column and
eluted with 30% ethyl acetate in hexane to give the product.
EXAMPLE 38H
2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl)methyl)piperazin-1-yl)benzoic acid
[2017] To a solution of EXAMPLE 38G (254 mg) in tetrahydrofuran (4
mL), methanol (2 mL) and water (2 mL) was added LiOH H.sub.2O (126
mg). The mixture was stirred at room temperature overnight. The
mixture was then neutralized with 5% aqueous HCl and diluted with
ethyl acetate (200 mL). After washing with brine, it was dried over
Na.sub.2SO.sub.4. Filtration and evaporation of solvent gave the
product.
EXAMPLE 38I
2-(2-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino-3-n-
itrophenyl)sulfonyl)benzamide
[2018] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 38H and EXAMPLE
3I, respectively. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.33 (d, 1H), 8.06 (d, 1H), 7.71 (dd, 1H), 7.64 (d, 1H),
7.38 (d, 2H), 7.33 (dd, 1H), 7.16 (d, 2H), 7.02 (m, 2H), 6.86 (m,
1H), 6.69 (dd, 1H), 6.49 (dd, 1H), 6.25 (d, 1H), 4.14 (m, 2H), 3.73
(m, 1H), 3.04 (m, 10H), 2.87 (m, 2H), 2.42 (m, 4H), 2.22 (m, 6H),
1.69 (m, 2H), 1.21 (s, 6H).
EXAMPLE 39
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimeth-
ylamino)ethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide
EXAMPLE 39A
2-(3-(benzyloxy)phenoxy)-N,N-dlmethylethanamine
[2019] A solution of 3-(benzyloxy)phenol (2.002 g),
2-chloro-N,N-dimethylethanamine (1.459 g) in N,N-dimethylformamide
(50 mL) was treated with cesium carbonate (3.91 g) and stirred at
50.degree. C. overnight. The mixture was diluted with ethyl acetate
and 1N aqueous NaOH and the layers were separated. The aqueous
layer was extracted with ethyl acetate and the combined organic
layers were dried over MgSO.sub.4, filtered and concentrated. The
residue was purified by flash chromatography (5% 7N NH.sub.3 in
methanol-dichloromethane) to give the desired product.
EXAMPLE 39B
3-(2-(dimethylamino)ethoxy)phenol
[2020] EXAMPLE 39A (450 mg) was dissolved in ethyl acetate (10 mL).
The flask was flushed with nitrogen three times followed by the
addition of 10% Pd/C (45 mg). The reaction mixture was kept under 1
atm of hydrogen at room temperature overnight. The mixture was
filtered and concentrated. The residue was filtered through a small
pad of silica gel and used in the next step without further
purification.
EXAMPLE 39C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamin-
o)ethoxy)phenoxy)benzoate
[2021] The title compound was prepared by substituting EXAMPLE 39B
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 39D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamin-
o)ethoxy)phenoxy)benzoic acid
[2022] The title compound was prepared by substituting EXAMPLE 39C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 39E
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimeth-
ylamino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide
[2023] The title compound was prepared by substituting EXAMPLE 39D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (m, 1H), 9.60 (m, 1H),
8.64 (s, 1H), 8.50 (d, 1H), 7.80 (d, 1H), 7.72 (s, 1H), 7.52 (d,
5H), 7.38 (d, 2H), 7.33 (s, 1H), 7.19 (m, 2H), 6.78 (d, 1H), 6.65
(d, 1H), 6.45 (dd, 3H), 4.24 (s, 2H), 3.86 (d, 2H), 3.67 (s, 10H),
3.48 (s, 2H), 3.35 (t, 2H), 3.27 (t, 2H), 2.85 (s, 6H), 1.91 (s,
1H), 1.63 (d, 2H), 1.27 (d, 2H).
EXAMPLE 40
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3--
nitrophenyl)sulfonyl)benzamide
EXAMPLE 40A
ethyl 2-(4-amino-3-chlorophenoxy)-4-fluorobenzoate
[2024] The title compound was prepared by substituting
4-amino-3-chlorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 40B
ethyl
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2025] The title compound was prepared by substituting EXAMPLE 40A
for methyl-2-bromo-4-fluorobenzoate and EXAMPLE 3F for EXAMPLE 1B
in EXAMPLE 1C.
EXAMPLE 40C
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2026] The title compound was prepared by substituting EXAMPLE 40B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 40D
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3--
nitrophenyl)sulfonyl)benzamide
[2027] The title compound was prepared by substituting EXAMPLE 40C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 10.70 (br s, 1H),
8.60 (s, 1H), 8.20 (dd, 1H), 7.90 (dd, 1H), 7.45 (d, 1H), 7.35 (d,
2H), 7.24 (d, 1H), 7.06 (d, 2H), 6.91 (d, 1H), 6.78 (s, 2H), 6.64
(d, 1H), 6.14 (d, 1H), 5.24 (s, 2H), 4.03 (m, 1H), 3.52 (m, 2H),
3.10 (m, 6H), 2.80 (m, 4H), 2.73 (s, 3H), 2.18 (m, 6H), 1.99 (m,
2H), 1.82 (m, 2H), 1.38 (m, 2H), 0.94 (s, 6H).
EXAMPLE 41
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitro-
phenyl)sulfonyl)benzamide
EXAMPLE 41A
4-(1-isopropylpiperidin-4-ylamino)-3-nitrobenzensulfonamide
[2028] A suspension of 4-chloro-3-nitrobenzenesulfonamide (1.664 g)
triethylamine (2 mL) and 1-isopropylpiperidin-4-amine (1 g) in
dioxane (10 mL) was stirred for 16 hours at 90.degree. C. The
reaction mixture was cooled to room temperature and the solid
material was filtered off. The solid material was washed with 20%
methanol/dichloromethane, and the mixture was dried under vacuum,
to provide the product.
EXAMPLE 41B
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-isopropylpiperidin-4-yl)amino)-3-nitro-
phenyl)sulfonyl)benzamide
[2029] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and. EXAMPLE 41A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 9.18 (d, 1H), 8.51
(d, 1H), 8.37 (dd, 1H), 8.01 (d, 1H), 7.40-7.49 (m, 3H), 7.10 (d,
2H), 7.00-7.06 (m, 2H), 6.94-6.99 (m, 1H), 6.86 (dd, 1H), 6.80 (dd,
1H), 6.54 (d, 2H), 3.90-3.99 (m, 1H), 3.41-3.55 (m, 3H), 3.10-3.21
(m, 6H), 2.87 (s, 2H), 2.24-2.45 (m, 10H), 1.99 (s, 2H), 1.41 (t,
2H), 1.25 (d, 6H), 0.95 (s, 6H).
EXAMPLE 42
2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
EXAMPLE 42A
Ethyl 2-(2-bromophenoxy)-4-fluorobenzoate
[2030] The title compound was prepared by substituting
2-bromophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 42B
[2031] Ethyl
2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)-
methyl)piperazin-1-yl)benzoate
[2032] The title compound was prepared by substituting EXAMPLE 42A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 42C
2-(2-Bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)m-
ethyl)piperazin-1-yl)benzoic acid
[2033] The title compound was prepared by substituting EXAMPLE 42B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 42D
2-(2-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
[2034] The title compound was prepared by substituting EXAMPLE 42C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.81 (s, 1H),
9.24-9.76 (m, 2H), 8.48 (d, 1H), 8.21 (d, 1H), 7.84 (dd, 1H),
7.50-7.60 (m, 2H), 7.41 (d, 2H), 7.25 (d, 1H), 7.18 (t, 1H), 7.11
(d, 2H), 6.95 (t, 1H), 6.80 (dd, 1H), 6.69 (d, 1H), 6.39 (s, 1H),
4.03-4.13 (m, 1H), 3.47-3.65 (m, 5H), 3.20-3.40 (m, 3H), 3.01-3.19
(m, 4H), 2.70-2.91 (m, 5H), 2.14-2.26 (m, 4H), 2.04 (s, 2H),
1.73-1.93 (m, 2H), 1.48 (t, 2H), 0.96 (s, 6H).
EXAMPLE 43
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)pi-
perazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl-
)benzamide
EXAMPLE 43A
ethyl 2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate
[2035] The title compound was prepared as described in EXAMPLE 38B
by replacing EXAMPLE 38A with ethyl
2-oxocyclohexanecarboxylate.
EXAMPLE 43B
ethyl 2-(4-chlorophenyl)cyclohex-1-enecarboxylate
[2036] The title compound was prepared as described in EXAMPLE 38C
by replacing EXAMPLE 38B with EXAMPLE 43A.
EXAMPLE 43C
(2-(4-chlorophenyl)cyclohex-1-enyl)methanol
[2037] The title compound was prepared as described in EXAMPLE 38D
by replacing EXAMPLE 38C with EXAMPLE 43B.
EXAMPLE 43D
(2-(4-chlorophenyl)cyclohex-1-enylcarbaldehyde
[2038] The title compound was prepared as described in EXAMPLE 38E
by replacing EXAMPLE 38D with EXAMPLE 43C.
EXAMPLE 43E
methyl
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-enyl)methy-
l)piperazin-1-yl)benzoate
[2039] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38E with EXAMPLE 43D.
EXAMPLE 43F
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-enyl)methyl)piper-
azin-1-yl)benzoic acid
[2040] The title compound was prepared as described in EXAMPLE 38 H
by replacing EXAMPLE 38G with EXAMPLE 43E.
EXAMPLE 43G
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-cyclohex-1-en-1-yl)methyl)pi-
perazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl-
)benzamide
[2041] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 43F and EXAMPLE
3I, respectively, .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.36 (d, 1H), 8.07 (d, 1H), 7.74 (dd, 1H), 7.62 (d, 1H),
7.35 (d, 2H), 7.09 (d, 2H), 7.04 (d, 1H), 6.89 (m, 1H), 6.70 (dd,
1H), 6.54 (dd, 1H), 6.25 (d, 1H), 3.80 (m, 1H), 3.11 (m, 8H), 2.77
(m, 4H), 2.59 (m, 4H), 2.15 (m, 8H), 1.70 (m, 8H).
EXAMPLE 44
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)ami-
no)-3-nitrophenyl)sulfonyl)benzamide
EXAMPLE 44A
4-methoxy-3-methyl-1H-indazole
[2042] A solution of 1-(2-fluoro-6-methoxyphenyl)ethanone (1 g),
hydrazine (1.04 g), and sodium acetate (0.49 g) was stirred for 72
hours in toluene (10 mL). The mixture was concentrated, taken up in
DMSO (8 mL), and heated to 135.degree. C. for 24 hours. The mixture
was cooled, poured into ethyl acetate (200 mL), and rinsed with
3.times. water, and brine. The organic layer was concentrated and
chromatographed on silica gel using 10-100% ethyl
acetate/hexanes.
EXAMPLE 44B
3-methyl-1H-indazol-4-ol
[2043] A 1M solution of BBr.sub.3 (6.57 mL) was added to a solution
of EXAMPLE 44A (0.71 g) in dichloromethane (30 mL), and the
reaction was stirred for 18 hours. The reaction was quenched by the
slow addition of methanol, and the mixture was concentrated and
chromatographed on silica gel using 10% methanol/ethyl acetate.
EXAMPLE 44C
ethyl 4-fluoro-2-(3-methyl-1H-indazol-4-yloxy)benzoate
[2044] The title compound was prepared by substituting EXAMPLE 44B
for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 44D
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-((3-methyl-1H-indazol-4-yl)benzoate
[2045] The title compound was prepared by substituting EXAMPLE 44C
for methyl-2-bromo-4-fluorobenzoate and EXAMPLE 3F for EXAMPLE 1B
in EXAMPLE 1C.
EXAMPLE 44E
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-((3-methyl-1H-indazol-4-yl)benzoic acid
[2046] The title compound was prepared by substituting EXAMPLE 40B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 44F
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((3-methyl-1H-indazol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)ami-
no)-3-nitrophenyl)sulfonyl)benzamide
[2047] The title compound was prepared by substituting EXAMPLE 44E
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11. 95 (br s, 2H),
8.47 (m, 1H), 8.27 (d, 1H), 7.62 (d, 1H), 7.36 (d, 2H), 7.07 (d,
2H), 6.93 (m, 2H), 6.72 (m, 2H), 6.36 1H), 5.92 (d, 1H), 3.61 (m,
4H), 3.04 (m, 4H), 2.75 (m, 2H), 2.39 (m, 4H), 2.18 (m, 6H), 1.99
(s, 3H), 1.90 (m, 6H), 1.77 (m, 2H), 1.41 (m, 2H), 0.94 (s,
6H).
EXAMPLE 45
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
EXAMPLE 45A
Ethyl 2-(2,3-difluorophenoxy)-4-fluorobenzoate
[2048] The title compound was prepared by substituting
2,3-difluorophenol 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 45B
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(2,3-difluorophenoxy)benzoate
[2049] The title compound was prepared by substituting EXAMPLE 45A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 45C
[2050] This EXAMPLE was prepared by substituting EXAMPLE 45B for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 45D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
[2051] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) 9.17 (d, 1H), 8.49 (d, 1H), 8.38
(dd, 1H), 7.99 (d, 1H), 7.46 (d, 2H), 7.10 (d, 2H), 7.01 (d, 1H),
6.85 (m, 3H), 6.69 (m, 2H), 3.70 (m, 1H), 3.21 (m, 4H), 3.05 (m,
2H), 2.84 (s, 2H), 2.57 (m, 2H), 2.46 (s, 3H), 2.28 (m, 6H), 2.11
(m, 2H), 1.94 (m, 4H), 1.42 (t, 2H), 0.96 (s, 6H).
EXAMPLE 46
2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
EXAMPLE 46A
Ethyl 2-(3-bromophenoxy)-4-fluorobenzoate
[2052] The title compound was prepared by substituting
3-bromophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 46B
Ethyl
2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
enyl)methyl)piperazin-1-yl)benzoate
[2053] The title compound was prepared by substituting EXAMPLE 46A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 46C
2-(3-Bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)m-
ethyl)piperazin-1-yl)benzoic acid
[2054] The title compound was prepared by substituting EXAMPLE 46B
for EXAMPLE 1E EXAMPLE 1F.
EXAMPLE 46D
2-(3-bromophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
[2055] The title compound was prepared by substituting EXAMPLE 46C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.97 (s, 1H),
9.46 (s, 1H), 9.38 (s, 1H), 8.39-8.48 (m, 1H), 8.21 (d, 1H), 7.78
(dd, 1H), 7.53 (d, 1H), 7.41 (d, 2H), 7.08-7.24 (m, 5H), 6.75-6.86
(m, 3H), 6.58 (d, 1H), 4.08 (s, 1H), 3, 62 (s, 3H), 3.55 (d, 4H),
3.23-3.39 (m, 3H), 3.05-3.20 (m, 4H), 2.78-2.91 (m, 5H), 2.70-2.78
(m, 1H), 2.13-2.28 (m, 4H), 2.05 (s, 2H), 1.78-1.92 (m, 2H), 1.48
(t, 2H), 0.96 (s, 6H).
EXAMPLE 47
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
EXAMPLE 47A
4-(3-Ethylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
[2056] The title compound was prepared by substituting
1-ethylpiperidin-4-amine for 1-isopropylpiperidin-4-amine in
EXAMPLE 41A.
EXAMPLE 47B
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-ethylpiperidin-4-yl)amino)-3-nitrophen-
yl)sulfonyl)benzamide
[2057] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 47A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 9.18 (d, 1H), 8.50
(d, 1H), 8.36 (dd, 1H), 8.01 (d, 1H), 7.39-7.47 (m, 3H), 7.10 (d,
5H), 7.03-7.06 (m, 2H), 7.02 (dd, 1H), 6.96 (td, 2H), 6.85 (dd,
1H), 6.80 (dd, 1H), 6.54 (d, 1H), 3.93-4.00 (m, 1H), 3.55 (s, 2H),
3.13-3.21 (m, 5H), 3.10 (q, 2H), 2.90 (s, 2H), 2.28-2.37 (m, 8H),
2.22-2.28 (m, 2H), 1.98 (s, 2H), 1.40 (t, 2H), 1.26 (t, 3H), 0.95
(s, 6H).
EXAMPLE 48
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin-4-
-yl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 48A
4-(1,2,2,6,6-Pentamethylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
[2058] The title compound was prepared by substituting
1,2,2,6,6-penamethylpiperidin-4-ylamine for
1-isopropylpiperidin-4-amine in EXAMPLE 41A.
EXAMPLE 48B
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1,2,2,6,6-pentamethylpiperidin-4-
-yl)amino)phenyl)sulfonyl)benzamide
[2059] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 48A for EXAMPLE 1G is EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 9.19 (d, 1H), 8.45
(d, 1H), 8.37 (dd, 1H), 8.01 (d, 1H), 7.45 (d, 3H), 7.09 (d, 2H),
7.06 (s, 1H), 7.02-7.05(m, 2H), 6.99 (td, 1H), 6.86 (dd, 2H), 6.80
(dd, 1H), 6.53 (d, 1H), 4.16-4.25 (m, 1H), 3.16-3.23 (m, 4H), 2.90
(s, 2H), 2.82 (s, 3H), 2.45-2.54 (m, 2H), 2.31 (d, 6H), 2.17 (dd,
2H), 1.98 (s, 2H), 1.55 (s, 6H), 1.46 (s, 6H), 1.40 (t, 2H), 0.95
(s, 6H).
EXAMPLE 49
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpi-
peridin-4-yl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 49A
tert-butyl 1-(tetrahydro-2 H-pyran-4-yl)piperidin-4-ylcarbamate
[2060] A mixture of tert-butyl piperidin-4-ylcarbamate (45 g) and
dihydro-2H-pyran-4(3H)-one (24.74 g) in dichloromethane (1000 mL)
waws treated with sodium triacetoxyborohydride (61.9 g), stirred at
room temperature for 16 hours, washed with 1M sodium hydroxide and
dried with anhydrous sodium sulfate, filtered and concentrated. The
concentrate was flash column chromatographed on silica gel with
10-20% methanol/dichloromethane.
EXAMPLE 49B
1-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine dihydrochloride
salt
[2061] A solution of EXAMPLE 49A (52.57 g) in dichloromethane (900
mL) was treated with 4M aqueous HCl (462 mL), mixed vigorously at
room temperature 16 hours and concentrated.
EXAMPLE 49C
3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)benzenesulfonam-
ide
[2062] A mixture of EXAMPLE 49B (22.12 g), water (43 mL), and
triethylamine (43.6 mL) in 1,4-dioxane (300 mL) was stirred at room
temperature until EXAMPLE 49B completely dissolved. The solution
was then treated with 4-chloro-3-nitrobenzenesulfonamide (20.3 g),
heated at 90.degree. C. for 16 hours, cooled and concentrated. 10%
Methanol in dichloromethane was added, and the solution was stirred
vigorously at room temperature until a fine suspension existed and
then the mixture was filtered.
EXAMPLE 49D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpi-
peridin-4-yl)amino)phenyl)sulfonyl)benzamide
[2063] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 9.18 (d, 1H), 8.53
(d, 1H), 8.40 (dd, 1H), 7.99 (d, 1H), 7.45 (d, 2H), 7.10 (d, 2H),
7.03 (d, 1H), 6.85 (m, 3H), 6.69 (m, 2H), 4.02 (m, 2H), 3.72 (m,
1H), 3.31 (t, 2H), 3.21 (m, 4H), 3.11 (m, 2H), 2.83 (m, 3H), 2.66
(m, 2H), 2.30 (m, 6H), 2.16 (m, 2H), 1.93 (m, 4H), 1.74 (m, 4H),
1.41 (t, 2H), 0.96 (s, 6H).
EXAMPLE 50
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino-
)-3-nitrophenyl)sulfonyl)benzamide
EXAMPLE 50A
((3-fluoro-4-nitrophenoxy)methylene)dibenzene
[2064] Bromodiphenylmethane (3.5 g) and 3-fluoro-4-nitrophenol were
dissolved in N,N-dimethylformamide (30 mL), and then
K.sub.2CO.sub.3 (4.2 g) was added and the reaction stirred at room
temperature for 60 hours. The reaciton was partitioned between
water and ethyl acetate. The organic layer was washed with 2M
aqueous Na.sub.2CO.sub.3 and brine, then dried over
Na.sub.2SO.sub.4. After filtration and concentration, the crude
material was purified by column chromatography using 1.5-2.0% ethyl
acetate in hexanes.
EXAMPLE 50B
5-(benzyhydryloxy)-7-fluoro-1H-indole
[2065] EXAMPLE 50A (2.0 g) was dissolved in tetrahydrofuran (60
mL), then that solution was cooled to -40.degree. C. Vinylmagnesium
bromide, 1.0M in tetrahydrofuran, (21 mL) was then added dropwise,
keeping the temperature below -30.degree. C. The reaction was
stirred at -40.degree. C. for 90 minutes, and was partitioned
between saturated NH.sub.4Cl and ethyl acetate. The organic layer
was washed with brine and dried over Na.sub.2SO.sub.4. After
filtration and concentration, the crude material was purified by
column chromatography using 2.5-3.0% ethyl acetate in hexanes.
EXAMPLE 50C
7-fluoro-1H-indol-5-ol
[2066] EXAMPLE 50B (240 mg) was dissolved in ethyl acetate (1 mL)
and methanol (9 mL), then palladium hydroxide on carbon (35 mg) was
added and the reaciton stirred at room temperature under a hydrogen
balloon for 90 minutes. The reaction was filtered through celite
and concentrated to give the crude product which was carried on in
the next step without further purificaction.
EXAMPLE 50D
ethyl 4-fluoro-2-(7-fluoro-1H-indol-5-yloxy)benzoate
[2067] The title compound was prepared by substituting EXAMPLE 50C
for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 50E
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(7-fluoro-1H-indol-5-yloxy)benzoate
[2068] The title compound was prepared by substituting EXAMPLE 50D
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 50F
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-((7-fluoro-1H-indol-
-5-yloxy)benzoic acid
[2069] The title compound was prepared by substituting EXAMPLE 50E
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 50G
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((7-fluoro-1H-indol-5-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino-
)-3-nitrophenyl)sulfonyl)benzamide bis(2,2,2-trifluoroacetate)
[2070] EXAMPLE 50F (35 mg), EXAMPLE 3I (17 mg),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (21
mg), and 4-dimethylaminopyridine (14 mg) were stirred in
CH.sub.2Cl.sub.2 (1.5 mL) overnight. The reaction was concentrated
and the crude material was purified by preparative HPLC using
250.times.50 mm C18 column and eluting with 20-100% CH.sub.3CN vs
0.1% trifluoroacetic acid in water, giving the product as a
trifluoroacetate salt. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.62 (br s, 1H), 9.65, 9.45
(both v br s, total 2H), 8.55 (d, 1H), 8.17 (br d, 1H), 7.84 (dd,
1H), 7.50 (d, 1H), 7.43 (t, 1H), 7.39 (d, 2H), 7.20 (d, 1H), 7.08
(d, 2H), 6.90 (d, 1H), 6.66 (m, 2H), 6.44 (m, 1H), 6.28 (d, 1H),
4.02, 3.82 (both br s, total 2H), 3.60 (v br m, 4H), 3.05 (v br m,
5H), 2.85, 2.80 (br m, br s, total 5H), 2.20 (br m, 5H), 2.00 (br
s, 3H), 1.80 (v br m, 2H) 1.44 (br t, 2H), 0.95 (s, 6H).
EXAMPLE 51
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
[2071] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, pyridine-d.sub.5) .delta. 9.21 (d, 1H), 9.00 (m, 1H),
8.36 (dd, 1H), 7.97 (d, 1H), 7.45 (d, 2H), 7.10 (d, 2H), 6.97 (d,
1H), 6.85 (d, 3H), 6.69 (d, 2H), 3.82 (m, 4H), 3.38 (q, 2H), 3.21
(m, 4H), 2.86 (s, 2H), 2.45 (m, 6H), 2.28 (m, 6H), 1.99 (s, 2H),
1.80 (m, 2H), 1.41 (t, 2H), 0.96 (s, 6H).
EXAMPLE 52
2-(4-amino-3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3--
nitrophenyl)sulfonyl)benzamide
[2072] The title compound was prepared by substituting EXAMPLE 40C
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H..sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.10 (br s, 1H),
8.80 (t, 1H), 8.56 (s, 1H), 7.82 (dd, 1H), 7.45 (d, 1H), 7.35 (d,
2H), 7.17 (d, 1H), 7.06 (d, 2H), 6.89 (d, 1H), 6.77 (s, 2H), 6.63
(d, 1H), 6.14 (d, 1H), 5.20 (br s, 2H), 3.61 (m, 4H), 3.46 (m,
214), 3.07 (m, 4H), 2.75 (m, 2H), 2.44 (m, 6H), 2.20 (m, 6H), 1.97
(m, 2H), 1.81 (m, 2H), 1.40 (m, 2H), 0.94 (s, 6H).
[2073] EXAMPLES 53
2-(3-chlorophenoxy)-4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biphe-
nyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylme-
thyl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 53A
methyl 5-formyl-2-(trifluoromethylsulfonyloxy)benzoate
[2074] Triflic anhydride (7.74 mL) was added to methyl
5-formyl-2-hydroxybenzoate (7.5 g) in 150 mL CH.sub.2Cl.sub.2 at
0.degree. C., and the reaction mixture was stirred and allowed to
warm to room temperature over 3 hours. The reaction mixture was
diluted with CH.sub.2Cl.sub.2 (150 mL), washed 3.times. with brine,
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
product was used without further purification.
[2075] EXAMPLES 53B
methyl 4'-chloro-4-formylbiphenyl-2-carboxylate
[2076] EXAMPLE 53A (14.5 g), 4-chlorophenylboronic acid (6.88 g)
CsF (12.2 g), and tetrakis(triphenylphosphine)palladium(0)
70.degree. C. for 24 hours. The reaction mixture was cooled,
filtered, and concentrated. The crude product was taken up in ethyl
acetate (250 mL), washed with 3.times.1 M aqueous NaOH, and brine,
concentrated, and chromatographed on silica gel with 10% ethyl
acetate/hexanes.
EXAMPLE 53C
[2077] methyl 4 '-chloro-4-(2-oxocthyl)biphcnyl-2-carboxylatc
[2078] To a solution of (methoxymethyl)diphenylphosphine oxide
(1.62 g) in 40 mL tetrahydrofuran at -78.degree. C., was added
lithium diisopropylamide (2M, 3.3 mL), and after stirring 3
minutes, EXAMPLE 53B (1.57 g) was added, and the solution was
warmed to room temperature. NaH (230 mg), and 40 mL
N,N-dimethylformamide were added, and the mixture was heated to
60.degree. C. for 1 hour. The reaction mixture was cooled and
poured into saturated aqueous NaH.sub.2PO.sub.4 solution. The
resulting solution was extracted twice with ether, and the combined
extracts were washed twice with water, and brine, and concentrated.
The crude mixutre of enol ethers was taken up in 1M aqueous HCl (50
mL) and dioxane (50 mL), and stirred at 60.degree. C. for 3 hours.
The reaction was cooled and poured into NaHCO.sub.3 solution. The
resulting solution was extracted twice with ether, and the combined
extracts were washed with water, and brine, and concentrated. The
product was used without further purification.
EXAMPLE 53D
methyl
4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-carboxylate
[2079] The title compound was prepared by substituting EXAMPLE 53C
for 4'-chlorobiphenyl-2-carboxaldehyde and pyrrolidine for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 53E
(4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methanol
[2080] Diisobutylaluminum hydride (1M in hexanes, 7.8 mL) was added
to a solution of EXAMPLE 53D (0.89 g) in dichloromethane (30 mL) at
0.degree. C., and the reaction was stirred for 20 minutes. The
reaction was quenched by the slow addition of methanol, and then
poured into 1M aqueous NaOH (50 mL). The mixture was extracted
twice with ethyl acetate, and extracts were combined, washed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated.
EXAMPLE 53F
4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyhl-2-carbaldehyde
[2081] EXAMPLE 53E (0.85 g) and Dess-Martin periodinane (1.26 g)
were stirred in dichloromethane (40 mL) for 90 minutes. The
reaction was quenched with methanol (5 mL), concentrated, and
chromatographed on silica gel with 10-50% ethyl acetate
hexanes.
EXAMPLE 53G
tert-butyl
4-(3-(3-chlorophenoxy)-4-(ethoxycarbonyl)phenyl)piperazine-1-ca-
rboxylate
[2082] The title compound was prepared by substituting EXAMPLE 36A
for methyl 2-bromo-4-fluorobenzoate and tert-butyl
piperazine-1-carboxylate for EXAMPLE 1B in EXAMPLE 1C.
EXAMPLE 53H
ethyl 2-(3-chlorophenoxy)-4-(piperazine-1-yl)benzoate
[2083] The title compound was prepared by substituting EXAMPLES 3G
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 53I
ethyl
4-(4-((4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methyl)pi-
perazin-1-yl)-2-(3-chlorophenoxy)benzoate
[2084] The title compound was prepared by substituting EXAMPLE 53F
for 4'-chlorobipheny-2-carboxaldehyde and EXAMPLE 53H for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 53J
4-(4-((4'-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methyl)piperazi-
n-1-yl)-2-(3-chlorophenoxy)benzoic acid
[2085] The title compound was prepared by substituting EXAMPLE 53I
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 53K
2-(3-chlorophenoxy)-4-(4-((4'-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1'-biphe-
nyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylme-
thyl)amino)phenyl)sulfonyl)benzamide
[2086] The title compound was prepared by substituting EXAMPLE 53J
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.80 (br s, 1H), 8.66 (t, 1H),
8.45 (s, 1H), 8.00 (m, 1H), 7.72 (dd, 1H), 7.52 (d, 2H), 7.35 (m,
4H), 7.16 (m, 2H), 6.94 (d, 1H), 6.80 (d, 1H), 6.66 (d, 2H), 6.55
(m, 1H), 4.32 (m, 1H), 3.85 (m, 2H), 3.56 (m, 2H), 3.33 (m, 8H),
3.07 (m, 6H), 2.85 (m, 2H), 2.43 (m, 2H), 2.02 (m, 2H), 1.91 (m,
4H), 1.63 (m, 2H), 1.27 (m, 2H).
EXAMPLE 54
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylphenyl-4-yl)amino)-3-nitroph-
enyl)sulfonyl)benzamide
EXAMPLE 54A
Ethyl 2-(2,3-dichlorophenoxy)-4-fluorobenzoate
[2087] The title compound was prepared by substituting
2,3-dichlorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 54B
Ethyl
2-(2,3-dichlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzoate
[2088] The title compound was prepared by substituting EXAMPLE 54A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 54C
2-(2,3-dichlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
nyl)methyl)piperazin-1-yl)benzoic acid
[2089] The title compound was prepared by substituting EXAMPLE 54B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 54D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-((4-((1-methylphenyl-4-yl)amino)-3-nitroph-
enyl)sulfonyl)benzamide
[2090] The title compound was prepared by substituting EXAMPLE 54C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1 H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 9.16 (d, IB), 8.50
(d, 1H), 8.33 (dd, 1H), 7.99 (d, 1H), 7.45 (d, 2H), 7.11 (t, 3H),
7.04 (d, 1H), 6.95 (t, 1H), 6.84 (dd, 1 H), 6.74 (d, 1H), 6.68 (d,
1H), 3.90-3.98 (m, 1H), 3.51 (d, 2H), 3.20-3.27 (m, 4H), 3.15 (t,
2H), 2.90 (s, 2H), 2.80 (s, 3H), 2.33 (d, 9 H), 2.17-2.26 (m, 2H),
1.99 (s, 2H), 1.41 (t, 2H), 0.96 (s, 6H).
EXAMPLE 55
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(3-methyl-1H-indazol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amin-
o)-3-nitrophenyl)sulfonyl)benzamide
[2091] The title compound was prepared by substituting EXAMPLE 44E
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.95 (br s, 2H),
8.30 (d, 1H), 8.02 (d, 1H), 7.61 (d, 1H), 7.36 (d, 2H), 7.07 (d,
2H), 6.94 (m, 2H), 6.69 (m, 2H), 6.36 (s, 1H), 5.92 (d, 1H), 3.27
(m, 4H), 3.04 (m, 7H), 2.75 (m, 4H), 2.49 (m, 4H), 2.22 (m, 8H),
1.99 (s, 3H), 1.77 (m, 2H), 1.39 (m, 2H), 0.94 (s, 6H).
EXAMPLE 56
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)pi-
perazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl-
)benzamide
EXAMPLE 56A
[2092] (Z)-methyl
2-(trifluoromethylsulfonyloxy)cyclohept-1-enecarboxylate
[2093] The title compound was prepared es described in EXAMPLE 38B
by replacing EXAMPLE 38A with methyl
2-oxocycloheptanecarboxylate.
EXAMPLE 56B
(Z)-methyl 2-(4-chlorophenyl)cyclohept-1-enecarboxylate
[2094] The title compound was prepared as described in EXAMPLE 38C
by replacing EXAMPLE 38B with EXAMPLE 56A.
EXAMPLE 56C
(Z)-(2-(4-chlorophenyl)cyclohept-1-enyl)methanol
[2095] The title compound was prepared as described in EXAMPLE 38D
by replacing EXAMPLE 38C with EXAMPLE 56B.
EXAMPLE 56D
(Z)-2-(4-chlorophenyl)cyclohept-1-enecarbaldehyde
[2096] The title compound was prepared as described in EXAMPLE 38E
by replacing EXAMPLE 38D with EXAMPLE 56C.
EXAMPLE 56E
(Z)-methyl
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)m-
ethyl)piperazin-1-yl)benzoate
[2097] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38E with EXAMPLE 56D.
EXAMPLE 56F
(Z)-2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)p-
iperazin-1-yl)benzoic acid
[2098] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 56E.
EXAMPLE 56G
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)pi-
perazin-1-yl)-N-((4-(1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-
benzamide
[2099] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 56F and EXAMPLE
3I, respectively, .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.35 (d, 1H), 8.06 (d, 1H), 7.73 (dd, 1H), 7.63 (d, 1H),
7.35 (d, 2H), 7.04 (m, 4H), 6.88 (m, 1H), 6.69 (dd, 1H), 6.52 (dd,
1H), 6.25 (d, 1H), 3.78 (m, 1H), 3.06 (m, 6H), 2.70 (m, 4H), 2.38
(m, 4H), 2.26 (m, 5H), 2.07 (m, 4H), 1.73 (m, 5 H), 1.52 (m,
5H).
EXAMPLE 57
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(-
trifluoromethyl)phenoxy)benzamide
EXAMPLE 57A
Ethyl 4-fluoro-2-(3-(trifluoromethyl)phenoxy)benzoate
[2100] The title compound was prepared by substituting
3-(trifluoromethyl)phenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 57B
Ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(3-(trifluoromethyl)phenoxy)benzoate
[2101] The title compound was prepared by substituting EXAMPLE 57A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 57C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)-2-(3-(tri-
fluoromethyl)phenoxy)benzoic acid
[2102] This EXAMPLE was prepared by substituting EXAMPLE 57B for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 57D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(3-(-
trifluoromethyl)phenoxy)benzamide
[2103] The title compound was prepared by substituting EXAMPLE 57C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.32 (d, 1H), 8.04
(m, 1H), 7.66 (m, 2H), 7.35 (m, 3H), 7.16 (d, 1H), 7.06 (d, 2H),
6.95 (m, 3H), 6.73 (dd, 1H), 6.42 (d, 1H), 3.80 (m, 1H), 3.11 (m,
4H), 2.83 (m, 4H), 2.63 (m, 3H), 2.21 (m, 6H), 2.08 (m, 2H), 1.97
(m, 5H), 1.76 (m, 2H), 1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 58
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahyd-
roquinolin-5-yl)oxy)benzamide
EXAMPLE 58A
methyl 4-(4-((4
'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-oxo-1,2,3,4-tetrahydroq-
uinolin-5-yloxy)benzoate
[2104] The title compound was prepared by substituting
3,4-dihydro-5-hydroxy-1H-quinolin-2-one for EXAMPLE 1D in EXAMPLE
1E.
EXAMPLE 58B
4-(4-((4
'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-oxo-1,2,3,4-tet-
rahydroquinolin-5-yloxy)benzoic acid
[2105] The title compound was prepared by substituting EXAMPLE 58A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 58C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((2-oxo-1,2,3,4-tetrahyd-
roquinolin-5-yl)oxy)benzamide
[2106] The title compound was prepared by substituting EXAMPLE 58B
for EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G is EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (s,
1H), 10.08 g (s, 1H), 8.64 (t, 1H), 8.48 (d, 1H), 7.81 (dd, 1H),
7.50 (m, 6H), 7.39 (m, 2H), 7.29 (m, 1H), 7.14 (d, 1H), 6.93 (t,
1H), 6.75 (dd, 1H), 6.51 (d, 1H), 6.39 (m, 1H), 6.13 (d, 1H), 4.36
(m, 1H), 3.72 (m, 1H), 3.40 (m, 6H), 3.13 (m, 4H), 2.80 (m, 4H),
2.78 (d, 6H), 2.40 (t, 2H), 1.96 (m, 2H).
EXAMPLE 59
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3((trifluo-
romethyl)sulfonyl)phenyl)sulfonyl)benzamide
[2107] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 131D for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 7.99 (d,
1H), 7.88 (m, 1H), 7.62 (d, 1H), 7.38 (m, 3H).7.06 (d, 3H)S 7.01
(d, 1H), 6.93 (t, 1H), 6.69 (m, 1H), 6.56 (d, 1H), 6.50 (s, 1H),
6.24 (d, 1H), 3.25 (m, 10H), 3.07 (s, 2H), 3.07 (s, 3H), 2.77 (d,
3H), 2.20 (d, 5H), 2.04 (s, 2H), 1.96 (d, 2H), 1.63 (s, 2H), 1.40
(t, 2H), 0.94 (s, 6H).
EXAMPLE 60
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
EXAMPLE 60A
Ethyl 2-(2,5-dichlorophenoxy)-4-fluorobenzoate
[2108] The title compound was prepared by substituting
2,5-dichlorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 60B
Ethyl 2-(2,5-dichlorophenoxy)-4-(piperazin-1-yl)benzoate
[2109] The title compound was prepared by substituting piperazine
for EXAMPLE 3F and EXAMPLE 60A for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 60C
2-chloro-4,4-dimethylcyclohex-1-enecarbaldehyde
[2110] Into a 250 mL round-bottomed flask was added
N,N-dimethylformamide (3.5 mL) in dichloromethane (30 mL) to give a
colorless solution. The mixture was cooled to -10.degree. C., and
phosphoryl trichloride (4 mL) was added dropewise. The solution was
warmed up to room temperature, and 3,3-dimethylcyclohexanone (5.5
mL) was added slowly. The mixture was heated tyo reflux for
overnight. The reaction mixture was quenched by 0.degree. C.
solution of sodium acetate (25 g in 50 mL water). TThe aqueous
layer was extracted with ether (3.times.200 mL). The organic
layer's were combined, dried over Na.sub.2SO.sub.4, filtered, and
dried under vacuum.
EXAMPLE 60D
2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde
[2111] Into a 1 L round-bottomed flask was added EXAMPLE 60C (6.8
g), 4-chlorophenylboronic acid (6.5 g) and palladium(II) acetate
(0.2 g) in water (100 mL) to give a suspension. Potassium carbonate
(15 g) and tetrabutylammonium bromide (10 g) were added. After
degassing by subjecting to vacuum and nitrogen, the mixture was
stirred at 45.degree. C. for 4 hours. After filtering through
silica gel, ether (4.times.200 mL) was used to extract the product.
The combined organic layers were dried over Na.sub.2SO.sub.4 and
filtered. The filtrate was concentrated and purified by flash
chromatography on silica with 0 to 10% ethyl acetate in hexanes to
provide the title compound.
EXAMPLE 60E
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-((2,5dichlorophenoxy)benzoate
[2112] The title compound was prepared by substituting EXAMPLE 60D
for 4'chlorobiphenyl-2-carboxaldehye and EXAMPLE 60B for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
[2113] EXAMPLE 60F
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-((2,5dichlorophenoxy)benzoic acid
[2114] The title compound was prepared by substituting EXAMPLE 60E
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 60G
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((2,5dichlorophenoxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
[2115] The title compound was prepared by substituting EXAMPLE 60F
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.01 (br.s, 1H),
9.92 (br.s, 1H), 9.68 (br.s, 1H), 8.43 (m, 1H), 8.19 (d, 1H), 7.80
(dd, 1H), 7.55 (d, 1H), 7.39 (m, 3H), 7.23 (d, 1H), 7.11 (d, 2H),
6.97 (dd, 1H), 6.85 (dd, 1H), 6.55 (m, 2H), 3.58 (m, 5H), 3.25 (m,
6H), 2.83 (m, 4H), 2.21 (m, 4H), 2.05 (s, 2H), 1.87 (m, 2H), 1.48
(t, 2H), 0.96 (s, 6H).
EXAMPLE 61
2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-
-nitrophenyl)sulfonyl)benzamide
EXAMPLE 61A
Ethyl 2-(2-chloro-4-fluorophenoxy)-4-fluorobenzoate
[2116] The title compound was prepared by substituting
2-chloro-4-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 61B
Ethyl 2-(2-chloro-4-fluorophenoxy)-4-(piperazin-1-yl)benzoate
[2117] The title compound was prepared by substituting piperazine
for EXAMPLE 3F and EXAMPLE 61A for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 61C
Ethyl
2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2118] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 61B for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 61D
2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2119] The title compound was prepared by substituting EXAMPLE 61C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 61E
2-(2-chloro-4-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-
-nitrophenyl)sulfonyl)benzamide
[2120] The title compound was prepared by substituting EXAMPLE 61D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.40 (m, 1H), 8.08
(m, 1H), 7.78 (dd, 1H), 7.59 (d, 1H), 7.33 (m, 3H), 7.07 (m, 3H),
6.92 (m, 1H), 6.69 (dd, 1H), 6.59 (m, 1H), 6.25 (d, 1H), 3.84 (m,
1H), 3.08 (m, 4H), 2.77 (m, 8H), 2.16 (m, 8 H), 1.97 (s, 2H), 1.75
(m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 62
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitroph-
enyl)sulfonyl)benzamide
EXAMPLE 62A
methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate
[2121] This compound was prepared according to WO 2006/035061 (page
53).
EXAMPLE 62B
methyl
4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclopent-2-enecarboxyla-
te
[2122] The title compound was prepared as described in EXAMPLE 38B
by replacing EXAMPLE 38A with EXAMPLE 62A.
EXAMPLE 62C
ethyl 2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enecarboxylate
[2123] The title compound was prepared as described in EXAMPLE 38C
by replacing EXAMPLE 38B with EXAMPLE 62B.
EXAMPLE 62D
(2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl)methanol
[2124] The title compound was prepared as described in EXAMPLE 38D
by replacing EXAMPLE 38C with EXAMPLE 62C.
EXAMPLE 62E
2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enecarbaldehyde
[2125] The title compound was prepared as described in EXAMPLE 38E
by replacing EXAMPLE 38D with EXAMPLE 62D.
EXAMPLE 62F
methyl
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-
-1-enyl)methyl)piperazin-1-yl)benzoate
[2126] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38E with EXAMPLE 62E.
EXAMPLE 62G
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
[2127] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 62F.
EXAMPLE 62H
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-
-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitroph-
enyl)sulfonyl)benzamide
[2128] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 62G and EXAMPLE
3I, respectively. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.35 (d, 1H), 8.06 (d, 1H), 7.73 (dd, 1H), 7.64 (d, 1H),
7.33 (m, 5H), 7.04 (m, 2H), 6.88 (m, 1H), 6.72 (dd, 1H), 6.52 (dd,
1H), 6.28 (d, 1H), 3.78 (d, 1H), 3.07 (d, 4H), 2.71 (m, 6H), 2.33
(m, 8H), 2.06 (m, 4H), 1.74 (m, 4H), 1.10 (m, 6H).
EXAMPLE 63
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide
EXAMPLE 63A
ethyl 4-fluoro-2-(3-methyl-1H-indol-4-yloxy)benzoate
[2129] The title compound was prepared by substituting
3-methyl-4-indolol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 63B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-((3-methyl-1H-indol-4-yloxy)benzoate
[2130] The title compound was prepared by substituting EXAMPLE 63A
for methyl-2-bromo-4-fluorobenzoate and EXAMPLE 3E for EXAMPLE 1B
in EXAMPLE 1C.
EXAMPLE 63C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-((3-methyl-1H-indol-4-yloxy)benzoic acid
[2131] The title compound was prepared by substituting EXAMPLE 63B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 63D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino-
)-3-nitrophenyl)sulfonyl)benzamide
[2132] The title compound was prepared by substituting EXAMPLE 63C
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 10.92 (br s, 2H),
8.77 (m, 1H), 8.57 (d, 1H), 7.82 (dd, 1H), 7.55 (d, 1H), 7.33 (d,
2H), 7.15 (m, 2H), 7.03 (d, 2H), 6.99 (m, 2H), 6.67 (d, 1H), 6.45
(d, 1H), 6.12 (d, 1H), 3.68 (m, 4H), 3.47 (m, 2H), 3.02 (m, 6H),
2.73 (m, 4H), 2.43 (m, 2H), 2.14 (m, 8H), 1.99 (s, 3H), 1.91 (m,
2H), 1.38 (m, 2H), 0.92 (s, 6H).
EXAMPLE 64
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4--
yl)amino)-3-nitrophenyl)sulfonyl)benzamide
EXAMPLE 64A
[2133] Ethyl
2-(2-chloro-3-(trifluoromethyl)phenoxy)-4-fluorobenzoate. The title
compound was prepared by substituting
2-chloro-3-(trifluoromethyl)phenol for 2-methyl-5-indolol EXAMPLE
3A.
EXAMPLE 64B
Ethyl
2-(2-chloro-3-(trifluoromethyl)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2134] The title compound was prepared by substituting EXAMPLE 64A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 64C
2-(2-chloro-3-(trifluoromethyl)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2135] The title compound was prepared by substituting EXAMPLE 64B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 64D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2-chloro-3-(trifluoromethyl)phenoxy)-N-((4-((1-methylpiperidin-4--
yl)amino)-3-nitrophenyl)sulfonyl)benzamide
[2136] The title compound was prepared by substituting EXAMPLE 64C
for EXAMPLE 1E and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.02 (s, 1H),
9.76 (s, 1H), 9.52 (s, 1H), 8.42 (m, 1H), 8.17 (d, 1H), 7.82 (dd,
1H), 7.58 (d, 1H), 7.41 (m, 3H), 7.27 (m, 2H), 7.11 (d, 2H), 6.93
(d, 1H), 6.84 (dd, 1H), 6.57(d, 1H), 3.15 (m, 6H), 2.83 (m, 8H),
2.11 (m, 8H), 1.83 (m, 2H), 1.47 (t, 2H), 0.96 (s, 6H).
EXAMPLE 65
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide
EXAMPLE 65A
4-(1-cyclopropylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
[2137] To a solution of 4-fluoro-3-nitrobenzenesulonamide (1.26 g)
and 1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20
mL) was added N,N-diisopropylethylamine (2.22 g) and
4-dimethylaminopyridine (35 mg). The mixture was stirred at reflux
overnight. The mixture was diluted with ethyl acetate (200 mL) and
washed with aqueous NaHCO.sub.3, water, and brine and dried over
Na.sub.2SO.sub.4. After filtration and concentration, the residue
was dissolved in dichloromethane and loaded on a column and eluted
with dichloromethane (500 mL), 5% 7N NH.sub.3 in 10% methanol in
dichloromethane (1.5 L) to give the product.
EXAMPLE 65B
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopropylpiperidin-4-yl)amino)-3-nit-
rophenyl)sulfonyl)benzamide
[2138] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 34C and EXAMPLE
65A, respectively. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.46 (dd, 1H), 8.22 (t, 1H), 7.81 (m, 2H), 7.53 (d, 1H),
7.37 (m, 4H), 7.14 (m, 1H), 7.07 (m, 1H), 6.99 (m, 1H), 6.72 (m,
1H), 6.29 (d, 1H), 3.75 (m, 1H), 3.13 (s, 3H), 2.93 (d, 3H), 2.78
(s, 1H), 2.20 (m, 5H), 1.97 (m, 5H), 1.59 (m, 5H), 0.94 (s, 6H),
0.42 (m, 5H).
EXAMPLE 66
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-((3-methyl-1H-indol-4-yl)oxy)-N-((4-((1-methylpiperidin-4-yl)amino-
)-3-nitrophenyl)sulfonyl)benzamide
[2139] The title compound was prepared by substituting EXAMPLE 63C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 10.86 (br s, 2B),
8.51 (br s, 1H), 8.15 (d, 1H), 7.82 (dd, 1H), 7.55 (d, 1H), 7.33
(d, 2H), 7.15 (m, 2H), 7.03 (d, 2H), 6.94 (m, 2H), 6.62 (d, 1H),
6.38 (d, 1H), 6.12 (d, 1H), 3.82 (m, 1H), 3.09 (m, 2H), 2.98 (m,
6H), 2.88 (m, 2H), 2.71 (m, 3H), 2.66 (m, 2H), 2.11 (m, 8H), 1.99
(s, 3H), 1.82 (m, 2H), 1.38 (m, 2H), 0.92 (s, 6H).
EXAMPLE 67
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin--
1-yl)-2-(2,5-dichlorophenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitr-
ophenyl)sulfonyl)benzamide
[2140] The title compound was prepared by substituting EXAMPLE 60D
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.71 (m, 1H), 8.43
(d, 1H), 7.75 (dd, 1H), 7.54 (d, 1H), 7.36 (m, 3H), 7.07 (m, 3H),
6.94 (dd, 1H), 6.79 (dd, 1H), 6.46 (dd, 2H), 3.67 (m, 4H), 3.48 (q,
2H), 3.20 (m, 4H), 2.83 (s, 2H), 2.65 (m, 6H), 2.24 (m, 6H), 1.98
(s, 2H), 1.88 (m, 2H), 1.42 (t, 2H), 0.95 (s, 6H).
EXAMPLE 68
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-
-indol-4-yl)oxy)
-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide
[2141] The title compound was prepared by substituting EXAMPLE 16D
for EXAMPLE 50F and EXAMPLE 4A for EXAMPLE 3I in EXAMPLE 50G.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.58 (br
s, 1H), 9.78 (br s, 1H), 8.67 (t, 1H), 8.44 (d, 1H), 7.77 (dd, 1H),
7.66 (br s, 1H), 7.50 (m, 5H), 7.37 (d, 2H), 7.30 (m, 1H), 7.25 (d,
1H), 7.19 (d, 1H), 7.06 (d, 1H), 7.00 (dd, 1H), 6.75 (dd, 1H), 6.40
(d, 1H), 6.38 (s, 1H), 6.23 (d, 1H), 4.35-2.80 (series of br m,
total 22 H), 3.80 (s, 3H), 1.96 (m, 2H).
EXAMPLE 69
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-morpholin-
-4-ylphenoxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl-
)benzamide
[2142] The title compound was prepared by substituting EXAMPLE 32B
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.63 (s, 1H),
9.86 (s, 1H), 8.71 (t, 1H), 8.50 (d, 1H), 7.83 (dd, 1H), 7.70 (s,
1H), 7.50 (m, 5H), 7.39 (d, 2H), 7.32 (m, 1H), 7.16 (d, 1H), 7.08
(m, 1H), 6.74 (dd, 1H), 6.59 (dd, 1H), 6.40 (m, 2H), 6.23 (dd, 1H),
4.24 (m, 2H), 3.97 (m, 2H), 3.70 (m, 4H), 3.63 (m, 4H), 3.54 (m,
4H), 3.18 (m, 4H), 3.07 (m, 4H), 3.00 (m, 4H), 2.83 (m, 2H), 1.98
(m, 2H).
EXAMPLE 70
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3--
oxopropyl)-1H-indol-5-yl)oxy)benzamide
EXAMPLE 70A
(Z)-tert-butyl
5-(benzyloxy)-3-(3-morpholino-3-oxoprop-1-enyl)-1H-indole-1-carboxylate
[2143] A mixture of tert-butyl
5-(benzyloxy)-3-bromo-1H-indole-1-carboxylate (2.011 g),
1-morpholinoprop-2-in-1-one (0.776 g), palladium acetate (31 mg),
tri-o-tolylphosphine (187 mg) and triethylamine (1.14 mL) in
N,N-dimethylformamide (14 mL) under nitrogen atmosphere was stirred
at 100.degree. C. overnight. The mixture was diluted with ethyl
acetaate and saturated ammonium chloride. The aqueous layer was
extracted with ethyl acetate and the combined organic layers were
dried over MgSO.sub.4, filtered and concentrated. The residue was
purified by flash chromatography (80% ethyl acetate-hexane) to give
the desired product.
EXAMPLE 70B
tert-butyl
5-(benzyloxy)-3-(3-morpholino-3-oxopropyl)-1H-indole-1-carboxyl-
ate
[2144] The title compound was prepared by substituting EXAMPLE 70A
for EXAMPLE 39A in EXAMPLE 39B.
EXAMPLE 70C
tert-butyl
5-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(meth-
oxycarbonyl)phenoxy)-3-(3-morpholino-3-oxopropyl)-1H-indole-1-carboxylate
[2145] The title compound was prepared by substituting EXAMPLE 70B
for EXAMPLE 1D in EXAMPLE 1E .
EXAMPLE 70D
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(3-morpho-
lino-3-oxopropyl)-1H-indol-5-yloxy)benzoate
[2146] A solution of EXAMPLE 70C (300 mg) in dioxane (2 mL) was
treated with concentrated aqueous hydrogen chloride (0.378 mL) and
stirred at room temperature overnight. The solution was
concentrated and the residue was used for the next step without
further purification.
EXAMPLE 70E
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(3-morpholino-3--
oxopropyl)-1H-indol-5-yloxy)benzoic acid
[2147] The title compound was prepared by substituting EXAMPLE 70D
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 70F
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-((3-(3-morpholin-4-yl-3--
oxopropyl)-1H-indol-5-yl)oxy)benzamide
[2148] The title compound was prepared by substituting EXAMPLE 70E
for EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.37 (s,
1H), 10.88 (s, 1H), 9.33 (s, 1H), 8.64 (m, 2H), 7.88 (d, 1H), 7.66
(s, 1H), 7.51 (dd, 5H), 7.35 (dd, 3H), 7.29 (s, 1H), 7.21 (s, 1H),
7.13 (d, 2H), 6.82 (dd, 1H), 6.67 (d, 1H), 6.21 (s, 1H), 3.42 (s,
20H), 3.12 (s, 2H), 2.85 (m, 2H), 2.78 (d, 6H), 2.61 (m, 2H), 1.95
(m, 2H).
EXAMPLE 71
2-(3-benzylxoy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperaz-
in-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sulfo-
nyl)benzamide
EXAMPLE 71A
2-(3-benzyloxy)phenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-y-
l)benzoic acid
[2149] The title compound was prepared by substituting EXAMPLE 33A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 71B
2-(3-benzylxoy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperaz-
in-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pryan-4-ylmethyl)amino)phenyl)sulfo-
nyl)benzamide
[2150] The title compound was prepared by substituting EXAMPLE 71A
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.69 (m, 1H), 8.62 (m, 1H),
8.48 (d, 1H), 7.76 (dd, 1H), 7.65 (m, 1H), 7.50 (m, 5H), 7.38 (m,
6H), 7.32 (m, 2H), 7.11 (m, 2H), 6.77 (dd, 1H), 6.62 (dd, 1H), 6.41
(m, 2H), 6.35 (m, 1H), 4.98 (s, 2H), 3.83 (m, 2H), 3.28 (m, 12H),
3.17 (m, 2H), 1.89 (m, 1H), 1.59 (m, 2H), 1.26 (m, 2H).
EXAMPLE 72
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide
EXAMPLE 72A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-cyanophen-
oxy)benzoate
[2151] The title compound was prepared by substituting
4-cyanophenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 72B
4-(4-((4
'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-cyanophenoxy)be-
nzoic acid
[2152] The title compound was prepared by substituting EXAMPLE 72A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 72C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-cyanophen-
oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-
benzamide
[2153] The title compound was prepared by substituting EXAMPLE 72B
for EXAMPLE 1G in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.97 (s, 1H), 9.54 (s, 1H),
8.62 (t, 1H), 8.44 (d, 1H), 7.66 (m, 4H), 7.53 (m, 5H), 7.37 (m,
3H), 7.12 (d, 1H), 6.82 (m, 3H), 6.64 (d, 1H), 4.37 (m, 1H), 3.86
(dd, 2H), 3.49 (m, 2H), 3.26 (m, 8H), 3.10 (m, 2H), 2.84 (s, 1H),
1.92 (m, 1H), 1.64 (dd, 2H), 1.28 (m, 2H).
EXAMPLE 73
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpho-
lin-4-yl-3-oxopropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyr-
an-4-ylmethyl)amino)phenyl)sulfonyl)benzamide
[2154] The title compound was prepared by substituting EXAMPLE 70E
for EXAMPLE 1F in EXAMPLE 1H, .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.38 (s, 1H), 10.87 (s, 1H),
8.59 (m, 2H), 7.79 (dd, 1H), 7.68 (s, 1H), 7.51 (dd, 5H), 7.34 (dd,
4H), 7.20 (s, 1H), 7.10 (d, 2H), 6.81 (dd, 1H), 6.68 (d, 1H), 6.23
(s, 1H), 3.85 (d, 2H), 3.44 (s, 18H), 3.28 (m, 4H), 2.84 (m, 2H),
2.60 (t, 2H), 1.89 (s, 1H), 1.63 (m, 2H), L 27 (m, 2H).
EXAMPLE 74
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpho-
lin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 74A
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholinopr-
opyl)-1H-indol-5-yl)oxy)benzoate
[2155] EXAMPLE 70C (107 mg) was dissolved in anhydrous
tetrahydrofuran (0.7 mL), followed by the addition of 1M borane in
tetrafuran solution (0.57 mL). The reaction mixture was stirred at
room temperature overnight. The reaction was quenched with 1N HCl
was removed under vacuum. The residue was purified by flash column
chromatography on silica gel using 10-50% ethyl acetate in hexanes
to afford the product.
EXAMPLE 74B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpholinopr-
opyl)-1H-indol-5-yl)oxy)benzoic acid
[2156] The title compound was prepared by substituting EXAMPLE 74A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 74C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-morpho-
lin-4-ylpropyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-y-
lmethyl)amino)phenyl)sulfonyl)benzamide
[2157] The title compound was prepared by substituting EXAMPLE 74B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.35 (m, 1H), 10.95 (s, 1H),
9.58 (m, 1H), 8.60 (m, 2H), 7.86 (dd, 1H), 7.63 (m, 1H), 7.50 (dd,
5H), 7.35 (t, 3H), 7.28 (s, 1H), 7.22 (dd, 2H), 7.17 (d, 1H), 6.84
(d, 1H), 6.65 (d, 1H), 6.16 (s, 1H), 3.93 (s, 1H), 3.84 (d, 2H),
3.50 (m, 15H), 3.32 (m, 2H), 3.26 (m, 2H), 3.13 (m, 2H), 3.03 (s,
2H), 2.68 (t, 2H), 1.97 (d, 2H), 1.89 (s, 1H), 1.61 (d, 2H), 1.27
(m, 2H).
EXAMPLE 75
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4((dimethyl-
amino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide
EXAMPLE 75A
4-((dimethylamino)methyl)phenol
[2158] The title compound was prepared by substituting
4-hydroxybenzaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde and
dimethylamine for tert-butylpiperazine-1-carboxylate in EXAMPLE
1A.
EXAMPLE 75B
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((dimethy-
lamino)methyl)phenoxy)benzoate
[2159] The title compound was prepared by substituting EXAMPLE 75A
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 75C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-dimethylamino)me-
thyl)phenoxy)benzoic acid
[2160] The title compound was prepared by substituting EXAMPLE 75B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 75D
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4((dimethyl-
amino)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino-
)phenyl)sulfonyl)benzamide
[2161] The title compound was prepared by substituting EXAMPLE 75C
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.80 (br s, 1H), 9.60 (br s,
1H), 8.59 (m, 1H), 8.48 (m, 1H), 7.80 (d, 1H), 7.50 (d, 2H), 7.46
(m, 2H), 7.36 (m, 4H), 7.24 (m, 2H), 6.90 (d, 2H), 6.77 (d, 1H),
6.44 (d, 1H), 4.16 (m, 2H), 3.84 (dd, 2H), 3.30 (m, 8H), 3.15 (m,
4H), 2.68 (m, 4H), 2.35 (m, 4H), 1.88 (m, 1H), 1.61 (dd, 2H), 1.23
(m, 2H).
EXAMPLE 76
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imida-
zol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)ph-
enyl)sulfonyl)benzamide
EXAMPLE 76A
methyl
2-((4-(1H-imidazol-1-yl)-phenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)met-
hyl)piperazin-1-yl)benzoate
[2162] The title compound was prepared by substituting
4-(1H-imidazol-1-yl)phenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 76B
2-((4-(1H-imidazol-1-yl)-phenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)pip-
erazin-1-yl)benzoic acid
[2163] The title compound was prepared by substituting EXAMPLE 76A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 76C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-(1H-imida-
zol-1-yl)-phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)ph-
enyl)sulfonyl)benzamide
[2164] The title compound was prepared by substituting EXAMPLE 76B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.50 (s, 1H), 8.17 (d, 1H), 7.78
(m, 1H), 7.66 (m, 1H), 7.40-7.58 (m, 8H), 7.37 (d, 2H), 7.25 (m,
1H), 7.10 (d, 2H), 6.94 (d, 1H), 6.75 (d, 1H), 6.63 (d, 1H), 6.43
(d, 1H), 3.82 (m, 2H), 3.37 (m, 4H), 3.08-3.21 (m, 6H), 2.35 (m,
4H), 1.82 (m, 1H), 1.58 (m, 2H), 1.40 (m, 2H).
EXAMPLE 77
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitropheno-
xy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 77A
4-((tetrahydro-2H-pyran-4-yl)methylamino)phenyl)benzenesulfonamide
[2165] 4-Aminobenzenesulfonamide (6.80 g),
tetrahoydropyran-4-carboxaldehyde (4.96 g), and sodium
triacetoxyborohydride (16.74 g) in tetrahydrofuran (300 mL) and
acetic acid (15 mL) were stirred at room temperature for 24 hours.
The reaction was concentrated and taken up in ethyl acetate. The
resulting solution was washed with water and brine, concentrated,
and chromatographed on silica gel with 50% ethyl
acetate/hexanes.
EXAMPLE 77B
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-nitropheno-
xy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide
2,2,2-trifluoroacetate
[2166] The title compound was prepared by substituting EXAMPLE 8B
for EXAMPLE 50F and EXAMPLE 77A for EXAMPLE 3I in EXAMPLE 50G.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.58 (br
s, 1H), 9.58 (br s, 1H), 7.86 (m, 1H), 7.71 (br s, 1H), 7.52 (m,
7H), 7.40 (m, 5H), 7.30 (m, 1H), 6.82 (dd, 1H), 6.71 (br s, 1H),
6.60 (d, 1H), 6.47 (d, 2H), 4.37 (v br s, 1H), 3.83 (dd, 2H), 3.70
(v br s, 1H), 3.50-3-40 (envelope, 6H), 3.26, (m, 2H), 3.05, 2.96,
2.94, 2.85 (all br s, total 4H), 1.79 (m, 1H), 1.65 (m, 2H), 1.22
(m, 2H).
EXAMPLE 78
tert-butyl
4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-
-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amin-
o)carbonyl)phenoxy)benzyl(ethyl)carbamate
EXAMPLE 78A
tert-butyl ethyl(4-hydroxybenzyl)carbamate
[2167] Diethylamine gas was bubbled into a solution of
4-hydroxybenzaldehyde (2.0 g) and sodium triacetoxyborohydride (5.2
g) in dichloromethane (60 mL) until saturated. The reaction flask
was stoppered and the reaction stirred for 24 hours. 1 M NaOH (10
mL) was then added, followed by di-tert-butyl deicarbonate (3.57 g)
and triethylamine (2.28 mL), and the reaction was stirred for 24
hours. The reaction was acidified with saturated NaH.sub.2PO.sub.4
solution, extracted twice with ethyl acetate, and the combined
extracts were washed with brine and concentrated. The crude product
was chromatographed on silica gel using 20% ethyl acetate/hexanes
as the eluent to give the product.
EXAMPLE 78B
methyl
2-(4-((tert-butoxycarbonyl(ethyl)amino)methyl)phenoxy)-4-(4-((4
'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate
[2168] The title compound was prepared by substituting EXAMPLE 78A
for EXAMPLE 1D in EXAMPLE 1E .
EXAMPLE 78C
2-(4-((tert-butoxycarbonyl(ethyl)amino)methyl)phenoxy)-4-(4-((4
'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoic acid
[2169] The title compound was prepared by substituting EXAMPLE 78B
for EXAMPLE 1E in EXAMPLE 1E.
EXAMPLE 78D
tert-butyl
4-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-((((3-
-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)ph-
enoxy)benzyl(ethyl)carbamate
[2170] The title compound was prepared by substituting EXAMPLE 78C
for EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 79
tert-butyl
3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-
-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amin-
o)carbonyl)phenoxy)benzyl(ethyl)carbamate
EXAMPLE 79A
tert-butyl ethyl(4-hydroxybenzyl)carbamate
[2171] The title compound was prepared by substituting
3-hydroxybenzaldehyde for 4-hydroxybenzaldehyde in EXAMPLE 78A.
EXAMPLE 79B
methyl
2-(3-((tert-butyxoycarbonyl(ethyl)amino)methyl)phenoxy)-4-(4-((4'-c-
hlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate
[2172] The title compound was prepared by substituting EXAMPLE 79A
for EXAMPLE 1D in EXAMPLE 1E .
EXAMPLE 79C
2-(3-((tert-butyxoycarbonyl(ethyl)amino)methyl)phenoxy)-4-(4-((4'-chlorobi-
phenyl-2-yl)methyl)piperazin-1-yl)benzoic acid
[2173] The title compound was prepared by substituting EXAMPLE 79B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 79D
tert-butyl
3-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-ni-
tro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)pheno-
xy)benzyl(ethyl)carbamate
[2174] The title compound was prepared by substituting EXAMPLE 79C
for EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 80
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-((ethylami-
no)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)ph-
enyl)sulfonyl)benzamide
[2175] The title compound was prepared by substituting EXAMPLE 78D
for EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.63 (br s, 1H), 8.52 (br s,
1H), 8.43 (s, 1H), 7.78 (dd, 1H), 7.60 (d, 1H), 7.46 (s, 4H), 7.35
(d, 2H), 7.31 (m, 1H), 7.24 (d, 1H), 7.13 (d, 1H), 6.84 (d, 2H),
6.72 (d, 1H), 6.36 (s, 1H), 4.04 (s, 2H), 3.84 (dd, 2H), 3.27 (m,
6H), 3.11 (m, 4H), 2.94 (m, 2H), 2.36 (m, 4H), 1.91 (m, 1H), 1.62
(dd, 2H), 1.23 (m, 2H), 1.17 (t, 3H).
EXAMPLE 81
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-((ethylami-
no)methyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)ph-
enyl)sulfonyl)benzamide
[2176] The title compound was prepared by substituting EXAMPLE 79D
for EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.60 (br s, 1H), 8.80 (br s,
1H), 8.62 (br s, 1H), 8.51 (s, 1H), 7.82 (dd, 1H), 7.30-7.55 (m,
7H), 7.24 (m, 2H), 7.19 (d, 1H), 7.04 (d, 1H), 6.89 (d, 1H), 6.77
(d, 1H), 6.36 (s, 1H), 4.06 (s, 2H), 3.86 (dd, 2H), 3.27 (m, 6H),
3.11 (m, 4H), 2.96 (m, 2H), 2.34 (m, 4H), 1.90 (m, 1H), 1.61 (dd,
2H), 1.24 (m, 2H), 1.19 (t, 3H).
EXAMPLE 82
2-(4-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide
EXAMPLE 82A
methyl
2-(4-acetamidophenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperaz-
in-1-yl)benzoate
[2177] The title compound was prepared by substituting
4-acetamidophenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 82B
2-(4-acetamidophenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl-
)benzoic acid
[2178] The title compound was prepared by substituting EXAMPLE 82A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 82C
2-(4-(acetylamino)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipe-
razin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)su-
lfonyl)benzamide
[2179] The title compound was prepared by substituting EXAMPLE 82B
for EXAMPLE 1G in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.58 (s, 1H), 9.91 (s, 1H),
8.62 (t, 1H), 8.54 (d, 1H), 7.76 (dd, 1H), 7.68 (m, 1H), 7.51 (m,
7H), 7.34 (m, 3H), 7.16 (d, 1H), 6.85 (d, 2H), 6.72 (dd, 1H), 6.30
(m, 1H), 4.35 (s, 1H), 3.85 (dd, 2H), 3.68 (m, 1H), 3.27 (m, 9 H),
3.02 (m, 2H), 2.83 (m, 1H), 2.04 (s, 3H), 1.89 (m, 1H), 1.62 (dd,
2H), 1.24 (m, 2H).
EXAMPLE 83
tert-butyl
4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-
-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amin-
o)carbonyl)phenoxy)phenylcarbamate
[2180] This EXAMPLE was prepared by substituting EXAMPLE 18B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.37 (s, 1H), 9.32 (s, 1H),
8.61 (t, 1H), 8.57 (d, 1H), 7.81 (dd, 1H), 7.44 (m, 8H), 7.34 (m,
2H), 7.22 (m, 2H), 6.88 (d, 2H), 6.69 (dd, 1H), 6.20 (d, 1H), 3.85
(m, 2H), 3.28 (m, 6H), 3.09 (m, 4H), 2.33 (m, 4H), 1.90 (m, 1H),
1.63 (m, 2H), 1.47 (m, 9 H), 1.26 (m, 2H).
EXAMPLE 84
2-(1,1'-biphenyl-2-yloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide
EXAMPLE 84A
methyl
2-(biphenyl-2-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-
-1-yl)benzoate
[2181] The title compound was prepared by substituting
2-phenylphenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 84B
methyl
2-(biphenyl-2-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-
-1-yl)benzoic acid
[2182] The title compound was prepared by substituting EXAMPLE 84A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 84C
2-(1,1'-biphenyl-2-yloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide 2,2,2-trifluoroacetate
[2183] The title compound was prepared by substituting EXAMPLE 84B
for EXAMPLE 50F EXAMPLE 1G for EXAMPLE 3I in EXAMPLE 50G. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.56 (v br s,
1H), 9.50 (v br s, 1H), 8.62 (t, 1H), 8.45 (d, 1H), 7.76 (dd, 1H)
7.70 (br s, 1H), 7.50 (m, 7H), 7.37 (d, 2H), 7.27 (m, 5H), 7.12 (m,
2H), 7.04 (m, 1H), 6.70 (dd, 1H), 6.64 (d, 1H), 6.27 (s, 1H), 4.35
(v br s, 1H), 3.83 (dd, 2H), 3.70 (v br s, 1H), 3.40 (m, 4H), 3.25,
3.20 (both m, total 4H), 3.00, 2.80 (both br s, total 4H), 1.83 (m,
1H), 1.59 (m, 2H), 1.24 (m, 2H).
EXAMPLE 85
tert-butyl
3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-
-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)amin-
o)carbonyl)phenoxy)phenylcarbamate
[2184] The title compound was prepared as described in EXAMPLE 19C.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.45 (s,
1H), 9.34 (s, 1H), 8.62 (t, 1H), 8.52 (d, 1H), 7.75 (dd, 1H), 7.46
(m, 6H), 7.36 (m, 2H), 7.23 (m, 1H), 7.11 (m, 4H), 6.74 (dd, 1H),
6.42 (m, 1H), 6.36 (d, 1H), 3.86 (dd, 2H), 3.30 (m, 6H), 3.15 (m,
4H), 2.35 (m, 4H), 1.90 (qd, 1H), 1.63 (dd, 2H), 1.45 (s, 9 H),
1.27 (m, 2H).
EXAMPLE 86
2-(1,1'-biphenyl-3-yloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide
EXAMPLE 86A
methyl
2-(biphenyl-3-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-
-1-yl)benzoate
[2185] The title compound was prepared by substituting
3-phenylphenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 86B
2-(biphenyl-3-yloxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)b-
enzoic acid
[2186] The title compound was prepared by substituting EXAMPLE 86A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 86C
2-(1,1'-biphenyl-3-yloxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piper-
azin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sul-
fonyl)benzamide 2,2,2-trifluoroacetic
[2187] The title compound was prepared by substituting EXAMPLE 86B
for EXAMPLE 50F and EXAMPLE 1G for EXAMPLE 3I in EXAMPLE 50G.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.82 (v
br s, 1H), 9.60 (v br s, 1H), 8.72 (t, 1H), 8.42 (d, 1H), 7.70 (br
s, 1H), 7.69 (dd, 1H), 7.55-7.20 (m, 15H), 7.00 (d, 1H), 6.96 (s,
1H), 6.80 (m, 2H), 6.53 (d, 1H), 4.35 (v br s, 1H), 3.83 (dd, 2H),
3.70 (v br s, 1H), 3.40 (m, 4H), 3.25, 3.20 (both m, total 4H),
3.00, 2.80 (both br s, total 4H), 1.81 (m, 1H), 1.58 (m, 2H), 1.22
(m, 2H).
EXAMPLE 87
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimeth-
ylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide
EXAMPLE 87A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimet-
hylamino)ethyl)phenoxy)benzoate
[2188] The title compound was prepared by substituting
4-(2-(dimethylamlno)ethyl)phenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 87B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamin-
o)ethyl)phenoxy)benzoic acid
[2189] The title compound was prepared by substituting EXAMPLE 87A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 87C
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimeth-
ylamino)ethyl)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide
[2190] The title compound was prepared by substituting EXAMPLE 87B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.67 (s, 1H), 9.51 (s, 1H),
8.66 (t, 1H), 8.52 (d, 1H), 7.84 (dd, 1H), 7.70 (s, 1H), 7.51 (dd,
5H), 7.36 (m, 3H), 7.22 (m, 3H), 6.84 (d, 2H), 6.76 (m, 1H), 6.42
(s, 1H), 3.85 (m, 2H), 3.52 (s, 10H), 3.35 (m, 2H), 3.26 (dd, 4H),
2.90 (m, 2H), 2.83 (d, 6H), 1.91 (s, 1H), 1.61 (d, 2H), 1.27 (dt,
2H).
EXAMPLE 88
2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipera-
zin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulf-
onyl)benzamide
EXAMPLE 88A
Methyl
2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piper-
azin-1-yl)benzoate
[2191] The title compound was prepared by substituting
4-(benzyloxy)phenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 88B
2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1--
yl)benzoic acid
[2192] The title compound was prepared by substituting EXAMPLE 88A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 88C
2-(4-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipera-
zin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulf-
onyl)benzamide
[2193] The title compound was prepared by substituting EXAMPLE 88B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.50 (m, 1H), 8.63 (t, 1H),
8.55 (d, 1H), 7.82 (dd, 1H), 7.66 (m, 1H), 7.41 (m, 13H), 7.20 (m,
1H), 6.96 (d, 2H), 6.88 (d, 2H), 6.70 (dd, 1H), 6.25 (m, 1H), 5.04
(m, 2H), 3.27 (m, 10 H), 2.90 (m, 6H), 1.88 (m, 1H), 1.57 (m, 2H),
1.23 (m, 2H).
EXAMPLE 89
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-morpholin--
4-ylphenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)s-
ulfonyl)benzamide
[2194] The title compound was prepared by substituting EXAMPLE 32B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.58 (s, 1H), 8.63 (t, 1H),
8.49 (d, 1H), 7.78 (dd, 1H), 7.69 (m, 1H), 7.52 (m, 5H), 7.38 (d,
2H), 7.33 (m, 1H), 7.15 (d, 1H), 7.07 (m, 1H), 6.74 (dd, 1H), 6.58
(dd, 1H), 6.40 (m, 2H), 6.22 (dd, 1H), 4.29 (m, 2H), 3.86 (m, 2H),
3.70 (m, 6H), 3.30 (m, 6H), 3.00 (m, 6H), 2.83 (m, 2H), 1.91 (m,
1H), 1.63 (d, 2H), 1.28 (m, 2H).
EXAMPLE 90
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-methyl-1,3-
-benzothiazol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)ami-
no)phenyl)sulfonyl)benzamide
[2195] The title compound was prepared by substituting EXAMPLE 24B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.83 (s, 1H), 9.48 (br s, 1H),
8.64 (t, 1H), 8.45 (d, 1H), 7.88 (d, 1H), 7.76 (dd, 1H), 7.50 (m,
5H), 7.37 (m, 2H), 7.30 (m, 1H), 7.18 (m, 1H), 7.04 (d, 1H), 6.97
(dd, 1H), 6.78 (dd, 1H), 6.48 (br s, 1H), 3.84 (dd, 2H), 3.37 (m,
6H), 3.23 (m, 4H), 2.89 (m, 2H), 2.75 (s, 3H), 2.36 (m, 3H), 1.62
(d, 2H), 1.24 (m, 2H).
EXAMPLE 91
tert-butyl
4-(3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl-
)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)a-
mino)carbonyl)phenoxy)phenyl)piperazine-1-carboxylate
EXAMPLE 91A
tert-butyl
4-(3-(5-(4-((4-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(me-
thoxycarbonyl)phenoxy)phenyl)piperazine-1-carboxylate
[2196] The title compound was prepared by substituting
1-(3-hydroxy-phenyl)-piperazine-4carboxylic acid tert-butyl ester
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 91B
2-(3-(4-(tert-butyxoycarbonyl)piperazin-1-yl)phenoxy)-4-(4-((4'-chlorobiph-
enyl-2-yl)methyl)piperazin-1-yl)benzoic acid
[2197] The title compound was prepared by substituting EXAMPLE 91A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 91C
tert-butyl
4-(3-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl-
)-2-((((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)a-
mino)carbonyl)phenoxy)phenyl)piperazine-1-carboxylate
[2198] The title compound was prepared by substituting EXAMPLE 91B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.65 (s, 1H), 8.65 (t, 1H),
8.47 (d, 1H), 7.76 (dd, 1H), 7.72 (m, 1H), 7.50 (m, 5H), 7.37 (d,
2H), 7.33 (m, 1H), 7.15 (d, 1H), 7.05 (m, 1H), 6.75 (dd, 1H), 6.57
(dd, 1H), 6.41 (m, 2H), 6.21 (dd, 1H), 4.31 (m, 2H), 3.86 (dd, 2H),
3.41 (m, 6H), 3.34 (t, 2H), 3.27 (m, 4H), 3.00 (m, 6H), 2.85 (m,
2H), 1.91 (m, 1H), 1.63 (d, 2H), 1.40 (m, 9 H), 1.28 (m, 2H).
EXAMPLE 92
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipera-
zin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)be-
nzamide
[2199] The title compound was prepared by substituting EXAMPLE 71A
for EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.72 (s,
1H), 9.52 (s, 1H), 8.69 (t, 1H), 8.50 (d, 1H), 7.81 (dd, 1H), 7.65
(s, 1H), 7.50 (m, 5H), 7.39 (m, 6H), 7.32 (m, 2H), 7.13 (m, 2H),
6.77 (dd, 1H), 6.64 (dd, 1H), 6.42 (s, 2H), 6.38 (m, 1H), 4.99 (s,
2H), 3.50 (m, 10H), 3.11 (m, 4H), 2.77 (s, 6H), 1.95 (m, 2H).
EXAMPLE 93
2-(3-(benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)pipera-
zin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)ben-
zamide
[2200] The title compound was prepared by substituting EXAMPLE 71A
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G is EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.74 (m, 1H),
9.78 (s, 1H), 8.71 (m, 1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.67 (s,
1H), 7.50 (m, 5H), 7.39 (m, 6H), 7.32 (m, 2H), 7.13 (m, 1H), 6.77
(dd, 1H), 6.64 (dd, 1H), 6.39 (m, 3H), 4.99 (s, 2H), 3.96 (m, 2H),
3.60 (s, 2H), 3.51 (m, 6H), 3.17 (m, 10H), 2.67 (m, 2H), 1.94 (m,
2H).
EXAMPLE 94
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morphol-
in-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide
EXAMPLE 94A
4-(2-(4-(benzyloxy)phenoxy)ethyl)morpholine
[2201] The title compound was prepared by substituting
4-(2-chloroethyl)morpholine for 2-chloro-N,N-dimethylethanamine and
4-(benzyloxy)phenol for 3-(benzyloxy)phenol in EXAMPLE 39A.
EXAMPLE 94B
4-(2-morpholinoethoxy)phenol
[2202] The title compound was prepared by substituting EXAMPLE 94A
for EXAMPLE 39A in EXAMPLE 39B.
EXAMPLE 94C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholinoeth-
oxy)phenoxy)benzoate
[2203] The title compound was prepared by substituting EXAMPLE 94B
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 94D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morpholinoeth-
oxy)phenoxy)benzoic acid
[2204] The title compound was prepared by substituting EXAMPLE 94C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 94E
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-morphol-
in-4-ylethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amin-
o)phenyl)sulfonyl)benzamide
[2205] The title compound was prepared by substituting EXAMPLE 94D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.46 (m, 1H), 9.98 (m, 1H),
8.64 (d, 1H), 8.55 (d, 1H), 7.87 (d, 1H), 7.49 (m, 5H), 7.39 (d,
2H), 7.31 (s, 1H), 7.25 (d, 1H), 6.96 (m, 5H), 6.71 (d, 1H), 6.29
(s, 1H), 4.30 (s, 2H), 3.98 (s, 2H), 3.85 (d, 2H), 3.72 (s, 2H),
3.42 (s, 16H), 3.27 (m, 2H), 1.91 (s, 1H), 1.62 (d, 2H), 1.28 (m,
2H).
EXAMPLE 95
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-(-
(tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-((2-oxo-1,2,3,4-t-
etrahydroquinolin-5-yl)oxy)benzamide
[2206] The title compound was prepared by substituting EXAMPLE 58B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.50 (s, 1H), 10.07 (s, 1H),
8.60 (t, 1H), 8.47 (d, 1H), 7.74 (dd, 1H), 7.46 (m, 6H), 7.36 (m,
2H), 7.24 (m, 1H), 7.14 (d, 1H), 6.92 (t, 1H), 6.74 (dd, 1H), 6.51
(d, 1H), 6.35 (d, 1H), 6.13 (d, 1H), 3.86 (dd, 2H), 3.36 (m, 4H),
3.25 (m, 2H), 3.16 (m, 4H), 2.83 (t, 2H), 2.41 (dd, 2H), 2.35 (m,
4H), 1.90 (m, 1H), 1.64 (dd, 2H), 1.28 (m, 2H).
EXAMPLE 96
2-(4-benzyloxy)phenoxy)-4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperaz-
in-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benz-
amide
[2207] The title compound was prepared bys substituting EXAMPLE 88B
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.53 (s, 1H),
9.74 (s, 1H), 8.69 (m, 1H), 8.59 (d, 1H), 7.90 (dd, 1H), 7.67
(m,1H), 7.41 (m, 13H), 7.21 (d, 1H), 6.99 (m, 2H), 6.91 (m, 2H),
6.70 (dd, 1H), 6.23 (s, 1H), 5.07 (s, 2H), 4.28 (m, 2H), 3.95 (s,
2H), 3.51 (m, 6H), 3.16 (m, 10H), 2.73 (d, 2H), 1.98 (m, 2H).
EXAMPLE 97
tert-butyl
4-(4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl-
)-2-((((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carb-
onyl)phenoxy)phenyl)piperazine-1-caraboxylate
EXAMPLE 97A
tert-butyl
4-(4-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(m-
ethoxycarbonyl)phenoxy)phenyl)piperazine-1-caraboxylate
[2208] The title compound was prepared by substituting
1-(4-hydroxy-phenol)-piperazine-4-carboxylic acid tert-butyl ester
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 97B
2-(4-(4-tert-butoxycarbonyl)piperazin-1-yl)phenoxy)-4-(4-(4'-chlorobipheny-
l-2-yl)methyl)piperazin-1-yl)benzoic acid
[2209] The title compound was prepared by substituting EXAMPLE 97A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 97C
tert-butyl
4-(4-(5-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl-
)-2-((((4-((3-morpholin-4-ylpropyl)amino-3-nitrophenyl)sulfonyl)amino)carb-
onyl)phenoxy)phenyl)piperazine-1-caraboxylate
[2210] The title compound was prepared by substituting EXAMPLE 97B
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.44 (m, 1H),
9.67 (s, 1H), 8.70 (t, 1H), 8.59 (d, 1H), 7.91 (dd, 1H), 7.69(s,
1H), 7.49 (m, 7H), 7.30 (m, 1H), 7.21 (d, 1H), 6.91 (m, 4H), 6.69
(dd, 1H), 6.24 (s, 1H), 3.95 (m, 2H), 3.67 (m, 4H), 3.52 (m, 10H),
3.17 (s, 4H), 3.04 (m, 10H), 1.97 (d, 2H), 1.43 (s, 9 H).
EXAMPLE 98
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morph-
olin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)be-
nzamide
EXAMPLE 98A
4-(3-(benzyloxy)phenyl)pyridine
[2211] The title compound was prepared by substituting
1-(benzyloxy)-3-bromobenzene for EXAMPLE 33C and
pyridin-4-ylboronic acid for
2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole
in EXAMPLE 33D.
EXAMPLE 98B
3-(pyridin-4-yl)phenol
[2212] The title compound was prepared by substituting EXAMPLE 98A
for EXAMPLE 33A in EXAMPLE 33B.
EXAMPLE 98C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-pyridin-4-
-ylphenoxy)benzoate
[2213] The title compound was prepared by substituting EXAMPLE 98B
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 98D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-pyridin-4-ylphen-
oxy)benzoic acid
[2214] The title compound was prepared by substituting EXAMPLE 98C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 98E
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morph-
olin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(3-pyridin-4-ylphenoxy)be-
nzamide
[2215] The title compound was prepared by substituting EXAMPLE 98D
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.87 (m, 1H),
8.68 (d, 2H), 8.58 (m, 1H), 8.42 (d, 1H), 7.73 (m, 4H), 7.52 (m,
5H), 7.36 (m, 6H), 7.14 (s, 1H), 7.03 (d, 1H), 6.91 (m, 1H), 6.80
(dd, 1H), 6.55 (d, 1H), 4.22 (m, 2H), 3.89 (m, 7H), 3.41 (m, 4H),
3.15 (m, 4H), 2.91 (m, 4H), 1.94 (m, 2H).
EXAMPLE 99
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morph-
olin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)be-
nzamide
EXAMPLE 99A
4-(4-(benzyloxy)phenyl)pyridine
[2216] The title compound was prepared by substituting
1-(benzyloxy)-4-bromobenzene for EXAMPLE 33C and
pyridin-4-ylboronic acidfor
2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiaz-
ole in EXAMPLE 33D.
EXAMPLE 99B
4-(pyridin-4-yl)phenol
[2217] The title compound was prepared by substituting EXAMPLE 99A
for EXAMPLE 33A in EXAMPLE 33B.
EXAMPLE 99C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(pyridin--
4-ylphenoxy)benzoate
[2218] The title compound was prepared by substituting EXAMPLE 99B
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 99D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(pyridin-4-yl)ph-
enoxy)benzoic acid
[2219] The title compound was prepared by substituting EXAMPLE 99C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 99E
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morph-
olin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-4-ylphenoxy)be-
nzamide
[2220] The title compound was prepared by substituting EXAMPLE 99D
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.80 (d, 2H), 8.55
(m, 1H), 8.49 (d, 1H), 7.93 (m, 5H), 7.74 (m, 1H), 7.53 (m, 5H),
7.36 (m, 3H), 7.13 (m, 2H), 6.93 (d, 1H), 6.83 (dd, 1H), 6.62 (d,
1H), 4.60 (s, 4H), 4.29 (m, 2H), 3.67 (s, 4H), 3.42 (m, 4H), 3.13
(m, 4H), 2.92 (m, 4H), 1.90 (m, 2H).
EXAMPLE 100
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morph-
olin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)be-
nzamide
EXAMPLE 100A
3-(4-(benzyloxy)phenyl)pyridine
[2221] The title compound was prepared by substituting
1-(benzyloxy)-4-bromobenzene for EXAMPLE 33C and
pyridin-3-ylboronic acid for
2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole
in EXAMPLE 33D.
EXAMPLE 100B
4-(pyridin-4-yl)phenol
[2222] The title compound was prepared by substituting EXAMPLE 100A
for EXAMPLE 33A in EXAMPLE 33B.
EXAMPLE 100C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(pyridin--
4-ylphenoxy)benzoate
[2223] The title compound was prepared by substituting EXAMPLE 100B
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 100D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(pyridin-4-ylphe-
noxy)benzoic acid
[2224] The title compound was prepared by substituting EXAMPLE 100C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 100E
4-(4-((4'chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpho-
lin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(4-pyridin-3-ylphenoxy)ben-
zamide
[2225] The title compound was prepared by substituting EXAMPLE 100D
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.84 (s, 1H),
8.95 (d, 1H), 8.66 (d, 1H), 8.57 (m, 1H), 8.52 (d, 1H), 8.24 (d,
1H), 7.83 (dd, 1H), 7.72 (m, 5H), 7.53 (m, 5H), 7.35 (m, 3H), 7.11
(m, 1H), 6.93 (d, 2H), 6.81 (dd, 1H), 6.57 (d, 1H), 4.31 (s, 2H),
3.80 (m, 8H), 3.42 (m, 4H), 3.14 (m, 8H), 1.94 (m, 2H).
EXAMPLE 101
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimeth-
ylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmeth-
yl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 101A
2-(4-(benzyloxy)phenoxy)-N,N-dimethylacetamide
[2226] The title compound was prepared by substituting
2-chloro-N,N-dimethylacetamide for 2-chloro-N,N-dimethylethanamine
and 4-(benzyloxy)phenol for 3-(benzyloxy)phenol in EXAMPLE 39A.
EXAMPLE 101B
2-(4-hydroxyphenoxy)-N,N-dimethylacetamide
[2227] The title compound was prepared by substituting EXAMPLE 101A
for EXAMPLE 39A in EXAMPLE 39B.
EXAMPLE 101C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimet-
hylamino)-2-oxoethoxy)phenoxy)benzoate
[2228] The title compound was prepared by substituting EXAMPLE 101B
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 101D
4-(4-((4'chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimethylamino-
)-2-oxoethoxy)phenoxy)benzoic acid
[2229] The title compound was prepared by substituting EXAMPLE 101C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 101E
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(4-(2-(dimeth-
ylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmeth-
yl)amino)phenyl)sulfonyl)benzamide
[2230] The title compound was prepared by substituting EXAMPLE 101D
for EXAMPLE 1F to EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.68 (t, 1H), 8.57 (d, 1H), 7.87
(dd, 1H), 7.72 (s, 1H), 7.53 (dd, 4H), 7.34 (m, 4H), 7.16 (d, 1H),
6.84 (m, 4H), 6.71 (dd, 1H), 6.34 (d, 1H), 4.60 (s, 2H), 3.84 (d,
2H), 3.51 (s, 10H), 3.36 (m, 2H), 3.26 (m, 2H), 2.81 (d, 6H), 1.91
(s, 1H), 1.62 (d, 2H), 1.28 (m, 2H).
EXAMPLE 102
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-
-benzimidazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitropheny-
l)sulfonyl)-benzamide
EXAMPLE 102A
methyl 4-bromo-2-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzoate
[2231] 1-methyl-1H-benzo[d]imidazol-5-ol (296 mg), methyl
4-bromo-2-fluorobenzoate (311 mg) and potassium carbonate (553 mg)
were combined in dimethylsulfoxide and ehated to 90.degree. C.
overnight. The reaction mixture was diluted with ethyl acetate and
washed thoroughly with water and with brine, dried voer MgSO.sub.4,
filtered and concentrated.
EXAMPLE 102B
methyl
4-(4-((2-(4-chlorobiphenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipe-
razin-1-yl)-2-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzoate
[2232] EXAMPLE 102A (480 mg) and EXAMPLE 1B (457 mg) were taken up
in dimethoxyethane (7.5 mL) in a microwave vial.
Tris(dibenzylideneacetone)dipalladium(0) (37 mg),
2-(di-tert-butylphosphino)biphenyl (48 mg) and potassium phosphate
tribasic (423 mg) were added. The vial was capped and heated in a
CEM Discover microwave reactor for 30 minutes at 150.degree. C. The
crude reaction mixture was filtered through celite and
concentrated. The material was dissovled in 1:1
dimethylsulfoxide:methanol and purified by HPLC.
EXAMPLE 102C
4-(4-((2-(4-chlorobiphenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-
-yl)-2-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzoic acid
[2233] The title compound was prepared by substituting EXAMPLE 102B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 102D
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((1-methyl-1H-
-benzimidazol-5-yl)oxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitropheny-
l)sulfonyl)-benzamide
[2234] The title compound was prepared by substituting EXAMPLE 102C
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, pyridine-d.sub.6) .delta. 9.34 (d, 1H), 8.99 (t, 1H),
8.91 (s, 1H), 8.55 (s, 1H), 8.48 (dd, 1H), 7.94 (t, 1H), 7.50 (m,
4H), 7.42 (m, 3H), 7.35 (m, 3H), 7.05 (s, 1H), 7.02 (d, 1H), 6.70
(m, 2H), 3.79 (t, 4H), 3.39 (s, 3H), 3.35 (m, 2H), 3.15 (m, 4H),
2.36 (m, 12H), 1.74 (m, 2H).
EXAMPLE 103
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl-
)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamide
EXAMPLE 103A
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylca-
rbamoyl)phenoxy)benzoate
[2235] The title compound was prepared by substituting
3-hydroxy-N-methylbenzamide for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 103B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl-
)phenoxy)benzoic acid
[2236] The title compound was prepared by substituting EXAMPLE 103A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 103C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(methylcarbamoyl-
)phenoxy)-N-(4-(3-morpholinopropylamino-3-nitrophenylsulfonyl)benzamide
bis(2,2,2-trifluoroacetate)
[2237] The title compound was prepared by substituting EXAMPLE 103B
for EXAMPLE 50F and EXAMPLE 4A for EXAMPLE 3I in EXAMPLE 50G.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.79 (v
br s, 1H), 9.38 (v br s, 1H), 8.65 (t, 1H), 8.48 (d, 1H), 8.37 (q,
1H), 7.78 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 6H), 7.35 (m, 4H),
7.26 (s, 1H), 7.11 (d, 1H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.43 (s,
1H), 4.35 (v br s, 1H), 3.99 (br m, 2H), 3.70 (v br s, 1H), 3.60,
3.50, 3.40 (all br m, total 10H), 3.20, 310, 2.80 (all br s, total
8M), 2.79, 2.77 (both s, total 3H), 1.99 (m, 2H).
EXAMPLE 104
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylami-
no)propylamino)-3-nitrophenylsulfonyl)-2-(3-(methylcarbamoyl)phenoxy)benza-
mide
[2238] The title compound was prepared by substituting EXAMPLE 103B
for EXAMPLE 50F and EXAMPLE 11A for EXAMPLE 3I in EXAMPLE 50G.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.79 (v
br s, 1H), 9.38 (v br s, 1H), 8.65 (t, 1H), 8.48 (d, 1H), 8.37 (q,
1H), 7.78 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 6H), 7.39 (m, 2H),
7.31 (m, 2H), 7.26 (s, 1H), 7.11 (d, 1H), 6.98 (dd, 1H), 6.79 (dd,
1H), 6.43 (s, 1H), 4.35 (v br s, 1H), 3.80 (v br s, 1H), 3.50, (br
m, 8H), 3.10, 3.05 (m, br s, 4H), 2.81, 2.80 (both s, 6H), 2.78,
2.77 (both s, 3H), 1.96 (m, 2H).
EXAMPLE 105
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimeth-
ylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmeth-
yl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 105A
2-(3-(benzyloxy)phenoxy)-N,N-dimethylacetamide
[2239] The title compound was prepared by substituting
2-chloro-N,N-dimethylacetamide for 2-chloro-N,N-dimethylethanamine
in EXAMPLE 39A.
EXAMPLE 105B
2-(3-hydroxyphenoxy)-N,N-dimethylacetamide
[2240] The title compound was prepared by substituting EXAMPLE 105A
for EXAMPLE 39A in EXAMPLE 39B.
[2241] EXAMPLE 105C
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimet-
hylamino)-2-oxoethoxy)phenoxy)benzoate
[2242] The title compound was prepared by substituting EXAMPLE 105B
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 105D
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimethylamin-
o)-2-oxoethoxy)phenoxy)benzoic acid
[2243] The title compound was prepared by substituting EXAMPLE 105C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 105E
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(2-(dimeth-
ylamino)-2-oxoethoxy)phenoxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmeth-
yl)amino)phenyl)sulfonyl)benzamide
[2244] The title compound was prepared by substituting EXAMPLE 105D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.66 (d, 1H), 8.54 (d, 1H), 7.84
(dd, 1H), 7.72 (s, 1H), 7.51 (m, 5H), 7.35 (m, 3H), 7.28 (t, 1H),
7.16 (dd, 2H), 6.75 (dd, 1H), 6.46 (m, 3H), 4.60 (s, 2H), 3.83 (d,
2H), 3.48 (s, 10H), 3.34 (m, 2H), 3.24 (m, 2H), 2.78 (s, 6H), 1.89
(s, 1H), 1.60 (d, 2H), 1.26 (m, 2H).
EXAMPLE 106
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dimet-
hylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4--
ylmethyl)amino)phenyl)sulfonyl)benzamide
EXAMPLE 106A
(Z)-tert-butyl
5-(benzyloxy)-3-(3-(dimethylamino)-3-oxoprop-1-enyl)-1H-indole-1-carboxyl-
ate
[2245] The title compound was prepared by substituting
N,N-dimethylacrylamide for 1-morpholinoprop-2-en-1-one in EXAMPLE
70A.
EXAMPLE 106B
tert-butyl
3-(3-(dimethylamino)-3-oxopropyl-5-hydroxy-1H-indole-1-carboxyl-
ate
[2246] The title compound was prepared by substituting EXAMPLE 106A
for EXAMPLE 39A in EXAMPLE 39B.
EXAMPLE 106C
tert-butyl
5-(5-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(meth-
oxycarbonyl)phenoxy)-3-(3-(dimethylamino)-3-oxopropyl)-1H-indole-1-carboxy-
late
[2247] The title compound was prepared by substituting EXAMPLE 106B
for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 106D
methyl
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(3-(dimet-
hylamino)propyl)-1H-indol-5-yloxy)benzoate
[2248] The title compound was prepared by substituting EXAMPLE 106C
for EXAMPLE 70C in EXAMPLE 74A.
EXAMPLE 106E
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(3-(3-(dimethylamin-
o)propyl)-1H-indol-5-yloxy)benzoic acid
[2249] The title compound was prepared by substituting EXAMPLE 106D
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 106F
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((3-(3-(dimet-
hylamino)propyl)-1H-indol-5-yl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4--
ylmethyl)amino)phenyl)sulfonyl)benzamide
[2250] The title compound was prepared by substituting EXAMPLE 106E
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.97 (d, 1H), 9.34 (s, 1H),
8.61 (m, 2H), 7.86 (dd, 1H), 7.54-7.36 (m, 8H), 7.22 (m, 4H), 6.86
(m, 1H), 6.67 (dd, 1H), 6.16 (d, 1H), 3.83 (m, 2H), 3.34-3.24 (m,
8H), 3.07 (m, 6H), 2.76 (s, 6H), 2.67 (m, 2H), 1.95 (m, 3H), 1.65
(m, 2H), 1.29 (m, 4H), 0.88 (m, 2H).
EXAMPLE 107
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dime-
thylamino)propyl)amino-3-nitrophenyl)sulfonyl)-2-(3-(hydroxymethyl)phenoxy-
)benzamide
[2251] The title compound was prepared by substituting EXAMPLE 9A
for EXAMPLE 50F and EXAMPLE 11A for EXAMPLE 3I in EXAMPLE 50G.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.60 (v
br s, 1H), 9.40 (v br s, 1H)s 8.76 (t, 1H), 8.51 (d, 1H), 7.80 (dd,
1H), 7.65 (br s, 1H), 7.50 (m, 5H), 7.40 (m, 2H), 7.30 (br s, 1H),
7.20 (dd, LH), 7.16 (d, 1H), 6.96 (d, 1H), 6.82 (s, 1H), 6.65 (d,
1H), 6.60 (d, 1H), 6.40 (s, 1H), 4.41 (s, 2H), 3.55 (m 4H), 3.40,
(m, 6H), 3.13 (m, 4H), 2.80, 2.79 (both s, total 6H), 1.98 (m,
2H).
EXAMPLE 108
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-methoxybe-
nzyl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulf-
onyl)benzamide
EXAMPLE 108A
4-Fluoro-2-(4-methoxy-benzyloxy)-benzoic acid methyl ester
[2252] Methyl 4-fluoro-2-hydroxybenzoate (1661 mg) was added to
N,N-dimethylformamide (50 mL). Sodium hydride (60%) in mineral oil,
430 mg) was added, the solution stirred for 15 minutes at room
temperature, and 1-(bromomethyl)-4-methoxybenzene (2061 mg) was
added. The solution was stirred at room temperature for three days,
added to 0.01M aqueous HCl, and extracted with ethyl acetate. The
organic phase was washed with water twice washed with brine, and
dried over anhydrous sodium sulfate. After filtration, the solvent
was removed under vacuum.
EXAMPLE 108B
4-[4-(4'-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-2-(4-methoxy-benzylox-
y)-benzoic acid methyl ester
[2253] The title compound was prepared by substituting EXAMPLE 108A
for methyl 2-bromo-4-fluorobenzoate in EXAMPLE 1C.
EXAMPLE 108C
4-[4-(4'-Chloro-biphenyl-2-ylmethyl)-piperazin-1-yl]-2-(4-methoxy-benzylox-
y)-benzoic acid
[2254] The title compound was prepared by substituting EXAMPLE 108B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 108D
4-(4-((4'-chloro-1,1'-biphenyl-2-yl)methyl)piperazin-1-yl)-2-((4-methoxybe-
nzyl)oxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulf-
onyl)benzamide
[2255] The title compound was prepared by substituting EXAMPLE 108C
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.79 (br s, 1H), 8.65 (t, 1H),
8.58 (d, 1H), 7.82 (dd, 1H), 7.53-7.41 (m, 7H), 7.38 (m, 2H),
7.27-7.19 (m, 2H), 6.98 (d, 2H), 6.69 (br s, 1H), 6.55 (dd, 1H),
5.16 (s, 2H), 3.84 (dd, 2H), 3.78 (s, 3H), 3.40 (s, 2H), 3.37-3.32
(m, 8H), 2.38 (m, 4H), 1.90 (m, 1H), 1.62 (dd, 2H), 1.26 (m,
2H).
EXAMPLE 109
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)benzamide
EXAMPLE 109A
4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide
[2256] A mixture of 4-chloro-3-nitrobenzenesulfonamide,
4-(aminomethyl)tetrahydro-2H-pyran-4-amine, hydrochloric acid and
triethylamine in dioxane (10 mL) was heated at 110.degree. C.
overnight. After cooling, the mixture was diluted with water (10
mL), and filtered.
EXAMPLE 109B
N-(4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrophenylsulfonyl)-
-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzamide
[2257] This example was prepared by substituting EXAMPLE 6B for
EXAMPLE 1F and EXAMPLE 109A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. 8.41 (s, 1H), 8.35 (d, J=1.83
Hz, 1H), 7.70 (dd, J=9.0, 1.98 Hz, 1H), 7.64 (d, j=8.85 Hz, 1H),
7.36 (d, J=8.54 Hz, 2H), 7.11-7.18 (m, 2H), 7.07 (d, J=8.24 Hz,
2H), 6.91 (dd, J=7.93, 1.22 Hz, 1H), 6.77 (dd, J=8.85, 2.14 Hz,
1H), 6.65 (dd, J=8.09, 1.98 Hz, 1H), 6.61-6.62 (m, 1H), 6.38 (d,
J=2.14 Hz, 1H), 3.67-3.71 (m, 6H), 3.11 (m, 3H), 2.77 (s, 2H),
2.18-2.24 (m, 6H), 1.97-1.99 (m, 2H), 1.76-1.79 (m, 2H), 1.65-1.67
(m, 2H), 1.39-1.42 (m, 2H), 0.94 (s, 6H).
EXAMPLE 110
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophe-
noxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
EXAMPLE 110A
1-(4'-chlorobiphenyl-2-yl)ethanone
[2258] A mixture of 1-(2-bromophenyl)ethanone (3.1 g)
4-chlorophenylboronic acid (2.92 g),
bis(triphenylphosphine)palladium(II) dichloride (1.202 g) and
Na.sub.2CO.sub.3 (3.30 g) in 7:2:3 dimethoxyethane/ethanol/water
(50 mL) was heated at 100.degree. C. for 3 hours and concentrated.
The concentrate was suspended in dichloromethane (30 mL) and
filtered. The filtrate was loaded onto a silica gel column and
flash chromatographed with 0%-50% dichlommethane/hexane.
EXAMPLE 110B
tert-butyl
4-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazine-1-carboxylate
[2259] A mixture of EXAMPLE 110A (1.9 g) in dichloromethane (3 mL)
was treated with 1M titanium(IV) chloride in dichloromethane (9.06
mL), cooled to 0.degree. C., treated with tert-butyl
piperazine-1-carboxylate (3.07 g), stirred at ambient temperature
for 3 hours, treated with NaCNBH.sub.3 (0.828 g) in methanol (5
ml), stirred at room temperature overnight, neutralized with
aqueous NaOH and concentrated. The concentrate was treated with
ethyl acetate and filtered. The organic filtrate was washed with
water and concentrated. The concentrate was dissolved in
methanol/trifluoroacetic acid/dimethylsulfoxide, loaded onto a
reverse phase C18 column and eluted with 0-80% acetonitrile in 0.1%
trifluoroacetic acid water over 70 minutes.
EXAMPLE 110C
1-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazine
[2260] To a solution of EXAMPLE 110B (650 mg) in dichloromethane (6
mL) at 0.degree. C. was added trifluoroacetic acid (6 mL). The
mixture was stirred at 0.degree. C. for 50 minutes and
concentrated. The concentrate was dissolved in dichloromethane,
washed with aqueous NaHCO.sub.3 and dried over Na.sub.2SO.sub.4,
filtered and concentrated.
EXAMPLE 110D
ethyl
4-(4-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophe-
noxy)benzoate
[2261] EXAMPLE 110C (252 mg) and ethyl
2-(2-chlorophenoxy)-4-fluorobenzoate (272 mg) in dimethylsulfoxide
(15 mL) was treated with potassium hydrogenphosphate (219 mg),
stirred at 135.degree. C. overnight, cooled, diluted with
dichloromethane, washed with water and concentrated. The
concentrate was dissolved in dichloromethane, loaded onto a silica
gel column and eluted with 5% 10M ammonia methanol in
dichloromethane.
EXAMPLE 110E
4-(4-(1-(4'-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)-2-(2-chlorophenoxy)b-
enzoic acid
[2262] A mixture of EXAMPLE 110D (300 mg) in tetrahydrofuran (10
mL) and methanol (10 mL) at 50.degree. C. was treated with 10% NaOH
(2085 .mu.L), stirred overnight, neutralized with HCl and
concentrated. The concentrate was taken up in water and extracted
with dichloromethane. The organic layer was dried over
Na.sub.2SO.sub.4, filtered and concentrated.
EXAMPLE 110F
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophe-
noxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
[2263] To a mixture of EXAMPLE 110E (65 mg), Example 1G (74.9 mg)
and 4-dimethylaminopyridine (58 mg) in dichloromethane (5 mL) was
added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
hydrochloride (45.5 mg). The mixture was stirred at ambient
temperature overnight and concentrated. The concentrate was
purified by RP HPLC (10-70% acetonitrile 0.1% trifluoroacetic acid
water/70 min). Fractions containing product were conenctrated, and
the concentrate was diluted with dichloromethane, neutralized with
aqueous NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 11.58 (s,
1H), 8.64 (t, 1H), 8.47 (d, 1H), 7.78 (dd, 1H), 7.56 (d, 1H),
7.45-7.52 (m, 3H), 7.38-7.43 (m, 2H), 7.27-7.33 (m, 3H), 7.11-7.19
(m, 3H), 6.99 (t, 1H), 6.70-6.77 (m, 2H), 6.28 (d, 1H), 3.86 (dd,
2H), 3.33-3.37 (m, 1H), 3.24-3.31 (m, 4H), 3.12 (s, 4H), 2.33-2.47
(m, 2H), 2.20-2.31 (m, 2H), 1.85-1.96 (m, 1H), 1.64 (d, 2H),
1.17-1.33 (m, 5H)
EXAMPLE 111
N-{[4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(3,5-dich-
lorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3-nitrobenz-
amide
EXAMPLE 111A
4-(1-methylpiperidin-4-ylamino)-3-nitrobenzoic acid
[2264] To a solution of ethyl 4-fluoro-3-nitrobenzoate (2.13 g) and
1-methylpiperidin-4-amine (1.14 g) in tetrahydrofuran (40 mL) was
added N,N-diisopropylethylamine (5 mL). The mixture was then
stirred at reflux overnight. The solvent was evaporated and the
resiude was dissolved in ethyl acetate (300 mL) and washed with
aqueous NaHCO.sub.3, water and brine. After evaporation of the
solvent, the residue was dissolved in tetrahydrofuran (20 mL),
methanol (10 mL) and water (10 mL). Then, LiOH H.sub.2O (2 g) was
added. The mixture was stirred at room temperature overnight. The
mixture was then concentrated and the resiude was neutralized with
5% aqueous HCl. The precipitate was filtered, washed with brine,
and dried under vacuum to give the product.
EXAMPLE 111B
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-fluorobenzenesulfon-
amide
[2265] To a solution of 2.4-difluorobenzenesulfonamide (1.56 g) and
1-((4'-chlorobiphenyl-2-yl)methyl)piperazine (2.32 g) in
dimethylsulfoxide (20 mL) was added N,N-diisopropylethylamine (5
mL). The mixture was stirred at 120.degree. C. overnight. The
mixture was diluted with ethyl acetate (300 mL) and washed with
water (3.times.) brine and dried over Na.sub.2SO.sub.4. After
filtration and evaporation of the solvent, the residue was loaded
on a column and eluted with 40% ethyl acetate in hexane to give the
title compound.
[2266] EXAMPLE 111C
4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-fluorobenzenesulfon-
yl)-4-(1-methylpiperidin-4-ylamino)-3-nitrobenzamide
[2267] The title compound was prepared as described in EXAMPLE 1G
by replacing EXAMPLE 1E and EXAMPLE 1F with EXAMPLE 111A and
EXAMPLE 111B, respectively.
EXAMPLE 111D
N-{[4-{4-[(4'-chloro-1,1'-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(3,5-dich-
lorophenoxy)phenyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]-3-nitrobenz-
amide
[2268] To a solution of 3,5-dichlorophenol (81 mg) and EXAMPLE 111C
(72 mg) in diglyme (3 mL) was added K.sub.2HPO.sub.4 (53 mg). The
mixture was stirred at 200.degree. C. in a CEM Discover microwave
reactor for 2 hours. The mixture was filtered and purified by RP
HPLC (10-70% acetonitrile in 0.1% trifluoroacetic acid water/70
min). Fractions containing product was concentrated, and the
concentrate was diluted with dichloromethane, neutralized with
aqueous NaHCO.sub.3, dried over Na.sub.2SO.sub.4, filtered, and
concentrated. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.56 (d, 1H), 8.12 (d, 1H), 7.94 (m, 1H), 7.84 (m, 2H),
7.51 (m, 514), 7.36 (m, 4H), 7.17 (d, 1H), 7.05 (m, 1H), 6.94 (m,
1H), 6.71 (m, 1H), 4.36 (m, 1H), 3.92 (m, 2H), 3.15 (m, 4H), 2.79
(m, 6H), 2.22 (m, 8H), 1.29 (m, 2H).
EXAMPLE 112
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
EXAMPLE 112A
ethyl 4-fluoro-2-(3-fluorophenoxy)benzoate
[2269] The title compound was prepared by substituting
3-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 112B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(3-fluorophenoxy)benzoate
[2270] The title compound was prepared by substituting EXAMPLE 112A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 112C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)
methyl)piperazin-1-yl)-2-(3-fluorophenoxy)benzoic acid
[2271] The title compound was prepared by substituting EXAMPLE 112B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 112D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2272] The title compound was prepared by substituting EXAMPLE 112C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.34 (d, 1H), 8.08
(d, 1H), 7.69 (dd, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.14 (m, 1H),
7.06 (d, 2H), 7.03 (d, 1H), 6.72 (dd, 1H), 6.65 (m, 1H), 6.49 (dd,
1H), 6.41 (m, 2H), 3.81 (m, 1H), 3.22 (m, 2H), 3.11 (m, 4H), 2.88
(m, 2H), 2.77 (m, 2H), 2.64 (s, 3H), 2.22 (m, 6H), 2.10 (m, 2H),
1.98 (m, 2H), 1.79 (m, 2H), 1.40 (m, 2H), 0.94 (s, 6H).
EXAMPLE 113
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperi-
din-4-yl)amino]phenyl}sulfonyl)benzamide
[2273] The title compound was prepared by substituting EXAMPLE 112C
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.34 (d,
1H), 8.10 (d, 1H), 7.67 (dd, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.14
(m, 1H), 7.06 (d, 2H), 7.01 (d, 1H), 6.72 (dd, 1H), 6.65 (m, 1H),
6.49 (dd, 1H), 6.41 (m, 2H), 3.93 (dd, 2H), 3.77 (br s, 2H), 3.30
(m, 2H), 3.10 (m, 6H), 2.77 (s, 2H), 2.69 (m, 2H), 2.24 (m, 4H),
2.18 (t, 2H), 2.06 (d, 2H), 1.98 (s, 2H), 1.80 (d, 2H), 1.68 (m,
2H), 1.52 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 114
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2274] The title compound was prepared by substituting EXAMPLE 112C
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.74 (br m, 1H),
8.43 (d, 1H), 7.73 (dd, 1H), 7.52 (d, 1H), 7.35 (m, 2H), 7.19 (m,
1H), 7.06 (m, 3H), 6.73 (m, 2H), 6.50 (m, 2H), 6.44 (d, 1H), 3.64
(t, 4H), 3.45 (m, 2H), 3.18 (m, 5H), 2.79 (m, 2H), 2.58 (m, 3H),
2.22 (m, 7H), 1.98 (m, 3H), 1.83 (m, 2H), 1.41 (m, 2H), 0.94 (s,
6H).
EXAMPLE 115
2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperid-
in-4-yl)amino]phenyl}sulfonyl)benzamide
[2275] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.33 (d,
1H), 8.09 (s, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.34 (m, 3H), 7.03
(m, 4H), 6.87 (t, 1H), 6.69 (m, 1H), 6.50 (d, 1H), 6.25 (d, 1H),
3.91 (d, 2H), 3.57 (s, 4H), 3.30 (m, 6H), 3.06 (s, 4H), 2.20 (d,
6H), 1.96 (d, 4H), 1.73 (s, 2H), 1.63 (s, 2H), 1.48 (s, 2H), 1.40
(t, 2H), 0.94 (s, 6H).
EXAMPLE 116
2-(2-chlorophenyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-y-
l]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophen-
yl}sulfonyl)benzamide
[2276] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.70 (t, 1H), 8.44
(d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.40 (dd, 1H), 7.35 (m, 2H),
7.12 (m, 1H), 7.06 (m, 3H), 6.98 (td, 1H), 6.73 (dd, 1H), 6.68 (dd,
1H), 6.26 (d, 1H), 4.62 (s, 2H), 3.62 (m, 4H), 3.46 (dd, 2H), 3.11
(s, 4H), 2.75 (d, 2H), 2.47 (m, 4H), 2.20 (d, 6H), 1.97 (s, 2H),
1.82 (p, 2H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 117
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide
EXAMPLE 117A
4-(1-cyclopentylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
[2277] The title compound was prepared by substituting
1-cyclopentylpiperidin-4-amine for 3-(N-morpholinyl)-1-propylamine
in EXAMPLE 4A.
EXAMPLE 117B
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide
[2278] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 117A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.35 (d,
1H), 8.06 (d, 1H), 7.73 (dd, 1H), 7.63 (d, 1H), 7.35 (m, 3H), 7.04
(m, 4H), 6.88 (td, 1H), 6.69 (dd, 1H), 6.53 (dd, 1H), 6.25 (d, 1H),
4.57 (s, 1H), 3.29 (s, 8H), 3.05 (d, 4H), 2.75 (s, 2H), 2.62 (s,
2H), 2.20 (d, 5H), 2.07 (s, 1H), 1.95 (d, 3H), 1.66 (s, 3H), 1.53
(s, 3H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 118
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
EXAMPLE 118A
ethyl 4-fluoro-2-(4-fluorophenoxy)benzoate
[2279] The title compound was prepared by substituting
4-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 118B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yi)-2-(4-fluorophenoxy)benzoate
[2280] The title compound was prepared by substituting EXAMPLE 118A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 118C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(4-fluorophenoxy)benzoic acid
[2281] The title compound was prepared by substituting EXAMPLE 118B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 118D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(4-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2282] The title compound was prepared by substituting EXAMPLE 118C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.39 (d, 1H), 8.08
(d, 1H), 7.75 (dd, 1H), 7.55 (d, 1H), 7.36 (d, 2H), 7.06 (m, 3H),
6.98 (m, 2H), 6.73 (m, 2H), 6.07 (dd, 1H), 6.29 (d, 1H), 3.82 (m,
1H), 3.18 (m, 2H), 3.08 (m, 4H), 2.80 (m, 4H), 2.60 (m, 3H), 2.22
(m, 6H), 2.07 (m, 2H), 1.97 (m, 2H), 1.77 (m, 2H), 1.40 (m, 2H),
0.94 (s, 6H).
EXAMPLE 119
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide
[2283] The title compound was prepared as described EXAMPLE 1H by
replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 36C and EXAMPLE
65A, respectively. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.35 (d, 1H), 8.17 (d, 1H), 7.66 (dd, 1H), 7.58 (d, 1H),
7.36 (d, 2H), 7.15 (t, 1H), 7.05 (m, 3H), 6.88 (d, 1H), 6.74 (dd,
1H), 6.64 (m, 2H), 6.41 (d, 1H), 3.69 (m, 1H), 3.16 (m, 4H), 2.97
(m,4H), 2.77 (m, 2H), 2.72 (s, 2H), 2.44 (m, 3H), 2.21 (m, 3H),
1.96 (m, 2H), 1.58 (m, 3H), 0.94 (s, 6H), 0.40 (m, 5H).
EXAMPLE 120
2-(2-chloro-4-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
[2284] The title compound was prepared by substituting EXAMPLE 61D
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.73 (m, 1H), 8.48
(d, 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.36 (m, 3H), 7.07 (m, 4H),
6.75 (m, 2H), 6.25 (d, 1H), 3.63 (m, 4H), 3.47 (m, 2H), 3.12 (m,
4H), 2.77 (s, 2H), 2.21 (m, 6H), 1.97 (s, 2H), 1.82 (m, 2H), 1.41
(t, 2H), 0.94 (s, 6H).
EXAMPLE 121
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(2,3-difluorophenoxy)benzamide
[2285] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 65A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.42 (d,
1H), 8.21 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.35 (d, 2H), 7.15
(d, 1H), 7.06 (d, 2H), 6.89 (m, 2H), 6.75 (dd, 1H), 6.44 (m, 2H),
3.76 (m, 1H), 3.17 (m, 4H), 3.00 (m, 2H), 2.81 (s, 2H), 2.59 (m,
2H), 2.24 (m, 6H), 1.92 (m, 5H), 1.61 (m, 2H), 1.41 (t, 2H), 0.94
(s, 6H), 0.46 (m, 4H).
EXAMPLE 122
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
EXAMPLE 122A
methyl 4-fluoro-2-(2-fluorophenoxy)benzoate
[2286] The title compound was prepared by substituting
2-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 122B
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(2-fluorophenoxy)benzoate
[2287] The title compound was prepared by substituting EXAMPLE 122A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 122C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(2-fluorophenoxy)benzoic acid
[2288] The title compound was prepared by substituting EXAMPLE 122B
for EXAMPLE 1E in EXAMPLE 1F.
[2289] EXAMPLE 122D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-fluorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2290] The title compound was prepared by substituting EXAMPLE 122C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.87 (s, 1H),
9.54 (s, 1H), 8.50 (d, 1H), 8.20 (d, 1H), 7.86 (dd, 1H), 7.52 (d,
1H), 7.40 (d, 2H), 7.24 (m, 2H), 7.10 (d, 2H), 7.03 (m, 2H), 6.78
(m, 2H), 6.42 (s, 1H), 3.62 (m, 10H), 3.10 (m, 4H), 2.82 (m, 2H),
2.82 (s, 3H), 2.21 (m, 4H), 2.03 (s, 2H), 1.85 (m, 1H), 1.46 (t,
2H), 0.96 (s, 6H).
EXAMPLE 123
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(2-fluorophenoxy)benzamide
[2291] The title compound was prepared by substituting EXAMPLE 122C
for EXAMPLE 1F and EXAMPLE 65A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.51 (d,
1H), 8.19 (s, 1H), 7.87 (dd, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.24
(m, 2H), 7.11 (d, 2H), 7.03 (m, 2H), 6.78 (m, 2H), 6.43 (d, 1H),
3.97 (m, 4H), 3.21 (s, 8H), 3.21 (s, 4H), 2.83 (m, 4H), 2.22 (m,
4H), 2.06 (m, 2H), 1.81 (m, 1H), 1.47 (t, 2H), 0.96 (s, 6H).
EXAMPLE 124
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-fluorophenoxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperi-
din-4-yl)amino]phenyl}sulfonyl)benzamide
[2292] The title compound was prepared by substituting EXAMPLE 122C
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.90 (s,
1H), 9.59 (s, 1H), 8.51 (m, 1H), 8.20 (d, 1H), 7.87 (dd, 1H), 7.53
(d, 1H), 7.39 (d, 2H), 7.24 (m, 2H), 7.10 (d, 2H), 7.03 (m, 2H),
6.78 (m, 2H), 6.42 (s, 1H), 4.01 (m, 2H), 3.71 (m, 4H), 3.34 (m,
6H), 3.17 (m, 4H), 2.78 (m, 2H), 2.24 (m, 4H), 1.94 (m, 8H), 1.70
(m, 2H), 1.46 (t, 2H), 0.96 (s, 6H).
EXAMPLE 125
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-fluorophenoxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2293] The title compound was prepared by substituting EXAMPLE 122C
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.85 (s, 1H),
9.94 (s, 1H), 9.63 (s, 1H), 8.71 (m, 1H), 8.53 (d, 1H), 7.86 (dd,
1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.26 (m, 1H), 7.19 (d, 1H), 7.07
(m, 4H), 6.80 (m, 2H), 6.41 (d, 1H), 3.97 (m, 2H), 3.54 (m, 6H),
3.31 (m, 4H), 3.19 (m, 8H), 2.22 (m, 2H), 1.99 (m, 4H), 1.47 (t,
2H), 0.97 (s, 6H).
EXAMPLE 126
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophen-
yl}sulfonyl)benzamide
EXAMPLE 126A
4-(2-morpholinoethylamino)-3-nitrobenzenesulfonamide
[2294] The title compound was prepared by substituting
2-(N-morpholinyl)-2-ethylamine for 3-(N-morpholinyl)-1-propylamine
in EXAMPLE 4A.
EXAMPLE 126B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophen-
yl}sulfonyl)benzamide
[2295] The title compound was prepared by substituting EXAMPLE 122C
for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.81 (s,
1H), 8.50 (d, 1H), 7.82 (dd, 1H), 7.50 (d, 1H), 7.36 (d, 2H), 7.23
(m, 1H), 7.04 (m, 5H), 6.79 (m, 1H), 6.73 (dd, 1H), 6.31 (d, 1H),
3.62 (m, 4H), 3.50 (q, 2H), 3.32 (m, 6H), 3.14 (m, 4H), 2.79 (s,
2H), 2.67 (m, 2H), 2.20 (m, 6H), 1.99 (m, 2H), 1.40 (t, 2H), 0.94
(s, 6H).
EXAMPLE 127
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperi-
din-4-yl)amino]-phenyl}sulfonyl)benzamide
[2296] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G is EXAMPLE 1 H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.38 (m,
1H), 8.13 (m, 1H), 7.70 (m, 1H), 7.59 (m, 1H), 7.36 (d, 2H), 7.16
(m, 1H), 7.05 (m, 3H), 6.89 (m, 1H), 6.74 (dd, 1H), 6.66 (dd, 1H),
6.61 (m, 1H), 6.42 (m, 1H), 3.94 (m, 2H), 3.26 (m, 6H), 3.15 (m,
6H), 2.78 (m, 2H), 2.18 (m, 9 H), 1.98 (m, 3H), 1.86 (m, 2H), 1.74
(m, 2H), 1.57 (m, 2H), 1.41 (m, 2H), 0.93 (s, 6H).
EXAMPLE 128
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2297] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.75 (t, 1H), 8.41
(d, 1H), 7.71 (dd, 1H), 7.52 (d, 1H), 7.36 (d, 2H), 7.18 (m, 1H),
7.06 (m, 3H), 6.93 (dd, 1H), 6.77 (dd, 1H), 6.69 (m, 2H), 6.46 (d,
1H), 3.65 (t, 4H), 3.47 (q, 2H), 3.29 (m, 2H), 3.18 (m, 4H), 2.79
(s, 2H), 2.56 (m, 4H), 2.22 (m, 6H), 1.98 (m, 2H), 1.85 (m, 2H),
1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 129
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-fluorophenoxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophen-
yl}sulfonyl)benzamide
[2298] The title compound was prepared by substituting EXAMPLE 112C
for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.48 (a,
1H), 8.81 (t, 1H), 8.45 (d, 1H), 7.75 (dd, 1H), 7.49 (d, 1H), 7.36
(d, 2H), 7.19 (m, 1H), 7.06 (m, 3H), 6.77 (dd, 1H), 6.72 (m, 1H),
6.54 (m, 2H), 6.47 (d, 1H), 3.62 (m, 4H), 3.50 (q, 2H), 3.32 (m,
4H), 3.19 (m, 4H), 2.82 (s, 2H), 2.69 (t, 2H), 2.27 (m, 4H), 2.18
(s, 2H), 1.99 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 130
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nit-
rophenyl}sulfonyl)benzamide
[2299] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 117A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.35 (d,
1H), 8.08 (d, 1H), 7.69 (dd1H), 7.61 (d, 1H), 7.3 S(d, 2H), 7.14
(m, 1H), 7.04 (m, 3H), 6.88 (dd, 1H), 6.72 (dd, 1H), 6.65 (dd, 1H),
6.60 (m, 1H), 6.39 (d, 1H), 3.87 (s, 1H), 3.11 (m, 6H), 2.93 (m,
2H), 2.77 (s, 2H), 2.21 (m, 8H), 1.98 (m, 5H), 1.69 (m, 4H), 1.56
(m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 131
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(triflu-
oromethyl)sulfonyl]phenyl}sulfonyl)benzamide
EXAMPLE 131A
(2-fluorophenyl)(trifluoromethyl)sulfane
[2300] Methyl viologen hydrochloride (1.17 g) in
N,N-dimethylformamide (80 mL) at 25.degree. C. was saturated with
trifluoromethyl iodide, treated wih 2-fluorobenzenethiol (9.7 mL)
and triethylamine (20 mL), stirred for 24 hours, diluted with water
(240 mL) and extracted with diethyl ether. The extract was washed
with 1M aqueous NaOH, saturated ammonium chloride and brine and
concentrated.
EXAMPLE 131B
1-fluoro-2-(trifluoromethylsulfonyl)benzene
[2301] EXAMPLE 131A (17.346 g) in 1:1:2 carbon
tetrachloride:acetonitrile:water (800 mL) at 25.degree. C. was
treated with sodium periodate (56.8 g) and ruthenium(III) chloride
hydrate (183 mg), stirred for 18 hours, diluted with
dichloromethane (100 mL) and filtered through diatomaceous earth
(Celite.RTM.). The filtrate was washed with saturated sodium
bicarbonate and extracted with dichloromethane. The extract was
washed with brine and dried (MgSO.sub.4), filtered and
concentrated. The concentrate was filtered through silica gel.
EXAMPLE 131C
4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide
[2302] EXAMPLE 131B (37.3 g) in chlorosulfonic acid (32.8 mL) at
120.degree. C. was stirred for 18 hours, cooled to 25.degree. C.
and pipetted onto crushed ice. The mixture was extracted with ethyl
acetate, and the extract was washed with water and brine and dried
(MgSO.sub.4), filtered and concentrated. The crude product was
taken up in isopropanol (706 mL) at -78.degree. C., treated with
ammonium hydroxide (98 mL) over 1 hour, stirred for 1 hour,
quenched with 6M aqueous HCl (353 mL), warmed to 25.degree. C. and
concentrated. The concentrate was mixed with water and extracted
with ethyl acetate. The extract was dried over MgSO.sub.4, filtered
and concentrated. The concentrate was recrystallized from ethyl
acetate/hexane.
[2303] EXAMPLE 131D
4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzensulfonami-
de
[2304] The title compound was prepared by substituting
1-methyl-4-aminopiperidine for 3-(N-morpholinyl)-1-propylamine and
EXAMPLE 131C for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE
4A.
EXAMPLE 131E
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(triflu-
oromethyl)sulfonyl]phenyl}sulfonyl)benzamide
[2305] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 131D for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.00 (d,
1H), 7.83 (dd, 1H), 7.61 (d, 1H), 7.36 (m, 2H), 7.19 (m, 1H), 7.07
(d, 2H), 7.01 (d, 1H), 6.93 (d, 1H), 6.72 (dd, 1H), 6.66 (m, 2H),
6.51 (d, 1H), 6.39 (d, 1H), 3.79 (none, 1H), 3.11 (m, 6H), 2.90 (t,
2H), 2.78 (s, 2H), 2.65 (s, 3H), 2.20 (m, 6H), 2.09 (m, 2H), 1.97
(m, 3H), 1.64 (m, 2H), 1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 132
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(3-fluorophenoxy)benzamide
[2306] The title compound was prepared by substituting EXAMPLE 112C
for EXAMPLE 1F and EXAMPLE 65A for EXAMPLE 1G is EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.43 (d,
1H), 8.23 (d, 1H), 7.75 (dd, 1H), 7.51 (d, 1H), 7.35 (d, 2H), 7.17
(m, 2H), 7.06 (d, 2H), 6.73 (m, 2H), 6.56 (dd, 1H), 6.51 (dd, 1H),
6.45 (d, 1H), 3.74 (m, 1H), 3.18 (m, 4H), 2.97 (m, 2H), 2.80 (s,
2H), 2.54 (m, 2H), 2.20 (m, 6H), 1.98 (m, 4H), 1.85 (m, 1H), 1.62
(m, 2H), 1.41 (t, 2H), 0.94 (s, 6H), 0.50 (m, 2H), 0.41 (m,
2H).
EXAMPLE 133
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(2,3-difluorophenoxy)benzamide
[2307] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 117A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.35 (d,
1H), 8.05 (s, 1H), 7.73 (dd, 1H), 7.64 (d, 1H), 7.36 (d, 2H), 7.06
(m, 3H), 6.84 (m, 2H), 6.72 (dd, 1H), 6.43 (d, 1H), 6.31 (m, 1H),
3.89 (s, 1H), 3.12 (m, 6H), 2.97 (m, 2H), 2.77 (s, 2H), 2.21 (m,
8H), 1.98 (m, 5H), 1.63 (m, 8H), 1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 134
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-(2-fluorophenoxy)benzamide
[2308] The title compound was prepared by substituting EXAMPLE 122C
for EXAMPLE 1F and EXAMPLE 117A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.39 (m,
1H), 8.07 (d, 1H), 7.76 (m, 1H), 7.61 (d, 1H), 7.34 (d, 2H), 7.18
(m,2H), 7.07 (m, 3H), 6.91 (m, 2H), 6.68 (m, 1H), 6.28 (m, 1H),
3.26 (m, 8H), 3.17 (m, 2H), 3.05 (m, 4H), 2.75 (s, 2H), 2.23 (m,
7H), 2.00 (m, 4H), 1.64 (m, 6H), 1.40 (m, 2H), 0.94 (s, 6H).
EXAMPLE 135
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2,3-difluorophenoxy-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrop-
henyl}sulfonyl)benzamide
[2309] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.77 (m,
1H), 8.45 (d, 1H), 7.78 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.06
(m, 3H), 6.91 (m, 2H), 6.76 (dd, 1H), 6.45 (m, 2H), 3.62 (m, 4H),
3.49 (m, 2H), 3.18 (m, 4H), 2.81 (s, 2H), 2.68 (t, 2H), 2.23 (m,
6H), 1.97 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 136
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperidi-
n-4-yl]amino}phenyl)sulfonyl]benzamide
EXAMPLE 136A
4-(2-Nitro-4-sulfamoyl-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester
[2310] Tert-butyl-4-aminopiperidine-1-carboxylate (8.63 g) was
dissolved in 1,4-dioxane (250 mL), and
4-chloro-3-nitrobenzenesulfonamide (6.00 g) was added followed by
triethylamine (10.60 mL). The solution was heated at 90.degree. C.
for 20 hours and then cooled. The solvent was removed under vacuum,
and the material was purified by flash column chromatography on
silica gel using 50% ethyl acetate in hexanes, increasing to 100%
ethyl acetate and increasing further to 20% methanol in
dichloromethane.
EXAMPLE 136B
3-Nitro-4-(piperidin-4-ylamino)-benzenesulfonamide
[2311] The title compound was prepared by substituting EXAMPLE 136A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 136C
3-nitro-4-(1-(thiophen-3-ylmethyl)piperidin-4-ylamino)benzenesulfonamide
[2312] The title compound was prepared by substituting
thiophene-3-carbaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde and
EXAMPLE 136B for tert-butyl piperazine-1-carboxylate in EXAMPLE
1A.
EXAMPLE 136D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-[(3-nitro-4-{[1-(thien-3-ylmethyl)piperidi-
n-4-yl]amino}phenyl)sulfonyl]benzamide
[2313] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 136C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.39 (d,
1H), 8.16 (d, 1H), 7.74 (dd, 1H), 7.54 (m, 3H), 7.35 (d, 2H), 7.10
(m, 4H), 6.87 (m, 2H), 6.74 (dd, 1H), 6.40 (m, 2H), 3.84 (m, 3H),
3.15 (m, 4H), 3.03 (m, 2H), 2.79 (s, 2H), 2.62 (m, 2H), 2.23 (m,
6H), 2.02 (m, 4H), 1.73 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 137
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-f-
luorophenoxy)benzamide
[2314] EXAMPLE 122C (203 mg), EXAMPLE 11A (124 mg),
1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (142
mg), and 4-dimethylaminopyridine (90 mg) were stirred in
CH.sub.2Cl.sub.2 (8 mL) overnight. The reaction was concentrated
and the crude was purified by preparative HPLC using a C18 column,
250.times.50 mm, 10.mu., and eluting with a gradient of 20-100%
CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving the
product as a trifluoroacetate salt. The salt was dissolved in
dichloromethane (6 mL) and washed with 50% aqueous NaHCO.sub.3. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated to give the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.71 (br t, 1H), 8.38 (d, 1H),
7.75 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 2H), 7.18 (m, 1H), 7.06 (d,
2H), 6.98 (d, 1H), 6.92 (m, 2H), 6.66 (dd, 1H), 6.60 (m, 1H), 6.26
(d, 1H), 3.47 (dd, 2H), 3.05 (br m, 4H), 2.89 (br m, 2H), 2.75 (s,
2H), 2.60 (s, 6H), 2.20 (br m, 6H), 1.98 (s, 2H), 1.88 (m, 2H),
1.40 (t, 2H), 0.93 (s, 6H).
EXAMPLE 138
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-f-
luorophenoxy)benzamide
[2315] The title compound was prepared by substituting EXAMPLE 112C
for EXAMPLE 122C in EXAMPLE 137. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.70 (br t, 1H), 8.35 (d, 1H),
7.69 (dd, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.15 (dd, 1H), 7.06 (d,
2H), 6.95 (d, 1H), 6.70 (m, 2H), 6.50 (dd, 1H), 6.41 (m, 1H), 6.38
(d, 1H), 3.47 (dd, 2H), 3.10 (br m, 4H), 2.94 (br m, 2H), 2.78 (s,
2H), 2.62 (s, 6H), 2.23 (br m, 6H),1.99 (s, 2H), 1.90 (m, 2H) 1.40
(t, 2H), 0.93 (s, 6H).
EXAMPLE 139
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(4--
fluorophenoxy)benzamide
[2316] The title compound was prepared by substituting EXAMPLE 118C
for EXAMPLE 122C is EXAMPLE 137. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.75 (br t, 1H), 8.39 (d, 1H),
7.75 (dd, 1H), 7.58 (d, 1H), 7.37 (d, 2H), 7.06 (d, 2H), 7.00 (m,
3H), 6.75 (m,2H), 6.66 (dd, 1H), 6.28 (d, 1H), 3.47 (dd, 2H), 3.05
(br m, 4H), 2.89 (br m, 2H), 2.75 (s, 2H), 2.60 (s, 6H), 2.20 (br
m, 6H), 1.98 (s, 2H), 1.88 (m, 2H) 1.40 (t, 2H), 0.93 (s, 6H).
EXAMPLE 140
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 140A
4-(2-Nitro-4-sulfamoyl-phenylamino)-piperidine-1-carboxylic acid
tert-butyl ester
[2317] Tert-butyl 4-aminopiperidine-1-carboxylate (8.63 g) was
dissolved in 1,4-dioxane (250 mL), and
4-chloro-3-nitrobenzenesulfonamide (6.00 g) was added followed by
triethylamin (10.60 mL). The solution was heated at 90.degree. C.
for 20 hours and then cooled. The solvent was removed under vacuum,
and the material purified by flash column chromatography on silica
gel using 50% ethyl acetate in hexanes, increasing to 100% ethyl
acetate and increasing further to 20% methanol in
dichloromethane.
[2318] EXAMPLE 140B
3-Nitro-4-(piperidin-4-ylamino)-benzenesulfonamide
[2319] The title compound was prepared by substituting EXAMPLE 140A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 140C
4-[1-(2-Fluoro-ethyl)-piperidin-4-ylamino]-3-nitro-benzenesulfonamide
[2320] To EXAMPLE 140B (1000 mg) was added N,N-dimethylformamide
(10 mL). 1-Fluoro-2-iodoethane (462 mg) and triethylamine (1.18 mL)
were added and the solution was heated at 70.degree. C. for 16
hours. The solvent was removed under vacuum, and the mateiral
purified by flash column chromatography on silica gel using ethyl
acetate increasing to 10% methanol in dichloromethane.
EXAMPLE 140D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-(2-fluoroethyl)piperidin-4-yl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide
[2321] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 140C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.41 (d,
1H), 8.21 (d, 1H), 7.76 (dd, 1H), 7.56 (d, 1H), 7.37 (d, 2H), 7.14
(d, 1H), 7.07 (d, 2H), 6.94-6.82 (m, 2H), 6.76 (dd, 1H), 6.48 (d,
1H), 6.41-6.34 (m, 1H), 4.71 (t, 1H), 4.55 (t, 1H), 3.89-3.70 (m,
2H), 3.17 (br s, 4H), 3.09-2.90 (m, 4H), 2.91-2.77 (m, 3H), 2.26
(br s, 4H), 2.18 (m, 2H), 2.08-1.96 (m, 4H), 1.71 (q, 2H), 1.41 (t,
2H), 0.95 (s, 6H).
EXAMPLE 141
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-nitrophen-
yl}sulfonyl)benzamide
[2322] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.81 (t,
1H), 8.44 (d, 1H), 7.73 (dd, 1H), 7.51 (d, 1H), 7.36 (d, 2H), 7.18
(t, 1H), 7.07 (d, 2H), 7.04 (d, 1H), 6.93 (dt, 1H), 6.78 (dd, 1H),
6.71 (dd, 1H), 6.69 (d, 1H), 6.47 (d, 1H), 3.62 (t, 4H), 3.50 (q,
2H), 3.20 (br s, 4H), 2.81 (br s, 2H), 2.69 (t, 2H), 2.26 (m, 4H),
2.18 (t, 2H), 2.02-1.93 (m, 4H), 1.41 (t, 2H), 1.37-1.22 (m, 2H),
0.95 (s, 6H).
EXAMPLE 142
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitroph-
enyl)sulfonyl]benzamide
[2323] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 122C in EXAMPLE 137. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.71 (br t, 1H), 8.34 (d, 1H),
7.65 (dd, 1H), 7.63 (d, 1H), 7.37 (d, 2H), 7.16 (dd, 1H), 7.07 (d,
2H), 6.93 (d, 1H), 6.89 (m, 1H), 6.73 (dd, 1H), 6.64 (dd, 1H), 6.60
(dd, 1H), 6.38 (d, 1H), 3.45 (dd, 2H), 3.09 (br m, 4H), 2.93 (br m,
2H), 2.78 (s, 2H), 2.62 (s, 6H), 2.23 (br m, 6H), 1.98 (s, 2H),
1.90 (m, 2H), 1.41 (t, 2H), 0.93 (s, 6H).
EXAMPLE 143
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}--
3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 143A
4-[3-(4-Methyl-piperazin-1-yl)-propylamino]-3-nitro-benzenesulfonamide
[2324] The title compound was prepared by substituting
1-(3-aminopropyl)-4-methylpiperazine for tert-butyl
4-aminopiperidine-1-carboxylate is EXAMPLE 140A.
EXAMPLE 143B
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}--
3-nitrophenyl)sulfonyl]benzamide
[2325] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 143A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.55 (t,
1H), 8.39 (d, 1H), 7.67 (dd, 1H), 7.61 (d, 1H), 7.36 (d, 2H), 7.15
(t, 1H), 7.07 (d, 2H), 6.95 (d, 1H), 6.89 (dd, 1H), 6.73 (dd, 1H),
6.65 (d, 1H), 6.60 (t, 1H), 6.40 (d, 1H), 3.43 (q, 2H), 3.12 (br s,
4H), 2.89 (br s, 2H), 2.77 (s, 2H), 2.60-2.45 (m, 9H), 2.29-2.15
(m, 8H), 1.98 (br s, 2H), 1.81 (m, 2H), 1.41 (t, 2H), 0.94 (s,
6H).
EXAMPLE 144
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
EXAMPLE 144A
methyl 2-(3-chlorophenoxy)-4-(piperazin-1-yl)benzoate
[2326] This example was prepared by substituting piperazine for
EXAMPLE 3E and EXAMPLE 36A for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 144B
methyl
2-(3-chlorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihy-
dro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
[2327] This example was prepared by substituting EXAMPLE 144A for
EXAMPLE 38F in EXAMPLE 38G.
EXAMPLE 144C
2-(3-chlorophenoxy)-4-(4-((4(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-p-
yran-3-yl)methyl)piperazin-1-yl)benzoic acid
[2328] The title compound was prepared as described in EXAMPLE 38 H
by replacing EXAMPLE 38G with EXAMPLE 144B.
EXAMPLE 144D
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
[2329] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 144C and
EXAMPLE 3I, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.33 (d, 1H), 8.07 (d, 1H), 7.68
(dd, 1H), 7.62 (d, 1H), 7.40 (d, 2H), 7.15 (m, 3H), 7.01 (d, 1H),
6.86 (m, 1H), 6.72 (m, 1H), 6.64 (dd, 1H), 6.58 (m, 1H), 6.39 (d,
1H), 4.15 (s, 2H), 3.83 (m, 1H), 3.17 (m, 8H), 2.87 (s, 3H), 2.63
(m, 5H), 2.26 (m, 4H), 2.13 (m, 3H), 1.79 (m, 1H), 1.20 (s,
6H).
EXAMPLE 145
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 145A
methyl 2-(2,3-difluorophenoxy)-4-(piperazin-1-yl)benzoate
[2330] This exmple was prepared for substituting piperazine for
EXAMPLE 3F and EXAMPLE 45A for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 145B
methyl
2-(2,3-difluorophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6--
dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
[2331] This example was prepared by substituting EXAMPLE 145A for
EXAMPLE 38F in EXAMPLE 38G.
[2332] EXAMPLE 145C
4-(4
-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)p-
iperazin-1-yl)benzoic acid
[2333] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 145B.
EXAMPLE 145D
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(1methylpiperidin-4-yl)amino]-
-3-nitrophenyl}sulfonyl)benzamide
[2334] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 145C and
EXAMPLE 3I, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.32 (d, 1H), 8.06 (d, 1H), 7.71
(dd, 1H), 7.66 (d, 1H), 7.40 (d, 2H), 7.15 (s, 2H), 7.03 (d, 1H),
6.81 (m, 2H), 6.73 (m, 1H), 6.43 (m, 1H), 6.27 (m, 1H), 4.15 (m,
2H), 3.83 (m, 1H), 3.16 (m, 8H), 2.88 (s, 3H), 2.70 (m, 4H), 2.26
(s, 4H), 2.13 (m, 4H), 1.78 (m, 1H), 1.21 (s, 6H).
EXAMPLE 146
N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-c-
hlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3--
difluorophenoxy)benzamide
EXAMPLE 146A
4-(1-allylpiperidin-4-ylamin)-3-nitrobenzenesulfonamide
[2335] 3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide
hydrochloride (0.27 g), triethylamine (0.2 mL) and
3-bromoprop-1-ene (0.1 g) was dissolved in N,N-dimethylformamide (5
mL). The mixture was stirred at room temperature overnight. The
solvent was dried under vacuum. The mixture was chromatographed on
silica gel with 0-20% methanol in dichloromethane.
EXAMPLE 146B
N-({4-[(1-allylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-c-
hlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3--
difluorophenoxy)benzamide
[2336] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 146A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.39 (d,
1H), 8.14 (d, 1H), 7.75 (dd, 1H), 7.59 (d, 1H), 7.35 (d, 2H), 7.08
(m, 3H), 6.86 (m, 2H), 6.74 (dd, 1H), 6.45 (d, 1H), 6.36 (m, 1H),
5.88 (m, 1H), 5.37 (m, 2H), 3.83 (m, 1H), 3.13 (m, 8H), 2.74 (m,
4H), 2.17 (m, 8H), 1.98 (s, 2H), 1.74 (m, 2H), 1.41 (t, 2H), 0.94
(s, 6H).
EXAMPLE 147
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
EXAMPLE 147A
methyl 2-(3-chloro-2-fluorophenoxy)-4-fluorobenzoate
[2337] The title compound was prepared by substituting
3-chloro-2-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 147B
Ethyl 2-(3-chloro-2-fluorophenoxy)-4-(piperazin-1-yl)benzoate
[2338] The title compound was prepared by substituting piperazine
for EXAMPLE 3F and EXAMPLE 147A for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 147C
Ethyl
2-(3-chloro-2-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2339] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 147B for
tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 147D
2-(3-chloro-2-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2340] The title compound was prepared by substituting EXAMPLE 147C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 147E
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
[2341] The title compound was prepared by substituting EXAMPLE 147D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.33 (d, 1H), 8.05
(d, 1H), 7.68 (m, 2H), 7.35 (d, 2H), 7.02 (m, 4H), 6.84 (m, 1H),
6.72 (d, 1H), 6.43 (m, 2H), 3.83 (m, 1H), 3.12 (m, 6H), 2.84 (m,
4H), 2.62 (s, 3H), 2.22 (m, 6H), 2.11 (m, 2H), 1.98 (s, 2H), 1.76
(m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 148
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
[2342] The title compound was prepared by substituting EXAMPLE 147D
for EXAMPLE 1F and EXAMPLE 4A for EXAMPLE 1G in EXAMPLE 1 H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.71 (m,
1H), 8.41 (d, 1H), 7.74 (dd, 1H), 7.56 (d, 1H), 7.35 (d, 2H), 7.05
(m, 4H), 6.91 (m, 1H), 6.75 (dd, 1H), 6.56 (m, 1H), 6.47 (d, 1H),
3.64 (m, 4H), 3.47 (q, 2H), 3.17 (m, 4H), 2.79 (s, 2H) 2.55 (m,
6H), 2.22 (m, 6H), 1.98 (s, 2H), 1.84 (m, 2H), 1.41 (t, 2H), 0.95
(s, 6H).
EXAMPLE 149
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl-
)amino]phenyl}sulfonyl)benzamide
EXAMPLE 149A
3-nitro-4-(3-(pyrrolidin-1-yl)propylamino)benzenesulfonamide
[2343] The title compound was prepared by substituting
3-(pyrrolidin-1-yl)propan-1-amine for
3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.
EXAMPLE 149B
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl-
)amino]phenyl}sulfonyl)benzamide
[2344] The title compound was prepared by substituting EXAMPLE 147D
for EXAMPLE 1F and EXAMPLE 149A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.43 (s,
1H), 8.32 (d, 1H), 7.70 (m, 2H), 7.35 (d, 2H), 7.07 (d, 2H), 6.97
(m, 2H), 6.85 (m, 1H), 6.71 (dd, 1H), 6.43 (m, 2H), 3.48 (q, 2H),
3.09 (m, 8H), 2.77 (s, 2H), 2.21 (m, 8H), 1.92 (m, 8H), 1,40 (t,
2H), 0, 94 (s, 6H).
EXAMPLE 150
2-(3-chloro-2-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-morpholin-4-ylethyl)amino]-3--
nitrophenyl}sulfonyl)benzamide
[2345] The title compound was prepared by substituting EXAMPLE 147D
for EXAMPLE 1F and EXAMPLE 126A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.79 (m,
1H), 8.44 (d, 1H), 7.76 (dd, 1H), 7.53 (d, 1H), 7.36 (d, 2H), 7.06
(m, 4H), 6.91 (m, 1H), 6.76 (dd, 1H), 6.58 (m, 1H), 6.48 (d, 1H),
3.62 (m, 4H), 3.50 (q, 2H), 3.19 (m, 4H), 2.81 (s, 2H), 2.69 (m,
2H), 2.23 (m, 6H), 1.98 (s, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 151
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
EXAMPLE 151A
methyl 2-(2-chloro-6-fluorophenoxy)-4-fluorobenzoate
[2346] The title compound was prepared by substituting
2-chloro-6-fluorophenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 151B
methyl
2-(2-chloro-6-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2347] The title compound was prepared by substituting EXAMPLE 151A
for EXAMPLE 153A in EXAMPLE 3G.
EXAMPLE 151C
2-(2-chloro-6-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2348] The title compound was prepared by substituting EXAMPLE 151B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 151D
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
[2349] The title compound was prepared by substituting EXAMPLE 151C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.51 (d, 1H), 8.09
(d, 1H), 7.92 (dd, 1H), 7.60 (d, 1H), 7.32 (m, 5H), 7.17 (d, 1H),
7.05 (d, 2H), 6.56 (dd, 1H), 5.83 (d, 1H), 3.85 (m, 1H), 3.17 (m,
2H), 2.95 (m, 4H), 2.81 (m, 2H), 2.73 (s, 2H), 2.59 (s, 3H), 2.15
(m, 8H), 1.97 (m, 2H), 1.77 (m, 2H), 1.39 (t, 2H), 0.93 (s,
6H).
EXAMPLE 152
2-(2-chloro-6-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2350] The title compound was prepared by substituting EXAMPLE 151C
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 10 in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.54 (d,
1H), 8.14 (d, 1H), 7.93 (dd, 1H), 7.58 (d, 1H), 7.34 (m, 5H), 7.20
(d, 1H), 7.04 (d, 2H), 6.59 (dd, 1H), 5.85 (d, 1H), 3.93 (dd, 2H),
3.85 (m, 1H), 3.21 (s, 6H), 2.97 (m, 4H), 2.73 (m, 4H), 2.16 (m,
8H), 1.96 (s, 2H), 1.81 (m, 2H), 1.69 (m, 2H), 1.54 (m, 2H), 1.39
(t, 214), 0.93 (s, 6H).
EXAMPLE 154
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 154A
6-fluoro-1H-indol-5-ol
[2351] The title compound was prepared from 2-fluoro-4-nitrophenol
according to WO 02/12227 (page 78).
EXAMPLE 154B
methyl 4-fluoro-2-(6-ftuoro-1H-indol-5-yloxy)benzoate
[2352] The title compound was prepared as described in EXAMPLE 3A
by replacing 2-methyl-5-indolol with EXAMPLE 154A.
EXAMPLE 154C
methyl 2-(6-fluoro-1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate
[2353] The title compound was prepared as describedin EXAMPLE 3G by
replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE
154B, respectively.
EXAMPLE 154D
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoate
[2354] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 154C and
EXAMPLE 60D, respectively.
EXAMPLE 154E
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(6-fluoro-1H-indol-5-yloxy)benzoic acid
[2355] The title compound was prepared as described in EXAMPLE 38 H
by replacing EXAMPLE 38G with EXAMPLE 154D.
EXAMPLE 154F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
[2356] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and
EXAMPLE 31, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.12 (m, 1H), 8.49 (d, 1H),
8.11 (d, 1H), 7.82 (dd, 1H), 7.55 (d, 1H), 7.33 (m, 3H), 7.28 (d,
1H), 7.11 (d, 1H), 7.05 (m, 2H), 6.59 (dd, 1H), 6.35 (m, 1H), 6.08
(m, 1H), 3.76 (m, 1H), 3.06 (m, 8H), 2.72 (m, 6H), 2.17 (s, 6H),
1.98 (m, 5H), 1.72 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 155
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3--
nitrophenyl)sulfonyl]benzamide
EXAMPLE 155A
4-((1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide
[2357] The title compound was prepared by substituting
4-aminomethyl-N-methylpiperidine for 3-(N-morpholinyl-1-propylamine
in EXAMPLE 4A.
EXAMPLE 155B
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3--
nitrophenyl)sulfonyl]benzamide
[2358] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 155A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.45 (br
t, 1H), 8.33 (d, 1H), 7.65 (m, 2H), 7.36 (d, 2H), 7.15 (t, 1H),
7.06 (d, 2H), 6.97 (d, 1H), 6.89 (d, 1H), 6.60 (m, 2H), 6.38 (d,
1H), 3.02-3.12 (m, 8H), 2.77 (m, 4H), 2.65 (m, 2H), 2.24 (m, 4H),
2.19 (m, 2H), 1.91 (m, 1H), 1.87 (m, 2H), 1.41 (m, 4H), 0.95 (s,
6H).
EXAMPLE 156
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2,3-difluorophenoxy)-N-[(4-{[1-methylpiperidin-4-yl)methyl]amino}-
-3-nitrophenyl)sulfonyl]benzamide
[2359] The title compound was prepared by substituting EXAMPLE 45C
for EXAMPLE 1F and EXAMPLE 155A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.54 (br
t, 1H), 8.37 (d, 1H), 7.72 (d, 1H), 7.60 (d, 1H), 7.36 (d, 2H),
7.07 (d, 3H), 6.88 (dd, 2H), 6.75 (d, 1H), 6.46 (s, 1H), 6.36 (br
s, 1H), 3.16 (m, 8H), 2.89 (m, 2H), 2.81 (m, 2H), 2.68 (s, 3H),
2.27 (m, 4H), 2.20 (m, 2H), 1.99 (m, 2H), 1.91 (m, 3H), 1.55 (m,
2H), 1.41 (m, 2H), 0.95 (s, 6H).
EXAMPLE 157
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 157A
4-fluoro-1H-indol-5-ol
[2360] The title compound was prepared from 2-fluoro-4-nitrophenol
according to WO 02 12227 (page 78).
EXAMPLE 157B
methyl 4-fluoro-2-(4-fluoro-1H-indol-5-yloxy)benzoate
[2361] The title compound was prepared as described in EXAMPLE 3A
by replacing 2-methyl-5-indolol with EXAMPLE 157A.
EXAMPLE 157C
methyl 2-(4-fluoro-1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate
[2362] The title compound was prepared as described in EXAMPLE 3G
by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE
157B respectively.
EXAMPLE 157D
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(4-fluoro)-1H-indol-5-yloxy)benzoate
[2363] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 157C and
EXAMPLE 60D, respectively.
EXAMPLE 157E
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(4-fluoro-1H-indol-5-yloxy)benzoic acid
[2364] The title compound was prepared as described in EXAMPLE 38 H
by replacing EXAMPLE 38G with EXAMPLE 157D.
EXAMPLE 157F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(4-fluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
[2365] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1E and EXAMPLE 1G with EXAMPLE 157E and
EXAMPLE 31. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.40 (m, 1H), 8.53 (d, 1H), 8.12 (d, 1H), 7.88 (d, 1H),
7.53 (d, 1H), 7.42 (t, 1H), 7.33 (d, 2H), 7.16 (dd, 2H), 7.05 (d,
2H), 6.83 (m, 1H), 6.52 (m, 2H), 6.02 (s, 1H), 3.77 (m, 2H), 3.03
(m, 6H), 2.70 (s, 3H), 2.04 (m, 12H), 1.71 (m, 2H), 0.92 (s,
6H).
EXAMPLE 158
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[3-(methoxymethoxy)-2-methylphenoxy]-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 158A
Ethyl 4-fluoro-2-(3-hydroxy-2-methylphenoxy)benzoate
[2366] The title compound was prepared by substituting
2-methylbenzene-1,3-diol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 158B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(3-hydroxy-2-methylphenoxy)benzoate
[2367] The title compound was prepared by substituting EXAMPLE 158A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 158C
Ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(3-(methoxymethoxy)-2-methylphenoxy)benzoate
[2368] A mixture of EXAMPLE 158B (0.6 g), chloro(methoxy)methane
(0.18 g) and cesium carbonate (0.9 g) was suspended in
N,N-dimethylformamide (15 mL). After it stirred at room temperature
for 30 minutes, the crude product was purified by preparative HPLC
using a 250.times.50 mm C18 column and eluting with 20-100%
CH.sub.3CN vs 0.1% trifluoroacetic acid in water.
EXAMPLE 158D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3-(methoxymethoxy)-2-methylphenoxy)benzoic acid
[2369] The title compound was prepared by substituting EXAMPLE 158C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 158E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
[2370] The title compound was prepared by substituting EXAMPLE 158D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.43 (d, 1H), 8.10
(d, 1H), 7.73 (dd, 1H), 7.54 (d, 1H), 7.35 (d, 2H), 7.07 (m, 3H),
6.94 (t, 1H), 6.72 (d, 1H), 6.63 (dd, 1H), 6.19 (m, 2H), 5.21 (s,
2H), 3.79 (m, 1H), 3.40 (s, 3H), 3.09 (m, 6H), 2.73 (m, 4H), 2.56
(s, 2H), 2.19 (m, 6H), 2.07 (m, 6H), 1.96 (s, 2H), 1.74 (m, 2H),
1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 159
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-hydroxy-2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
[2371] Into a 10 m microwave tube was added EXAMPLE 158E (54 mg)
and hydrogen chloride (1.25 M in methanol) (0.5 mL) in
tetrahydrofuran (4 mL) to give a solution. The mixture was stirred
at 60.degree. C. in a CEM Discover microwave reactor for 20
minutes. the solvent was dried under vacuum and the crude product
was purified by preparative HPLC using a 250.times.50 mm C18 column
and eluting with 20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid
in water. The trifluoroacetic acid salt was solved in
dichloromethane with ammonium and washed with saturated
Na.sub.2CO.sub.3, dried over Na.sub.2CO.sub.4, filtered, and
concentrated to afford the free base product. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 9.38 (s, 1H), 8.46 (d, 1H), 8.13
(d, 1H), 7.77 (dd, 1H), 7.52 (d, 1H), 7.35 (d, 2H), 7.08 (m, 3H),
6.83 (t, 1H), 6.60 (dd, 1H), 6.51 (d, 1H), 6.08 (m, 2H), 3.03 (m,
6H), 2.73 (m, 4H), 2.19 (m, 6H), 2.00 (m, 9 H), 1.71 (m, 2H), 1,40
(t, 2H), 0.94 (s, 6H).
EXAMPLE 160
2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-p-
yran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-n-
itrophenyl}sulfonyl)benzamide
EXAMPLE 160A
methyl 2-(3-bromophenoxy)-4-fluorobenzoate
[2372] The title compound was prepared as described in EXAMPLE 3A
by replacing 2-methyl-5-indolol with 3-bromophenol.
EXAMPLE 160B
methyl 2-(3-bromophenoxy)-4-(piperazin-1-yl)benzoate
[2373] The title compound was prepared as described in EXAMPLE 3G
by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE
160A, respectively.
EXAMPLE 160C
methyl 2-(3-bromophenoxy)-4-(4-((4-(4
-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1--
yl)benzoate
[2374] The title compound was prepared as described in EXAMPLE 380
by replacing EXAMPLE 38F with EXAMPLE 160B.
EXAMPLE 160D
2-(3-bromophenoxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-p-
yran-3-yl)methyl)piperazin-1-yl)benzoic acid
[2375] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 160C.
EXAMPLE 160E
2-(3-bromophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-p-
yran-3-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-n-
itrophenyl}sulfonyl)benzamide
[2376] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 160D and
EXAMPLE 3I, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.29 (d, 1H), 8.10 (m, 2H), 7.64
(d, 1H), 7.60 (dd, 1H), 7.40 (d, 2H), 7.15 (d, 2H), 7.06 (t, 1H),
6.96 (m, 2H), 6.94 (d, 1H), 6.68 (m, 3H), 6.37 (d, 1H), 5.84 (m,
2H), 4.15 (m, 2H), 3.65 (m, 1H), 3.09 (m, 6H), 2.99 (m, 5H), 2.87
(s, 2H), 2.75 (m, 2H), 2.26 (m, 4H), 1.98 (m, 1H), 1.21 (s,
6H).
EXAMPLE 161
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide
EXAMPLE 161A
methy 4-fluoro-2-(3-iodophenoxy)benzoate
[2377] The title compound was prepared as described in EXAMPLE 3A
by replacing 2-methyl-5-indolol with 3-iodophenol.
EXAMPLE 161B
methyl 2-(3-iodophenoxy)-4-(piperazin-1-yl)benzoate
[2378] The title compound was prepared as described in EXAMPLE 3G
by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE
161A, respectively.
EXAMPLE 161C
methyl
4-(4-((4-(4-chlorophenyl-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)met-
hyl)piperazin-1-yl)-2-(3-iodophenoxy)benzoate
[2379] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLES 8F with EXAMPLE 161B.
EXAMPLE 161D
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)pi-
perazin-1-yl)-2-(3-iodophenoxy)benzoic acid
[2380] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 161C.
EXAMPLE 161E
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(3-iodophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide
[2381] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 161D and
EXAMPLE 3I, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.34 (d, 1H), 8.08 (d, 1H), 7.64
(m, 2H), 7.40 (d, 2H), 7.17 (m, 3H), 6.95 (m, 3H), 6.71 (m, 2H),
6.37 (d, 1H), 4.15 (s, 2H), 3.83 (m, 1H), 3.15 (m, 8H), 2.87 (s,
3H), 2.60 (m, 4H), 2.17 (m, 8H), 1.76 (m, 1H), 1.20 (s, 6H).
EXAMPLE 162
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}--
3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 162A
tert-butyl
4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate
[2382] The title compound was prepared by substituting tert-butyl
4-aminopiperidine-1-carboxylate for 3-(N-morpholinyl)-1-propylamine
in EXAMPLE 4A.
EXAMPLE 162B
[2383] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 162A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 162C
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)-
methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-
ylamino)phenylsulfonyl)benzamide
[2384] The title compound was prepared by substituting EXAMPLE 162B
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 162D
N-(4-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidin-4-ylamino)-3-nitrop-
henylsulfonyl)-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-enyl)methyl)piperazin-1-yl)benzamide
[2385] The title compound was prepared by substituting EXAMPLE 162C
for tert-butyl pieperazien-1-carboxylate and
2-(tert-butyldimethylsilyloxy)acetaldehyde for
4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 162E
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}--
3-nitrophenyl)sulfonyl]benzamide
[2386] A mixture of EXAMPLE 162D (270 mg) in anhydrous
tetrahydrofuran (5 mL) and tetrabutyl ammonium fluoride (5 mL 1M in
tetrahydrofuran) was stirred at room temperature for 2 hours. the
solvent was removed under vacuum. The residue was purified by
reverse phase HPLC on a C18 column using a gradient of 40-70%
acetonitrile/0.1% trifluoroacetic acid in water to give the title
compound as the trifluoroacetate salt. The trifluoroacetate salt
was dissovled in dichloromethane (6 mL) and washed with 50% aqueous
NaHCO.sub.3. The organic layer was dried over anhydrous
Na.sub.2SO.sub.4 and concentrated to give the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.35 (d,
1H), 8.09 (d, 1H), 7.69 (dd, 1H), 7.61 (d, 1H), 7.36 (d, 2H), 7.14
(m, 1H), 7.05 (m,3H), 6.88 (dd, 1H), 6.73 (dd, 1H), 6.65 (dd, 1H),
6.60 (m, 1H), 6.40 (d, 1H), 3.85 (m, 1H), 3.68 (m, 2H), 3.28 (m,
4H), 3.12 (m, 4H), 2.99 (m, 4H), 2.77 (s, 2H), 2.16 (m, 8H), 1.98
(s, 2H), 1.83 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 163
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(2-phenylethyl)-piperidin-4-yl-
]amino}phenyl)sulfonyl]benzamide
[2387] The title compound was prepared by substituting EXAMPLE 162C
for tert-butyl pieperazien-1-carboxylate and 2-phenylacetaldehyde
for 4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. .sup.1H NMR
(400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.37 (d, 1H), 8.16 (d,
1H), 7.70 (dd, 1H), 7.59 (d, 1H), 7.30 (m, 8H), 7.16 (m, 1H), 7.07
(m, 3H), 6.89 (d, 1H), 6.74 (dd, 1H), 6.66 (dd, 1H), 6.62 (d, 1H),
6.42 (d, 1H), 3.84 (m, 1H), 3.27 (m, 6H), 2.98 (m, 8H), 2.78 (s,
2H), 2.17 (m, 8H), 1.98 (s, 2H), 1.78 (m, 2H), 1.41 (t, 2H), 0.94
(s, 6H).
EXAMPLE 164
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
EXAMPLE 164A
Ethyl 2-(3,4-dichlorophenoxy)-4-fluorobenzoate
[2388] The title compound was prepared by substituting
2,3-dichlorophenol for 2-methyl-5-indolol is EXAMPLE 3A.
EXAMPLE 164B
Ethyl
2-(3,4-dichlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzoate
[2389] The title compound was prepared by substituting EXAMPLE 164A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 164C
2-(3,4-dichlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
nyl)methyl)piperazin-1-yl)benzoate
[2390] The title compound was prepared by substituting EXAMPLE 164B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 164D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3,4-dichlorophenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
[2391] The title compound was prepared by substituting EXAMPLE 164C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H, .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.35 (d, 1H), 8.06
(s, 1H), 7.62 (d, 2H), 7.31-7.40 (m, 3H), 7.04-7.10 (m, 2H), 6.98
(d, 1H), 6.98 (d, 1H), 6.70-6.81 (m, 2H), 6.64 (dd, 1H), 6.42 (d,
1H), 3.79 (s, 1H), 3.19-3.27 (m, 2H), 3.12 (s, 5H), 2.69-2.81 (m,
4H), 2.63 (s, 2H), 2.15-2.28 (m, 8H), 2.08 (s, 2H), 1.98 (s, 3H),
1.77 (s, 1H), 1.36-1.45 (m, 2H), 1.24 (s, 1H), 0.95 (s, 6H).
EXAMPLE 165
2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 165A
Ethyl 2-(2-chloro-3,5-difluorophenoxy)-4-fluorobenzoate
[2392] The title compound was prepared by substituting
2-chloro-3,5-difluorophenol for 2-methyl-5-indolol in EXAMPLE
3A.
EXAMPLE 165B
Ethyl
2-(2-chloro-3,5-difluorophenoxy)-4-(piperazin-1-yl)benzoate
[2393] The title compound was prepared by substituting piperazine
for EXAMPLE 3F and EXAMPLE 165A for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 165C
Ethyl
2-(2-chloro-3,5-difluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2394] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 165B for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 165D
2-(2-chloro-3,5-difluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2395] The title compound was prepared by substituting EXAMPLE 165C
for EXAMPLE 1E in EXAMPLE 1E.
EXAMPLE 165E
2-(2-chloro-3,5-difluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amin-
o]-3-nitrophenyl}sulfonyl)benzamide
[2396] The title compound was prepared by substituting EXAMPLE 165D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.30 (m, 1H), 8.06
(m, 1H), 7.68 (m, 2H), 7.36 (d, 2H), 7.07 (d, 2H), 7.00 (d, 1H),
6.78 (m, 2H), 6.45 (d, 1H), 5.93 (d, 1H), 3.77 (m, 1H), 3.12 (m,
4H), 2.76 (s, 3H), 2.21 (m, 6H), 2.07 (m, 2H), 1.98 (s, 2H), 1.72
(m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 166
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
EXAMPLE 166A
ethyl 4-fluoro-2-(3-methoxyphenoxy)benzoate
[2397] The title compound was prepared by substituting
3-methoxyphenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 166B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(3-methoxyphenoxy)benzoate
[2398] The title compound was prepared by substituting EXAMPLE 166A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 166C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3-methoxyphenoxy)benzoic acid
[2399] The title compound was prepared by substituting EXAMPLE 166B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 166D
[2400]
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-(3-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
[2401] The title compound was prepared by substituting EXAMPLE 166C
for EXAMPLE 122C and EXAMPLE 3I for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.39 (d,
1H), 8.10 (br d, 1H), 7.73 (dd, 1H), 7.57 (d, 1H), 7.37 (d, 2H),
7.05 (m, 4H), 6.68 (dd, 1H), 6.45 (dd, 1H), 6.30 (m, 3H), 3.80 (br
m, 1H), 3.64 (s, 3H), 3.18 (br m, 1H), 3.07 (br m, 4H), 2.80 (br m,
1H), 2.78 (s, 2H), 2.60 (s, 2H), 2.50 (s, 3H), 2.20 (br m, 6H),
2.09 (br m, 2H), 1.98 (s, 2H), 1.78 (br m, 2H), 1.40 (br t, 2H),
0.93 (s, 6H).
EXAMPLE 167
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
EXAMPLE 167A
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(3-formylphenoxy)benzoate
[2402] The title compound was prepared by substituting
3-hydroxybenzaldehyde for EXAMPLE 1D and EXAMPLE 214A for EXAMPLE
1C in EXAMPLE 1E.
EXAMPLE 167B
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3-formylphenoxy)benzoic acid
[2403] The title compound was prepared by substituting EXAMPLE 167A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 167C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3-formylphenoxy)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsul-
fonyl)benzamide
[2404] The title compound was prepared by substituting EXAMPLE 167B
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 167D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[3-hydroxymethyl)phenoxy]-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
[2405] EXAMPLE 167C (107 mg) was dissolved in ethanol (3 mL) and
tetrahydrofuran (9 mL), and NaBH.sub.4 (13 mg) was added and the
mixture stirred at room temperature for 10 minutes. After carefully
adding 2N aqueous HCl; (0.67 mL), the reaction was concentrated
andd the crude material was purified by preparative HPLC using a
C18 column, 250.times.50 mm, 10.mu., and eluting with a gradient of
20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving
the product as a trifluoroacetate salt. The salt was dissolved in
dichloromethane (6 Na.sub.2SO.sub.4, filtered, and concentrated to
give the title compound. .sup.1H NMR (500 MHz,
CDCl.sub.3/methanol-d.sub.4) .delta. 8.80 (d, 1H), 8.45 (br d, 1H),
8.03 (dd, 1H), 7.86 (d, 1H), 7.39 (m, 1H), 7.27 (m, 3H), 7.09 (s,
1H), 6.95 (d, 4H), 6.60 (dd, 1H), 6.12 (d, 1H), 4.67 (s, 2H), 3.63
(br s, 1H), 3.15 (br t, 4H), 2.82 (br s, 1H), 2.80 (s, 3H), 2.35
(m, 5H), 2.28 (br t, 4H), 2.20 (br t, 2H), 2.10 (br m, 2H), 1.99
(s, 2H), 1.73 (m, 2H), 1.43 (t, 2H), 0.94 (s, 6H).
EXAMPLE 168
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
EXAMPLE 168A
tert-butyl
4-(benzyloxycarbonylamino)-4-methylpiperidine-1-carboxylate
[2406] 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid
(5.0 g), diphenylphosphoryl azide (DPPA, 4.58 mL), triethylamine
(2.86 mL), and benzyl alcohol (4.26 mL) were stirred in toluene (45
mL) at 110.degree. C. for 24 hours. The mixture was cooled,
concentrated, and chromatographed on silica gel using 10% ethyl
acetate/hexanes as eluent to give the pure product.
EXAMPLE 168B
tert-butyl 4-amino-4-methylpiperidine-1-carboxylate
[2407] EXAMPLE 168A (4.5 g) and ethanol (100 mL) were added to 20%
Pd(OH).sub.2--C, wet (0.900 g) in a 250 mL SS pressure bottle and
stirred for 3 hours at 30 psi and room temperature. The mixture was
filtered through a nylon membrane and concentrated to give the
product.
EXAMPLE 168C
tert-butyl
4-methyl-4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxy-
late
[2408] The title compound was prepared by substituting EXAMPLE 168B
for 3-(n-morpholinyl)-1-propylamine in EXAMPLE 4A.
EXAMPLE 168D
4-(4-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
[2409] The title compound was prepared by substituting EXAMPLE 168C
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 168E
4-(1,4-dimethylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide
[2410] EXAMPLE 168D (1.33 g), iodomethane (0.29 mL), and
triethylamine (0.65 mL) in acetonitrile (20 mL) were stirred for 1
hour. The mixture was concentrated and chromatographed on silica
gel using 10% methanol/dichloromethane as eluent to give the
product.
EXAMPLE 168F
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
[2411] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1E and EXAMPLE 168E for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.55 (m,
1H), 8.43 (d, 1H), 7.82 (d, 1H), 7.52 (d, 1H), 7.43 (d, 1H), 7.38
(d, 2H), 7.18 (dd, 1H), 7.09 (d, 2H), 7.05 (m, 1H), 6.76 (d, 2H),
6.34 (d, 1H), 2.94-3.12 (m, 11H), 2.70 (m, 4H), 2.27 (m, 4H), 2.00
(s, 3H), 1.55 (s, 3H), 1.41 (m, 2H), 0.95 (s, 6H).
EXAMPLE 169
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dimethylpiperidin-4-yl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
[2412] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 168E for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.49 (m,
1H), 8.40 (d, 1H), 7.75 (d, 1H), 7.54 (d, 1H), 7.37 (d, 2H), 7.27
(m, 1H), 7.22 (t, 1H), 7.07 (d, 2H), 7.00 (d, 1H), 6.77 (d, 1H),
6.72 (d, 1H), 6.45 (d, 1H), 3.20 (m, 4H), 3.05 (m, 6H), 2.88 (m,
2H), 2.73 (m, 4H), 2.27 (m, 4H), 2.20 (m, 2H), 1.99 (s, 3H), 1.55
(s, 3H), 1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 170
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(2-methoxyethoxy)ethyl]piperidin-4--
yl}amino)-3-nitrophenyl]sulfonyl}benzamide
[2413] A mixture of EXAMPLE 162C (100 mg),
1-bromo-2-(2-methoxyethoxy)ethane (52 mg), cesium carbonate (70 mg)
in N,N-dimethylformamide was heated at 60.degree. C. overnight. The
solvent was removed under vacuum. The residue was purified by
reverse phase HPLC on a C18 column using a gradient of 40-70%
acetonitrile/0.1% TFA in water to give the title compound as the
trifluoroacetate salt. The TFA salt was dissolved in
dichloromethane (6 mL) and washed with 50% aqueous NaHCO.sub.3. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4 and
concentrated to give the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.36 (d, 1H), 8.12 (d, 1H), 7.69
(dd, 1H), 7.59 (d, 1H), 7.35 (d, 2H), 7.14 (m, 1H), 7.05 (m, 3H),
6.89 (m, 1H), 6.74 (dd, 1H), 6.66 (dd, 1H), 6.60 (m, 1H), 6.40 (d,
1H), 3.81 (s, 1H), 3.65 (t, 2H), 3.56 (m, 2H), 3.47 (m, 2H), 3.31
(m, 2H), 3.26 (m, 3H), 3.18 (m, 2H), 3.13 (m, 2H), 2.97 (m, 2H),
2.77 (m, 4H), 2.21 (m, 7H), 2.07 (m, 2H), 1.98 (s, 2H), 1.76 (m,
2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 171
2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 171A
2-chloro-3-(methoxymethoxy)phenol
[2414] The title compound was prepared by substituting
2-chlorobenzene-1,3-diol for EXAMPLE 158B in EXAMPLE 158C.
EXAMPLE 171B
Methyl 2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-fluorobenzoate
[2415] The title compound was prepared by substituting 171A for
2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 171C
Methyl
2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-(piperazin-1-yl)benzoate
[2416] The title compound was prepared by substituting piperazine
for EXAMPLE 3F and EXAMPLE 171B for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 171D
Methyl
2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2417] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 171C for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 171E
2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimet-
hylcyclchex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2418] The title compound was prepared by substituting 171D for
EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 171F
2-(2-chloro-3-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamin-
o)-3-nitrophenylsulfonyl)benzamide
[2419] The title compound was prepared by substituting EXAMPLE 171E
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 171G
2-(2-chloro-3-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
[2420] The title compound was prepared by substituting EXAMPLE 171F
for EXAMPLE 158 in EXAMPLE 159. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.13 (s, 1H), 8.41 (d, 1H),
8.08 (d, 1H), 7.77 (dd, 1H), 7.60 (d, 1H), 7.35 (d, 2H), 7.07 (m,
3H), 6.89 (t, 1H), 6.67 (dd, 1H), 6.59 (m, 1H), 6.19 (d, 1H), 6.08
(d, 1H), 3.80 (m, 1H), 3.09 (m, 6H), 2.79 (m, 4H), 2.57 (s, 3H),
2.21 (m, 6H), 2.08 (m, 2H), 1.97 (s, 2H), 1,74 (m, 2H), 1.40 (t,
2H), 0.94 (s, 6H).
EXAMPLE 172
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[1-(3-phenylpropyl)piperidin-4-yl-
]amino}phenyl)sulfonyl]benzamide
[2421] The title compound was prepared by substituting EXAMPLE 162C
for tert-butyl pieperazien-1-carboxylateand 3-phenylpropanal for
4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 8.36 (d, 1H), 8.10 (m, 1H),
7.69 (m, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.31 (m, 2H), 7.22 (m,
3H), 7.14 (m, 1H), 7.07 (d, 2H), 7.02 (d, 1H), 6.88 (d, 1H), 6.74
(dd, 1H), 6.65 (dd, 1H), 6.60 (m, 1H), 6.41 (d, 1H), 3.84 (m, 1H),
3.29 (m, 4H), 3.12 (m, 4H), 2.81 (m, 5H), 2.64 (m, 2H), 2.22 (m,
6H), 2.10 (m, 2H), 1.99 (m, 2H), 1.90 (m, 2H), 1.75 (m, 2H), 1.40
(t, 2H), 0.94 (s, 6H).
EXAMPLE 173
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}--
3-nitrophenyl)sulfonyl]benzamide
[2422] The title compound was prepared by substituting
1-bromo-2-methoxyethane for 1-bromo-2-(2-methoxyethoxy)ethane in
EXAMPLE 170. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.36 (d, 1H), 8.13 (d, 1H), 7.69 (dd, 1H), 7.59 (d, 1H),
7.36 (d, 2H), 7.15 (m, 1H), 7.06 (m, 3H), 6.89 (dd, 1H), 6.74 (dd,
1H), 6.66 (dd, 1H), 6.61 (d, 1H), 6.41 (d, 1H), 3.82 (m, 1H), 3.57
(t, 2H), 3.38 (m, 4H), 3.13 (m, 6H), 2.99 (m, 2H), 2.89 (m, 1H),
2.78 (s, 3H), 2.21 (m, 6H), 2.08 (m, 2H), 1.98 (s, 2H), 1.78 (m,
2H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 174
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1-ethylpiperidin-4-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide
[2423] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 47A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.34 (d,
1H), 8.07 (s, 1H), 7.58-7.71 (m, 2H), 7.36 (d, 2H), 7.00-7.14 (m,
4H), 6.85-6.94 (m, 1H), 6.73 (dd, 1H), 6.64 (dd, 1H), 6.59 (d, 1H),
6.39 (d, 1H), 3.86 (s, 1H), 3.11 (s, 5H), 2.94 (d, 2H), 2.72-2.81
(m, 3H), 2.12-2.27 (m, 8H), 1.98 (s, 2H), 1.77 (s, 2H), 1.41 (t,
2H), 1.18 (t, 3H), 0.94 (s, 6H).
EXAMPLE 175
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(1-isopropylpiperidin-4-yl)amino]-3-nitro-
phenyl}sulfonyl)benzamide
[2424] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 41A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.98 (bs,
1H), 8.34 (d, 1H), 8.04 (s, 1H), 7.59-7.73 (m, 2H), 7.36 (d, 2H),
7.14 (t, 1H), 7.04-7.09 (m, 2H), 7.01 (d, 1H), 6.87 (d, 1H), 6.72
(dd, 1H), 6.61-6.66 (m, 1H), 6.58 (s, 1H), 6.39 (d, 1H), 3.90 (s,
1H), 3.11 (s, 6H), 2.73-2.83 (m, 2H), 2.14-2.28 (m, 9 H), 1.98 (s,
3H), 1.76 (s, 2H), 1.41 (t, 3H), 1.14-1.29 (m, 6H), 0.94 (s,
6H).
EXAMPLE 176
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide
EXAMPLE 176A
Ethyl 2-(3-hydroxyphenoxy)-4-fluorobenzoate
[2425] The title compound was prepared by substitutingresommolfor
2-methyl-5-indololIn EXAMPLE 3A.
EXAMPLE 176B
Ethyl
2-(3-hydroxyphenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1--enyl)methyl)piperazin-1-yl)benzoate
[2426] The title compound was prepared by substituting EXAMPLE 176A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 176C
Ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(3-(methoxymethoxy)phenoxy)benzoate
[2427] A suspension of EXAMPLE 176B (0.295 g), methoxymethyl
chloride (0.117 mL) and cesium carbonate (0.334 g) in N,
N-dimethylformamide (3 mL) was stirred at 60.degree. C. for 16
hours. The reaction mixture was partitioned between dichloromethane
and water. The water layer was extracted with dichloromethane. The
combined organic extracts were washed with water (2.times.), dried
over magnesium sulfate, filtered and concentrated. The crude
product was purified by flash chromotography (silica gel, 5%-20%
ethyl acetate/hexanes) providing the product.
EXAMPLE 176D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3-(methoxymethoxy)phenoxy)benzoic acid
[2428] The title compound was prepared by substituting EXAMPLE 176C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 176E
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3-(meth)phenoxy)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsul-
fonyl)benzamide
[2429] The title compound was prepared by substituting EXAMPLE 176D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 176F
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-hydroxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrop-
henyl}sulfonyl)benzamide
[2430] A suspension of EXAMPLE 176E (35.5 mg) in tetrahydrofuran (3
mL) and HCl (1.25 M in methanol, 2 mL) was stirred for 1 hour at
60.degree. C. The product was concentrated. The crude product was
purified by RP HPLC (C8, 30%-100% CH.sub.3CN/water/0.1% TFA) to
yield the product. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 9.31 (s, 1H), 8.10 (s, 1H), 7.66-7.73 (m, 2H), 7.56 (d,
1H), 7.34-7.38 (m, 2H), 7.02-7.09 (m, 2H), 6.95-7.02 (m, 1H), 6.65
(dd, 1H), 6.34 (s, 1H), 6.29 (d, 1H), 6.20 (d, 1H), 6.14 (d, 1H),
4.14 (dd, 1H), 3.75 (s, 1H), 3.05 (d, 4H), 2.68-2.80 (m, 3H), 2.20
(d, 6H), 2.08 (d, 2H), 1.97 (s, 2H), 1.69-1.79 (m, 2H), 1.63 (s,
1H), 1.39 (d, 2H), 1.21-1.36 (m, 9 H), 0.94 (s, 6H).
EXAMPLE 177
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
EXAMPLE 177A
2-chloro-3-fluorophenol
[2431] To a solution of 2-chloro-3-fluorophenylboronic acid (5.0 g)
in tetrahydrofuran (50 mL) and 1 M aqueous NaOH (30 mL) at
0.degree. C. 30% hydrogen peroxide solution (4 mL), and the
reaction was stirred for 2 hours. The reaction was quenched with
saturated aqueous Na.sub.2S.sub.2O.sub.3 solution, acidified with
concentrated aqueous HCl, and extracted twice with ethyl acetate.
The combined extracts were washed with brine, concentrated, and
chromatographed on silica gel using 10% ethyl acetate/hexanes as
eluent to give the product.
EXAMPLE 177B
methyl 2-(2-chloro-3-fluorophenoxy)-4-fluorobenzoate
[2432] The title compound was prepared by substituting EXAMPLE 177A
for 2-methyl-5-indolol and methyl 2,4-difluorobenzoate for ethyl
2,4-difluorobenzoate EXAMPLE 3A.
EXAMPLE 177C
methyl
2-(2-chloro-3-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2433] The title compound was prepared by substituting EXAMPLE 177B
for methyl 2-bromo-4-fluorobenzoate and EXAMPLE 3F for EXAMPLE 1B
in EXAMPLE 1C.
EXAMPLE 177D
2-(2-chloro-3-fluorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2434] The title compound was prepared by substituting EXAMPLE 177C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 177E
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-
-nitrophenyl}sulfonyl)benzamide
[2435] The title compound was prepared by substituting EXAMPLE 177D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.39 (d, 1H), 8.15
(m, 1H), 7.76 (d, 1H), 7.58 (d, 1H), 7.37 (d, 2H), 7.15 (d, 1H),
7.07 (d, 2H), 7.02 (m, 1H), 6.88 (t, 1H), 6.77 (d, 1H), 6.44 (s,
1H), 6.33 (d, 1H), 3.91 (m, 1H), 3.18 (m, 4H), 3.07 (m, 2H), 2.77
(m, 6H), 2.27 (m, 4H), 2.19 (m, 4H), 1.99 (s, 3H), 1.77 (m, 2H),
1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 178
2-(2-chloro-3-fluorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2436] The title compound was prepared by substituting EXAMPLE 177D
for EXAMPLE 1E and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.28 (d,
1H), 8.10 (m, 1H), 7.65 (d, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.08
(d, 2H), 6.98 (m, 2H), 6.80 (t, 1H), 6.74 (d, 1H), 6.37 (d, 1H),
6.22 (d, 1H), 3.89 (m, 1H), 3.28 (m, 4H), 3.09 (m, 6H), 2.84 (m,
4H), 2.73 (m, 3H), 2.40 (m, 2H), 2.23 (m, 6H), 2.01 (m, 1H), 1.99
(s, 3H), 1.68 (m, 2H), 1.55 (m, 4H), 1.41 (t, 2H), 0.94 (s,
6H).
EXAMPLE 179
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[3-dimethylamino)propyl]amino}-3-nitrophe-
nyl)sulfonyl]benzamide
[2437] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 122C in EXAMPLE 137. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.50 (br t, 1H), 8.38 (d, 1H),
7.75 (dd, 1H), 7.63 (d, 1H), 7.37 (m, 3H), 7.06 (m, 3H), 6.98 (d,
1H), 6.92 (ddd, 1H), 6.70 (dd, 1H), 6.56 (dd, 1H), 6.24 (d, 1H),
3.47 (dd, 2H), 3.05 (br m, 4H), 2.90 (br m, 2H), 2.75 (s, 2H), 2.60
(s, 6H), 2.20 (br m, 6H), 1.98 (s, 2H), 1.90 (m, 2H) 1.40 (t, 2H),
0.93 (s, 6H).
EXAMPLE 180
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
EXAMPLE 180A
ethyl 4-fluoro-2-(2-methoxyphenoxy)benzoate
[2438] The title compound was prepared by substituting
2-methoxyphenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 180B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(2--methoxyphenoxy)benzoate
[2439] The title compound was prepared by substituting EXAMPLE 180A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 180C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(2-methoxyphenoxy)benzoic acid
[2440] The title compound was prepared by substituting EXAMPLE 180B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 180D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-methoxyphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitroph-
enyl}sulfonyl)benzamide
[2441] The title compound was prepared by substituting EXAMPLE 180C
for EXAMPLE 122C and EXAMPLE 3I for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.47 (d,
1H), 8.15 (br d, 1H), 7.83 (dd, 1H), 7.57 (d, 1H), 7.37 (d, 2H),
7.13 (d, 1H), 7.05 (m, 4H), 6.80 (m, 2H), 6.60 (dd, 1H), 6.07 (d,
1H), 3.80 (br m, 1H), 3.73 (s, 3H), 3.22 (br m, 1H), 3.05 (br m,
1H), 3.00 (br m, 4H), 2.75 (s, 2H), 2.62 (br s, 2H), 2.50 (s, 3H),
2.20 (br m, 6H), 2.04 (br m, 2H), 1.98 (s, 2H), 1.73 (br m, 2H),
1.40 (br t, 2H), 0.93 H).
EXAMPLE 181
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
EXAMPLE 181A
ethyl 4-fluoro-2-(2-methylphenoxy)benzoate
[2442] The title compound was prepared by substituting
2-methylphenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 181B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(2-methylphenoxy)benzoate
[2443] The title compound was prepared by substituting EXAMPLE 181A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 181C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(2-methylphenoxy)benzoic acid
[2444] The title compound was prepared by substituting EXAMPLE 181B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 181D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(2-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2445] The title compound was prepared by substituting EXAMPLE 181C
for EXAMPLE 122C and EXAMPLE 3I for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.40 (d,
1H), 8.12 (br d, 1H), 7.73 (dd, 1H), 7.54 (d, 1H), 7.37 (d, 2H),
7.10 (m, 2H), 7.05 (d, 2H), 6.96 (m, 1H), 6.84 (m, 1H), 6.64 (dd,
1H), 6.46 (d, 1H), 6.20 (d, 1H), 3.80 (br m, 1H), 3.10 (br m, 3H),
3.05 (br m, 4H), 2.77 (s, 2H), 2.76 (br m, 2H), 2.58 (s, 2H), 2.20
(br m, 6H), 2.16 (s, 3H), 2.09 (br m, 2H), 1.98 (s, 2H), 1.78 (br
m, 2H), 1.40 (br t, 2H), 0.93 (s, 6H).
EXAMPLE 182
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
EXAMPLE 182A
ethyl 4-fluoro-2-(3-methylphenoxy)benzoate
[2446] The title compound was prepared by substituting
3-methylphenol for 2-methyl-5-indolol in EXAMPLE 3A.
[2447] EXAMPLE 182B
ethyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperaz-
in-1-yl)-2-(3-methylphenoxy)benzoate
[2448] The title compound was prepared by substituting EXAMPLE 182A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 182C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3-methylphenoxy)benzoic acid
[2449] The title compound was prepared by substituting EXAMPLE 182B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 182D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-(3-methylphenoxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2450] The title compound was prepared by substituting EXAMPLE 182C
for EXAMPLE 122C and EXAMPLE 3I for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.40 (d,
1H), 8.10 (br d 3 1H), 7.74 (dd, 1H), 7.56 (d, 1H), 7.36 (d, 2H),
7.05 (m, 4H), 6.73 (d, 1H), 6.67 (dd, 1H), 6.52 (m, 2H), 6.29 (d,
1H), 3.80 (br m, 1H), 3.10 (br m, 3H), 3.05 (br m, 4H), 2.77 (s,
2H), 2.76 (br m, 2H), 2.58 (s, 2H), 2.20 (br m, 6H), 2.16 (s, 3H),
2.09 (br m, 2H), 1.98 (s, 2H), 1.78 (br m, 2H), 1.40 (br t, 2H),
0.93 (s, 6H).
EXAMPLE 183
2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl}-
piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfon-
yl)benzamide
EXAMPLE 183A
6-(4-chlorophenyl)benzo[d][1,3]dioxole-5-carbaldehyde
[2451] To a solution of 6-bromobenzo[d][1,3]dioxole-5-carbaldehyde
(4.6 g), 4-chlorophenylboronic acid (3.78 g) and
tetrakis(triphenylphosphine)palladium(0) (0.232 g) in toluene (80
mL) and methanol (30 mL) was added 2 N aqueous Na.sub.2CO.sub.3 (30
mL). The mixture was stirred at reflux overnight. The mixture was
diluted with ether (400 mL) and washed with water, brine and dried
over Na.sub.2O.sub.4. After filtratin and concentration of the
solvent, the residue was loaded on a column and eluted with 3%
ethyl acetate in hexane to give the product.
EXAMPLE 183B
methyl
2-(2-chlorophenoxy)-4-(4-((6-(4-chlorophenyl)benzo[d][1,3]dioxol-5--
yl)methyl)piperazin-1-yl)benzoate
[2452] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38E with EXAMPLE 183A.
EXAMPLE 183C
[2453]
2-(2-chlorophenoxy)-4-(4-((6-(4-chlorophenyl)benz[d][1,3]dioxol-5-y-
l)methyl)piperazin-1-yl)benzoic acid
[2454] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 183B.
EXAMPLE 183D
2-(2-chlorophenoxy)-4-(4-{[6-(4-chlorophenyl)-1,3-benzodioxol-5-yl]methyl}-
piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfon-
yl)benzamide
[2455] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 183C and
EXAMPLE 3I, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.35 (d, 1H), 8.07 (d, 1H), 7.73
(dd, 1H), 7.64 (d, 1H), 7.38 (m, 6H), 7.02 (m, 3H), 6.86 (m, 1H),
6.79 (s, 1H), 6.72 (dd, 1H), 6.51 (d, 1H), 6.28 (d, 1H), 6.04 (s,
2H), 3.81 (m, 1H), 3.25 (s, 3H), 3.08 (m, 6H), 2.72 (m, 5H), 2.33
(m, 4H), 2.07 (m, 2H), 1.74 (m, 1H).
EXAMPLE 184
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
EXAMPLE 184A
4-(4-methylpiperazin-1-ylamino)-3-nitrobenzenesulfonamide
[2456] The title compound was prepared by substituting
4-methylpiperazin-1-amine for 3-(N-morpholinyl)-1-propylamine in
EXAMPLE 4A.
EXAMPLE 184B
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2457] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.14 (s,
1H), 8.38 (d, 1H), 7.77 (dd, 1H), 7.55 (m, 2H), 7.37 (m, 3H), 7.08
(m, 3H), 6.95 (m, 1H), 6.72 (dd, 1H), 6.62 (d, 1H), 6.27 (d, 1H),
3.10 (m, 4H), 2.97 (m, 4H), 2.77 (s, 2H), 2.45 (s, 3H), 2.20 (m,
6H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94 (m, 6H).
EXAMPLE 185
2-(3-chlorophenoxy)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H--
pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
[2458] The title compound was prepared by substituting EXAMPLE 38H
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.15 (s,
1H), 8.34 (d, 1H), 7.68 (dd, 1H), 7.57 (d, 1H), 7.51 (d, 1H), 7.39
(d, 2H), 7.16 (m, 3H), 6.92 (m, 1H), 6.75 (dd, 1H), 6.68 (dd, 1H),
6.64 (m, 1H), 6.43 (d, 1H), 4.15 (s, 2H), 3.15 (m, 6H), 2.99 (m,
6H), 2.88 (s, 2H), 2.49 (s, 3H), 2.26 (m, 4H), 2.17 (s, 2H), 1.20
(s, 6H).
EXAMPLE 186
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-(2,3-difluorophenoxy)-N-({4-[(4-methylpiperazin-1-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
[2459] The title compound was prepared by substituting EXAMPLE 145B
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.15 (s,
1H), 8.34 (d, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 7.54 (d, 1H), 7.40
(d, 2H), 7.16 (d, 2H), 6.87 (m, 2H), 6.74 (dd, 1H), 6.46 (d, 1H),
6.34 (m, 1H), 4.15 (s, 2H), 3.14 (m, 6H), 3.00 (m, 4H), 2.88 (s,
2H), 2.52 (s, 3H), 2.26 (m, 4H), 2.17 (s, 2H), 1.21 (s, 6H).
EXAMPLE 187
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 187A
2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)
methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)piperidine-1--
carboxylate
[2460] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 162A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 187B
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)-
methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-ylamino)phenylsulfonyl)be-
nzamide
[2461] EXAMPLE 187A was treated with TFA (0.5 mL) and stirred for 6
hours. The product was concentrated and purified by RP HPLC (C8,
30%-100% CH.sub.3CN/water/0.1% TFA).
EXAMPLE 187C
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide
[2462] A suspension of EXAMPLE 187B (50 mg),
cyclopropanecarbaldehyde (100 mg) and MP-CNBH.sub.3 resin (0.2 g,
2.43 mmol/g) in dichloromethane (4 mL)/methanol (3 mL) was shaken
for 16 hours at room temperature. The product was filtered, washed
with dichloromethane/methanol and concentrated. The crude product
was purified by RP HPLC (C8, 30%-100% CH.sub.3CN/water/0.1% TFA) to
yield the product. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.35 (s, 1H), 8.10 (s, 1H), 7.67-7.75 (m, 1H), 7.60 (d,
1H), 7.36 (d, 2H), 7.15 (t, 1H), 7.07 (d, 3H), 6.89 (d, 1H), 6.73
(dd, 1H), 6.63 (s, 1H), 6.60 (s, 1H), 6.40 (s, 1H), 3.86 (s, 1H),
3.12 (s, 5H), 2.71-2.80 (m, 3H), 2.13-2.28 (m, 9H), 1.98 (s, 3H),
1.79 (s, 1H), 1.41 (t, 2H), 0.99-1.11 (m, 2H), 0.94 (s, 6H), 0.84
(d, 1H), 0.63 (d, 2H), 0.33 (s, 2H).
EXAMPLE 188
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 188A
tert-butyl
4-(4-(N-(2-(2-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenyl-
amino)piperadine-1-carboxylate
[2463] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 162A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 188B
2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)-
methyl)piperazin-1-yl)-N-(3-nitro-4-(piperidin-4-
ylamino)phenylsulfonyl)benzamide
[2464] The title compound was prepared by substituting EXAMPLE 188A
for EXAMPLE 187A is EXAMPLE 187B.
EXAMPLE 188C
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amin-
o}-3-nitrophenyl)sulfonyl]benzamide
[2465] The title compound was prepared by substituting EXAMPLE 188B
for EXAMPLE 187B in EXAMPLE 187C. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.41 (d, 1H), 8.13 (s, 1H), 7.79
(dd, 1H), 7.58 (d, 1H), 7.33-7.40 (m, 3H), 7.04-7.16 (m, 4H), 6.94
(t, 1H), 6.72 (dd, 1H), 6.61 (s, 1H), 6.27 (d, 1H), 3.91 (s, 1H),
3.44 (s, 2H), 3.02-3.15 (m, 5H), 2.95 (s, 2H), 2.69-2.82 (m, 3H),
2.13-2.28 (m, 8H), 1.97 (s, 3H), 1.83 (s, 2H), 1.32-1.46 (m, 3 H),
0.99-1.10 (m, 1H), 0.94 (s, 6H), 0.76-0.90 (m, 1H), 0.59-0.71 (m,
2H), 0.34 (d, 2H).
EXAMPLE 189
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-{[4-({1-[2-(dimethylamino)-2-oxoethyl]piperidi-
n-4-yl}amino)-3-nitrophenyl]sulfonyl}benzamide
[2466] The title compound was prepared by substituting
2-chloro-N,N-dimethylacetamide for
1-bromo-2-(2-methoxyethoxy)ethane in EXAMPLE 170. .sup.1H NMR (400
MHz, dimethylsulfoxide-d.sub.6) .delta. 9.63 (s, 1H), 8.46 (s, 1H),
8.21 (m, 1H), 7.78 (m, 1H), 7.53 (d, 1H), 7.40 (d, 2H), 7.22 (m,
2H), 7.11 (d, 2H), 6.96 (d, 1H), 6.82 (dd, 1H), 6.72 (m, 2H), 6.57
(s, 1H), 4.28 (m, 2H), 3.85 (m, 8H), 3.16 (m, 4H), 2.96 (m, 7H),
2.82 (m, 2H), 2.11 (m, 8H), 1.47 (s, 2H), 0.96 (s, 6H).
EXAMPLE 190
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-morpholin-4-ylethyl)piperidin-4-yl]-
amino}-3-nitrophenyl)sulfonyl]benzamide
[2467] The title compound was prepared by substituting EXAMPLE 162C
for tert-butyl pieperazien-1-carboxylate and
2-morpholinoacetaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde in
EXAMPLE 1A. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.46 (d, 1H), 8.29 (d, 1H), 7.78 (dd, 1H), 7.53 (d, 1H),
7.41 (d, 2H), 7.21 (m, 2H), 7.11 (d, 2H), 6.96 (dd, 1H), 6.83 (dd,
1H), 6.73 (dd, 1.83 Hz, 1H), 6.69 (m, 1H), 6.58 (s, 1H), 3.82 (m,
10H), 3.27 (m, 4H), 3.09 (m, 6H), 2.81 (m, 7H), 2.23 (m, 2H), 2.15
(m, 2H), 2.04 (s, 2H), 1.93 (m, 2H), 1.48 (t, 2H), 0.96 (s,
6H).
EXAMPLE 191
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)benzamide
EXAMPLE 191A
4-((4-aminotetrahydro-2
H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide
[2468] The title compound was prepared by substituting
4-(aminomethyl)tetrahydro-2H-pyran-4-amine for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 191B
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1--
en-1-yl]methyl}piperazin-1-yl)benzamide
[2469] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 191A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.57 (t,
1H), 8.47 (d, 1H), 8.18(s, 3H), 7.79 (dd, 1H), 7.53 (d, 1H), 7.41
(d, 2H), 7.34 (d, 1H), 7.24 (t, 1H), 7.11 (d, 2H), 7.01-7.03 (m,
2H), 6.82 (dd, 1H), 6.73-6.76 (m, 2H), 6.56 (s, 1H), 3.85 (d, 2H),
3.71-3.73 (m, 4H), 3.14 (br s, 2H), 2.23 (s, 2H), 2.04 (m, 2H),
1.82-1.87 (m, 2H), 1.70-1.75 (m, 2H), 1.47 (t, 2H), 0.96 (s,
6H).
EXAMPLE 192
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl-
]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 192A
[2470] The title compound was prepared by substituting
4-(aminomethyl)-1-methylpiperidin-4-ol for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 192B
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl-
]amino}-3-nitrophenyl)sulfonyl]benzamide
[2471] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 192A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.38 (s,
1H), .delta. 8.65 (t, 1H), 8.46 (d, 1H), 7.74 (dd, 1H), 7.53 (d,
1H), 7.40 (d, 2H), 7.19-7.22 (m, 2H), 7.11 (d, 2H), 6.97 (dd, 1H),
6.82 (dd, 1H), 6.70-6.74 (m, 2H), 6.57 (s, 1H), 3.60 (d, 2H), 3.47
(d, 2H), 3.10-3.17 (m, 4H), 2.80-2.81 (m, 4H), 2.23 (s, 2H), 2.04
(s, 2H), 1.76-1.85 (m, 4H), 1.47 (t, 2H), 0.96 (s, 6H).
EXAMPLE 193
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2472] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and
EXAMPLE 49C, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.15 (s, 1H), 8.51 (d, 1H),
8.16 (d, 1H), 7.82 (dd, 1H), 7.54 (d, 1H), 7.31 (m, 4H), 7.08 (m,
4H), 6.60 (dd, 1H), 6.36 (s, 1H), 6.08 (d, 1H), 3.92 (m, 2H), 3.74
(m, 1H), 3.04 (m, 7H), 2.71 (m, 3H), 2.16 (m, 6H), 1.99 (m, 4H),
1.49 (m, 10H), 0.92 (s, 6H).
EXAMPLE 194
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-ni-
trophenyl)sulfonyl]benzamide
EXAMPLE 194A
(S)-tert-butyl
3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate
[2473] The title compound was prepared by substituting
(S)-tert-butyl 3-aminopyrrolidine-1-carboxylate for tert-butyl
4-aminopiperidine-1-carboxylate in EXAMPLE 140A.
EXAMPLE 194B
(S)-tert-butyl
3-(4-(N-(2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)pyrr-
olidine-1-carboxylate
[2474] The title compound was prepared by substituting EXAMPLE 194A
for EXAMPLE 1G and EXAMPLE 36C for EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 194C
(S)-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
nyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(pyrrolidin-3-ylamino)phenylsuflon-
yl)benzamide
[2475] The title compound was prepared by substituting EXAMPLE 194B
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 194D
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-ni-
trophenyl)sulfonyl]benzamide
[2476] To a solution of EXAMPLE 194C (470 mg) in tetrahydrofuran (3
mL) and acetic acid (1 ml, ) was added 37% formaldehyde solution in
water (0.42 mL) and MP-CNBH.sub.3 resin (947 mg, 2.38 mmol/g)). The
reaction mixture was stirred overnight at room temperature. The
resin was filtered off and reaction mixture was then concentrated.
The residue was purified by flash chromatography, eluting with
ethyl acetate, followed by a gradient of 3-10%
methanol/dichloromethane. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.42 (d, 1H), 8.34 (m, 1H), 7.78
(dd, 1H), 7.53 (d, 1H), 7.36 (d, 2H), 7.19 (t, 1H), 7.08 (m, 3H),
6.95 (m, 1H), 6.76 (dd, 1H), 6.67 (m, 2H), 6.45 (d, 1H), 3.53 (m,
2H), 3.16 (m, 7H), 2.83 (m, 4H), 2.61 (br m, 1H), 2.27 (m, 4H),
2.18 (m, 3H), 1.98 (m, 3H), 1.41 (m, 2H), 0.94 (s, 6H).
EXAMPLE 195
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-ni-
trophenyl)sulfonyl]benzamide
EXAMPLE 195A
(R)-tert-butyl
3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate
[2477] The title compound was prepared by substituting
(R)-tert-butyl 3-aminopyrrolidine-1-carboxylate for tert-butyl
4-aminopiperidine-1-carboxylate in EXAMPLE 140A.
EXAMPLE 195B
(R)-tert-butyl
3-(4-(N-(2-(3-chloropbenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)pyrr-
olidine-1-carboxylate
[2478] The title compound was prepared by substituting EXAMPLE 195A
for EXAMPLE 1G and EXAMPLE 36C for EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 195C
(R)-2-(3-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
nyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(pyrrolidin-3-ylamino)phenylsulfon-
yl)benzamide
[2479] The title compound was prepared by substituting EXAMPLE 195B
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 195D
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-methylpyrrolidin-3-yl]amino}-3-ni-
trophenyl)sulfonyl]benzamide
[2480] The title compound was prepared by substituting EXAMPLE 195C
for EXAMPLE 194C in EXAMPLE 194D. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.36 (d, 1H), 8.23 (m, 1H), 7.72
(dd, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.16 (t, 1H), 7.06 (m, 2H),
6.98 (m, 1H), 6.90 (dd, 1H), 6.73 (dd, 1H), 6.64 (m, 2H), 6.41 (d,
1H), 4.01 (s, 1H), 3.28 (m, 2H), 3.24 (m, 1H), 3.13 (m, 5H), 2.76
(m, 2H), 2.69 (m, 3H), 2.56 (m, 1H), 2.24 (m, 7H), 1.90 (br s, 2H),
1.41 (m, 2H), 0.94 (s, 6H).
EXAMPLE 197
(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[3-(-
1H-pyrrol-2-yl)phenoxy]benzamide
[2481] A mixture of EXAMPLE 161 (0.095 g),
1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid (0.025 g),
tetrakis(triphenylphosphine)palladium(0) (0.012 g), and CsF (0.046
g) in dimethoxyethane (2 mL) and methanol (1 mL) was heated in a
CEM Discover microwave reactor (80.degree. C., 20 minutes). 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. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was then treated with 4 N HCl in dioxane.
The solvent was removed, and the residue was purified by reverse
phase Prep HPLC to give the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.21 (s, 1H), 8.39 (s, 1H),
8.04 (d, 1H), 7.70 (d, 1H), 7.57 (d, 1H), 7.34 (d, 2H), 7.11-7.25
(m, 5H), 7.04 (d, 2H), 6.96 (d, 1H), 6.80 (s, 1H), 6.66 (d, 2H),
6.48 (d, 1H), 6.41 (s, 1H), 6.28 (s, 1H), 6.08 (d, 1H), 3.05 (s,
6H), 2.73 (s, 2H), 2.18-2.24 (m, 6H), 1.74 (s, 3H), 1.38 (t, 2H),
0.92 (s, 6H).
EXAMPLE 198
4-(4-{[2-(4-chlorophenoxy)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-2-(3-fluorophenoxy)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methy-
l]amino}-3-nitrophenyl)sulfonyl]benzamide
[2482] The title compound was prepared by substituting EXAMPLE 112C
for EXAMPLE 1F and EXAMPLE 192A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.44 (s,
1H), 8.31 (d, 1H), 7.92 (s, 1H), 7.63-7.66 (m, 2H), 7.36 (d, 2H),
7.07 (d, 2H), 6.99 (d, 1H), 6.71 (dd, 1H), 6.62-6.65 (m, 1H), 6.47
(dd, 1H), 6.36-6.40 (m, 2H), 5.16 (s, 1H), 3.09 (s, 6H), 2.92 (br
s, 2H), 2.76 (a, 2H), 2.62-2.64 (m, 2H), 2.18-2.23 (m, 6H), 1.93
(d, J=5.49 Hz, 2H), 1.72-1.76 (m, 4H), 1.41 (t, 2H), 0.94 (s,
6H).
EXAMPLE 199
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophe-
nyl}sulfonyl)benzamide
[2483] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.12 (s,
1H), 8.33 (d, 1H), 7.66 (dd, 1H), 7.57 (d, 1H), 7.50 (d, 1H), 7.36
(d, 2H), 7.17 (t, 1H), 7.07 (d, 2H), 6.91 (m, 1H), 6.75 (dd, 1H),
6.68 (dd, 1H), 6.63 (m, 1H), 6.42 (d, 1H), 3.14 (m, 4H), 2.96 (m,
6H), 2.78 (s, 2H), 2.45 (s, 3H), 2.21 (m, 6H), 1.98 (s, 2H), 1.41
(t, 2H), 0.94 (s, 6H).
EXAMPLE 200
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)a-
mino]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 200A
2,3-difluoro-4-nitrophenol
[2484] A solution of 2,3-difluoro-4-nitroanisole (10 g) in 48% HBr
(60 mL) and 30% HBr in acetic acid (30 mL) was stirred at
120.degree. C. overnight. The mixture was cooled to room
temperature and extracted with ethyl acetate (3.times.200 ml) and
the combined extracts were washed with brine and dried over
Na.sub.2SO.sub.4. Filtration and evaporation of the solvent gave
the product.
EXAMPLE 200B
6,7-difluoro-1H-indol-5-ol
[2485] The title compound was prepared as in EXAMPLE 154A by
replacing 2-fluoro-4-nitrophenol with EXAMPLE 200A.
EXAMPLE 200C
methyl 2-(6,7-difluoro-1H-indol-5-yloxy)-4-fluorobenzoate
[2486] The title compound was prepared as described in EXAMPLE 3A
by replacing 2-methyl-5-indolol with EXAMPLE 200B.
EXAMPLE 200D
methyl
2-(6,7-difluoro-1H-indo-5-yloxy)-4-(piperazin-1-yl)benzoate
[2487] The title compound was prepared as described in EXAMPLE 3G
by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE
200C respectively.
EXAMPLE 200E
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(6,7-difluoro-1H-indol-5-yloxy)benzoate
[2488] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 200D and
EXAMPLE 60D.
EXAMPLE 200F
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(6,7-difluoro-1H-indol-5-yloxy)benzoic acid
[2489] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 200E.
EXAMPLE 200G
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)a-
mino]-3-nitrophenyl}sulfonyl)benzamide
[2490] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 200F and
EXAMPLE 3I, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.63 (s, 1H), 8.40 (d, 1H),
8.06 (d, 1H), 7.72 (dd, 1H), 7.59 (d, 1H), 7.35 (m, 3H), 7.05 (d,
2H), 6.96 (d, 1H), 6.72 (d, 1H), 6.64 (dd, 1H), 6.36 (d, 1H), 6.24
(d, 1H), 3.74 (m, 1H), 3.12 (m, 8H), 2.73 (s, 3H), 2.55 (m, 2H),
2.14 (m, 10H), 1.74 (m, 3H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 201
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H--
pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2491] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 200F and
EXAMPLE 49C, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.64 (s, 1H), 8.40 (d, 1H),
8.09 (s, 1H), 7.70 (dd, 1H), 7.58 (d, 1H), 7.35 (m, 4H), 7.05 (d,
2H), 6.92 (d, 1H), 6.64 (m, 2H), 6.36 (d, 1H), 6.23 (s, 1H), 3.92
(m, 2H), 3.67 (m, 1H), 3.01 (m, 8H), 2.73 (s, 2H), 2.25 (m, 8H),
1.97 (m, 5H), 1.53 (m, 8H), 0.94 (m, 6H).
EXAMPLE 202
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}-
sulfonyl)amino]carbonyl}phenoxy)-1H-indole-1-carboxylate
EXAMPLE 202A
ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate
[2492] The title compound was prepared by substituting
4-hydroxyindole for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 202B
ethyl
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-enyl)methyl)piperazin-1-yl)benzoate
[2493] The title compound was prepared by substituting EXAMPLE 202A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 202C
2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
[2494] The title compound was prepared by substituting EXAMPLE 202B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 202D
4-(4-{[2-(4-chlorophenyl)-4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1--
yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophen-
yl}sulfonyl)benzamide
[2495] The title compound was prepared by substituting EXAMPLE 202C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H, except
2-10% methanol in CH.sub.2Cl.sub.2 was used for the
chromatography.
EXAMPLE 202E
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}-
sulfonyl)amino]carbonyl}phenyoxy)-1H-indole-1-carboxylate
bis(2,2,2-trifluoroacetate)
[2496] EXAMPLE 202D (0.58 g) was dissolved in CH.sub.2Cl.sub.2 (30
mL), then di-tert-butyl dicarbonate (0.14 g) and
4-dimethylaminopyridine (0.02 g) was added and the reaction stirred
at room temperature for 60 hours. The reaction was then filtered
through celite,c oncentrated, and the crude was purified by
preparative HPLC using a 250.times.50 mm C18 column, eluting with
20-100% CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving
the product as a trifluoroacetate salt. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.80 (v br s, 1H), 9.65, 9.45
(both v br s, total 2H), 8.55 (d, 1H), 8.12 (br d, 1H), 7.80 (dd,
1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.55 (d, 1H), 7.40 (d, 2H), 7.19
(d, 1H), 7.10 (m, 3H), 6.80 (dd, 1H), 6.59 (d, 1H), 6.43 (s, 1H),
6.41 (d, 1H), 4.05 (v br s, 1H), 3.85 (v br s, 1H), 3.60, 3.50,
3.40 (all v br m, total 10H), 3.10 (v br m, 2H), 2.95, 2.90 (both
br m, total 5H), 2.20 br m, 4H), 2.05 (br s, 2H), 1.80 (br m, 1H),
1.67 (s, 9 H), 1.45 (br t, 2H), 0.95 (s, 6H).
EXAMPLE 203
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nit-
rophenyl)sulfonyl]benzamide
EXAMPLE 203A
4-(4-(dimethylamino)cyclohexylamino)-3-nitrobenzenesulfonamide
[2497] The title compound was prepared by substituting N.sup.1,
N.sup.1-dimethylcyclohexane-1,4-diamine for
1-isopropylpiperidin-4-amine in EXAMPLE 41A.
EXAMPLE 203B
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nit-
rophenyl)sulfonyl]benzamide
[2498] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 203A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 9.16 (d, 1H),
8.31-8.39 (m, 2H), 8.03-8.07 (m, 1H), 7.46 (d, 2H), 7.08-7.17 (m,
4H), 7.00-7.04 (m, 1H), 6.91-6.99 (m, 2H), 6.82 (dd, 1H), 6.69 (d,
1H), 3.44-3.52 (m, 1H), 3.14-3.20 (m, 4H), 2.84 (s, 2H), 2.64 (s,
1H), 2.49 (s, 6H), 2.31 (t 2H), 2.22-2.28 (m, 4H), 2.09-2.15 (m,
2H), 2.05 (s, 2H), 1.97-2.02 (m, 2H), 1.47-1.56 (m, 2H), 1.42 (t,
2H), 1.27-1.37 (m, 2H), 1.25 (s, 1H), 0.93-0.98 (m, 6H).
EXAMPLE 204
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide
EXAMPLE 204A
4-(4-(diethylamino)cyclohexylamino)-3-nitrobenzenesulfonamide
[2499] The title compound was prepared by substituting
N.sup.1,N.sup.1-diethylcyclohexane-1,4-diamine for
1-isopropylpiperidin-4-amine in EXAMPLE 41A.
EXAMPLE 204B
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide
[2500] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 204A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-.sub.5) .delta.9.18 (d, 1H),
8.32-8.39 (m, 2H), 8.05-8.09 (m, 1H), 7.46 (d, 2H), 7.15 (t, 1H),
7.08-7.13 (m, 3H), 6.98-7.05(m, 2H), 6.94 (dd, 1H), 6.82 (dd, 1H),
6.69 (d, 1H), 3.43-3.50 (m, 1H), 3.13-3.19 (m, 4H), 2.84 (s, 2H),
2.72 (t, 1H), 2.63 (q, 4H), 2.31 (t, 2H), 2.22-2.28 (m, 4H), 2.11
(d, 2H), 2.00 (s, 2H), 1.91 (d, 2H), 1.40-1.48 (m, 4H), 1.24-1.34
(m, 2H), 1.10 (t, 6H), 0.93-0.99 (m, 6H).
EXAMPLE 205
Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]--
3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 205A
trans-4-(4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide
[2501] The title compound was prepared by substituting trans
4-morpholinocyclohexanamine for 1-isopropylpiperidin-4-amine in
EXAMPLE 41A.
EXAMPLE 205B
Trans-2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]--
3-nitrophenyl}sulfonyl)benzamide
[2502] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 9.17(d, 1H), 8.42
(d, 1H), 8.32 (dd, 1H), 8.00 (d, 1H), 7.46 (d, 2H), 7.15 (t, 1H),
7.11 (d, 2H), 7.07 (d, 1H), 7.03(d, 1H), 6.99 (d, 1H), 6.93 (dd,
1H), 6.81 (dd, 1H), 6.69 (d, 1H), 3.73-3.78 (m, 4H), 3.43-3.50 (m,
1H), 3.15-3.21 (m, 4H), 2.84 (s, 2H), 2.50-2.54 (m, 4H), 2.31 (t,
2H), 2.21-2.27 (m, 5H), 2.11 (d, 2H), 2.00 (s, 2H), 1.91 (d, 2H),
1.36-1.43 (m, 4H), 1.28-1.34 (m, 2H), 0.96 (s, 6H).
EXAMPLE 206
4-{4-[1-(4'-chloro-1,1'-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(2-chlorophe-
noxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzami-
de
[2503] The title compound was prepared as described in EXAMPLE 137
by replacing EXAMPLE 122C with EXAMPLE and EXAMPLE 111A with
EXAMPLE 3I. .sup.1H NMR (400 MHz, CH.sub.2CD.sub.2) .delta. 8.80
(s, 1H), 8.41 (d, 1H), 8.01 (d, 1H), 7.87 (d, 1H), 7.55 (t, 2H),
7.29-7.37 (m, 4H), 7.17-7.28 (m, 4H), 7.10-7.15 (m, 2H), 6.94 (d,
1H), 6.58 (d, 1H), 5.95 (s, 1H), 3.53-3.64 (m, 1H), 3.39 (q, 1H),
3.01-3.12 (m, 4H), 2.77 (t, 2H), 2.38-2.46 (m, 2H), 2.15-2.31 (m,
7H), 2.05 (d, 2H), 1.63-1.74 (m, 2H), 1.22 (d, 3H).
EXAMPLE 207
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 207A
2-chloro 4-(medioxymethoxy)phenol
[2504] The title compound was prepared by substituting
2-chlorobenzene-1,4-diol for EXAMPLE 158B in EXAMPLE 158C.
EXAMPLE 207B
Ethyl 2-((2-chloro-4-(methoxymethoxy)phenoxy)-4-fluorobenzoate
[2505] The title compound was prepared by substituting 207A for
2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 207C
Ethyl 2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-fluorobenzoate
[2506] The title compound was prepared by substituting piperazine
for EXAMPLE 3F and EXAMPLE 207B for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 207D
Ethyl
2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorphenyl)-4,4--
dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2507] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 207C for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 207E
2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2508] The title compound was prepared by substituting EXAMPLE 207D
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 207F
2-(2-chloro-4-methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino-
)-3-nitrophenylsulfonyl)benzamide
[2509] The title compound was prepared by substituting EXAMPLE 207E
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 207G
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
[2510] The title compound was prepared by substituting EXAMPLE 207F
for EXAMPLE 158 in EXAMPLE 159. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 12.30 (br. s, 1H), 9.29 (d, 1H), 8.49 (d,
1H), 8.40 (dd, 1H), 8.08 (d, 1H), 7.45 (d, 2H), 7.09 (m, 3H), 7.01
(d, 1H), 6.93 (dd, 1H), 6.75 (dd, 1H), 6.58 (d, 1H), 3.54 (m, 1H),
3.13 (m, 4H), 2.81 (s, 2H), 2.65 (m, 2H), 2.29 (m, 2H), 2.21 (m,
4H), 2.16 (s, 3H), 2.07 (m, 2H), 1.96 (m, 4H), 1.66 (m, 2H), 1.41
(t, 2H), 0.95 (s, 6H).
EXAMPLE 208
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 208A
2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-enyl)methyl)piperazin-1-yl)
-N-(4-(4-methylpiperazin-1-ylamino)-3-nitrophenylsulfonyl)benzamide3
[2511] The title compound was prepared by substituting EXAMPLE 207E
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 208B
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]--
3-nitrophenyl}sulfonyl)benzamide
[2512] The title compound was prepared by substituting EXAMPLE 208A
for EXAMPLE 158E in EXAMPLE 159. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 12.33 (br. s, 1H), 9.28 (m, 2H), 8.44
(dd, 1H), 8.07 (d, 1H), 7.76 (d, 1H), 7.45 (d, 2H), 7.09 (m, 3H),
6.94 (dd, 1H), 6.75 (dd, 1H), 6.57 (d, 1H), 3.13 (m, 4H), 2.94 (m,
4H), 2.81 (m, 4H), 2.29 (m, 2H), 2.19 (m, 10H), 1.99 (s, 2H), 1.41
(t, 2H), 0.95 (m, 6H).
EXAMPLE 209
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 209A
6-Fluoro-4-methoxy-1H-indole-2-carboxylic acid methyl ester
[2513] Sodium methoxide solution (25% by weight in methanol, 22.25
mL) and methanol (52 mL) were added to a flask and cooled to
-20.degree. C. using an acetonitrile/dry ice bath. Ethyl
2-azidoacetate (25% by weight in ethanol, 50.3 g) and
4-fluoro-2-methoxybenzaldehyde (5.00 g, dissolved in ethyl
2-azidoacetate solution) were added drop-wise to the stirring
sodium methoxide solution at -20.degree. C. The solution was then
stirred at -20.degree. C. for 3.5 hours, then at 0.degree. C. for
one hour. The solution was poured over ice, vacuum filtered, and
washed with water. The filtered solid was taken up in xylenes (100
mL), washed twice with brine, and dried using anhydrous sodium
sulfate and filtered. In a separate flask xylenes (50 mL) was
brought to reflux. The xylene solution containing the filtered
material was added drop-wise to the refluxing xylenes. The solution
was then refluxed for five hours, cooled, and placed in a freezer
for 16 hours. The precipitate was filtered out. The volume of the
filtrate was reduced on vacuum to generate a second crop of
precipitate, which was washed with hexanes, then 5% ethyl acetate
in hexanes and combined with material from the first
filtration.
EXAMPLE 209B
6-Fluoro-4-methoxy-1H-indole-2-carboxylic acid
[2514] The title compound was prepared by substituting EXAMPLE 209A
for EXAMPLE 1E in EXAMPLE 1E.
EXAMPLE 209C
6-Fluoro-4-methoxy-1H-indole
[2515] EXAMPLE 209B (1775 mg) was dissolved in
N-methylpyrrolidinone (75 mL), and copper powder (2157 mg) was
added. The solution was stirred to keep the copper powder suspended
and the solution was split into nine microwave reactor vials, each
containing a stir bar. Each vial was heated in a CEM Discover
microwave reactor at 260.degree. C. for 25 minutes with stirring.
The vials were combined, added to water, and extracted with ethyl
ether. The ether was washed with brine and dried on anhydrous
sodium sulfate. The solution was filtered and the filtrate was
concentrated and purified by flash column chromatography on silica
gel using 10% ethyl acetate in hexanes.
EXAMPLE 209D
6-fluoro-1H-indol-4-ol
[2516] Aluminum chloride (727 mg) was added to dichloromethane (20
mL), the mixture was cooled to 0.degree. C., and benzylmercaptan
(4512 mg) was added. EXAMPLE 209C (600 mg) dissolved in
dichloromethane (5 mL) was added drop-wise. The solution was mixed
for 30 minutes at 0.degree. C. Benzylmercaptan (451 mg) and
aluminum chloride (727 mg) were added, and the solution was stirred
for 75 minutes at 0.degree. C. The reaction was quenched by adding
1M aqueous HCl. The solution was extracted with ethyl acetate,
which was subsequently washed with brine and dried on anhydrous
sodium sulfate. After filtration, the filtrate was concentrated and
purified by flash column chromatography on silica gel using 5%
ethyl acetate in hexanes increasing to 20% ethyl acetate in hexanes
and increasing again to 50% ethyl acetate in hexanes.
EXAMPLE 209E
4-Fluoro-2-(6-fluoro-1H-indol-4-yloxy)-benzoic acid ethyl ester
[2517] The title compound was prepared by substituting EXAMPLE 209D
for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 209F
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(6-fluoro-1H-indol-4-yloxy)-benzoic acid ethyl ester
[2518] The title compound was prepared by substituting EXAMPLE 209E
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 209G
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]piperazin-1-y-
l}-2-(6-fluoro-1H-indol-4-yloxy)-benzoic acid
[2519] The title compound was prepared by substituting EXAMPLE 209E
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 209H
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(1-methylpiperidin-4-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
[2520] The title compound was prepared by substituting EXAMPLE 209G
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.14 (br s, 1H),
8.37 (d, 1H), 8.08 (d, 1H), 7.68 (dd, 1H), 7.59 (d, 1H), 7.35 (d,
2H), 7.19 (t, 1H), 7.05 (d, 2H), 6.97 (d, 1H), 6.78 (dd, 1H), 6.71
(dd, 1H), 6.34 (d, 1H), 6.26 (t, 1H), 5.97 (dd, 1H), 3.74 (m, 1H),
3.18-3.09 (m, 2H), 3.05 (br s, 4H), 2.83-2.70 (m, 2H), 2.74 (br s,
2H), 2.57 (s, 3H), 2.25-2.12 (m, 6H), 2.09-2.01 (m, 2H), 1.96 (s,
2H), 1.72 (q, 2H), 1.39 (t, 2H), 0.93 (s, 6H).
EXAMPLE 210
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
[2521] The title compound was prepared by substituting EXAMPLE 209G
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (br
s, 1H), 8.39 (d, 1H), 7.64 (d, 1H), 7.57 (d, 1H), 7.38-7.32 (d,
2H), 7.21 (t, 1H), 7.05 (d, 2H), 6.99 (d, 1H), 6.80 (d, 1H), 6.73
(d, 1H), 6.35 (d, 1H), 6.26 (t, 2H), 6.00 (d, 1H), 3.99-3.89 (m,
3H), 3.76 (m, 1H), 3.26 (m, 2H), 3.07 (m, 4H), 2.72 (br s, 2H),
2.27-2.12 (m, 8H), 2.09-1.95 (m, 4H), 1.86-1.48 (m, 8H), 1.39 (t,
2H), 0.93 (s, 6H).
EXAMPLE 211
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperidin-1-yl)amino]--
3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
EXAMPLE 211A
4-(4-methylpiperazin-1-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonam-
ide
[2522] The title compound was prepared by substituting
4-methylpiperazin-1-amine for 3-(N-morpholinyl)-1-propylamine and
EXAMPLE 131C for 4-Fluoro-3-nitrobenzenesulfonamide in EXAMPLE
4A.
EXAMPLE 211B
2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-methylpiperazin-1-ylamin-
o)-3-(trifluoromethylsulfonyl)phenylsulfonyl)benzamide
[2523] The title compound was prepared by substituting EXAMPLE 207E
for EXAMPLE 1F and EXAMPLE 211A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 211C
2-(2-chloro-4-hydroxyphenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-methylpiperidin-1-yl)amino)-3-(tr-
ifluoromethylsulfonyl)phenylsulfonyl)benzamide
[2524] The title compound was prepared by substituting EXAMPLE 211B
for EXAMPLE 158E in EXAMPLE 159. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 9.87 (s, 1H), 8.08 (d, 1H), 7.96
(s, 1H), 7.90 (dd, 1H), 7.54 (d, 1H), 7.48 (d, 1H), 7.36 (d, 2H),
7.07 (d, 2H), 6.89 (d, 1H), 6.83 (d, 1H), 6.73 (dd, 1H), 6.65 (dd,
1H), 6.21 (d, 1H), 3.07 (m, 4H), 2.90 (m, 6H), 2.76 (s, 2H), 2.41
(s, 3H), 2.21 (m, 6H), 1.97 (s, 2H), 1.40 (t, 3H), 0.94 (s,
6H).
EXAMPLE 212
2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-
-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 212A
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
-indol-4-yloxy)benzamide
[2525] The title compound was prepared by substituting EXAMPLE 202C
for EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 212B
2-({1,3-bis[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)-4-(4-{[2-(4-
-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-
-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2526] EXAMPLE 212A (0.25 g) was dissolved in methanol (0.60 mL),
to which was added 37% (wt) formaldehyde in water (0.22 mL) and
1-methylpiperazine 10.33 mL). The reaction was heated at 60.degree.
for two hours, then cooled and concentrated. The crude was purified
by preparative HPLC using a C18 column, 250.times.50 mm, 10.mu.,
and eluting with a gradient of 20-100% CH.sub.3CN vs. 0.1%
trifluoroacetic acid in water, giving the product as a
trifuloroacetate salt. The salt was dissolved in dichloromethane (6
mL) and washed with 50% aqueous NaHCO.sub.3. The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated
to give the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.68 (br t, 1H), 8.00 (s, 1H),
7.82 (d, 1H), 7.38 (m, 3H), 7.25 (d, 1H), 7.08 (d, 2H), 6.87 (d,
1H), 6.75 (d, 1H), 6.67 (m, 2H), 6.58 (s, 1H), 5.58 (d, 1H), 4.85
(s, 2H), 3.40 (m, 4H), 3.20 (v br s, 4H), 3.05 (v br s, 4H), 2.79
(s, 2H), 2.60 (v br s, 2H), 2.40 (br m, 6H), 2.20 (m, 21H), 2.09
(s, 3H), 1.98 (s, 2H), 1.80 (m, 2H), 1.42 (t, 2H), 0.95 (s,
6H).
EXAMPLE 213
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-({3-
-[(4-methylpiperazin-1-yl)methyl]-1H-indol-4-yl}oxy)benzamide
[2527] To EXAMPLE 212A (0.13 g) in methanol (0.30 mL) was added 37%
(wt) formaldehyde in water (0.022 mL) and 1-methylpiperazine (0.035
mL). The reaction was heated at 60.degree. C. for 50 minutes, then
it was cooled and concentrated. The crude was purified by
preparative HPLC using a C18 column, 250.times.50 mm, 10.mu., and
eluting with a gradient of 20-100% CH.sub.3CN vs. 0.1%
trifluoroacetic acid in water, giving the product as a
trifluoroacetate salt. The salt was dissolved in dichloromethane (6
mL) and washed with 50% aqueous NaHCO.sub.3. The organic layer was
dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated
to give the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.23 (s, 1H), 8.68 (br t, 1H),
7.96 (s, 1H), 7.79 (d, 1H), 7.38 (d, 2H), 7.31 (s, 1H), 7.17 (br d,
1H), 7.08 (d, 2H), 6.75 (d, 2H), 6.66 (d, 1H), 6.60 (m, 2H), 5.65
(d, 1H), 4.33 (br s, 2H), 3.40 (m, 4H), 3.20 (v br s, 4H), 3.03 (v
br s, 4H), 2.79 (s, 2H), 2.60 (v br s, 2H), 2.42 (br m, 2H), 2.20
(m, 15 H), 1.98 (s, 2H), 1.83 (m, 2H), 1.42 (t, 2H), 0.95 (s,
6H).
EXAMPLE 214
2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin--
1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)ph-
eonxy)-N,N-dimethylbenzamide
EXAMPLE 214A
methyl
2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methy-
l)piperazin-1-yl)benzoate
[2528] The title compound was prepared by substituting EXAMPLE 3F
for EXAMPLE 1B in EXAMPLE 1C.
EXAMPLE 214B
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(2-(dimethylcarbamoyl)phenoxy)benzoate
[2529] The title compound was prepared by substituting EXAMPLE 214A
for EXAMPLE 1C and 2-hydroxy-N, N-dimethylbenzamide for EXAMPLE 1D
in EXAMPLE 1E .
EXAMPLE 214C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(2-(dimethylcarbamoyl)phenoxy)benzoic acid
[2530] The title compound was prepared by susbtituting EXAMPLE 214B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 214D
2-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin--
1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylcarbamoyl)ph-
eonxy)-N,N-dimethylbenzamide
[2531] The title compound was prepared by substituting EXAMPLE 214C
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.35 (s, 1H), 8.07
(d, 1H), 7.72 (d, 1H), 7.61 (d, 1H), 7.36 (d, 2H), 7.12 (m, 2H),
7.06 (d, 2H), 7.02 (d, 1H), 6.93 (t, 1H), 6.68 (dd, 1H), 6.47 (d,
1H), 6.18 (d, 1H), 3.72 (m, 1H), 3.04 (m, 4H), 2.95 (m, 2H), 2.86
(s, 3H), 2.75 (s, 2H), 2.70 (s, 3H), 2.42 (m, 2H), 2.19 (m, 6H),
2.01 (m, 4H), 1.67 (m, 2H), 1.40 (t, 2H), 1.24 (s, 3H), 0.94 (s,
6H).
EXAMPLE 215
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide
EXAMPLE 215A
methyl 2-(3-amino-2-methylphenoxy)-4-fluorobenzoate
[2532] The title compound was prepared by substituting
3-amino-2-methylphenol for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 215B
(E)-methyl
2-(3-(1-chloro-2,2,2-trifluoroethylideneamino)-2-methylphenoxy)-
-4-fluorobenzoate
[2533] To a mixture of triethylamine (0.476 g) and
triphenylphosphine (3.05 g) in CCL.sub.4(10 mL) was added
trifluoroacetic acid (0.477 g) dropwise at 0.degree. C. The
solution was stirred for 10 minutes. To this solution was added
EXAMPLE 215A (1.08 g) in CCl.sub.4 (5 mL). The solution wsas heated
under reflux for 3 hours. After cooling, the reaction mixture was
concentrated, and diluted with 3:7 ethyl acetate/hexanes. The solid
was filtered off, and the filtrate was concentrated. The residue
was purified by flash chromatography on silica gel eluting 1:10
ethyl acetate/hexane to give the title compound.
EXAMPLE 215C
(E)-methyl
2-(2-(bromomethyl)-3-(1-chloro-2,2,2-trifluoroethylideneamino)p-
henoxy)-4-fluorobenzoate
[2534] A mixture of EXAMPLE 215B (1.4 g), N-bromosuccinimide (0.671
g), and benzoyl peroxide (0.044 g) in CCl.sub.4 (20 mL) was heated
under reflux for 4 hours. After cooling, the solid was filtered
off. The filtrate was then concentrated. The residue was purified
by flash chromatography on silica gel eluting 1:20 ethyl
acetate/hexane to give the title compound.
EXAMPLE 215D
methyl
4-fluoro-2-(2-(trifluoromethyl)-1H-indol-4-yloxy)benzoate
[2535] Magnesium (0.081 g) in tetrahydrofuran (10 mL) was treated
with EXAMPLE 215C (1.3 g) in tetrahydrofuran (5 mL) drop-wise at
0.degree. C. After the addition was over, a couple of I.sub.2
crystals were added to the reaction. After stirring for 2 hours,
the magnesium started to disappear. The reaction was stirred for
another 6 hours at room temperature. The reaction was quenched with
saturated aqueous NH.sub.4Cl, and extracted with ethyl acetate. The
aqueous layer was extracted with additional ethyl acetate. The
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
flash chromatography on silica gel eluting with 1:4 ethyl
acetate/hexanes to give the title compound.
EXAMPLE 215E
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(2-(trifluoromethyl)-1H-indol-4-yloxy)benzoate
[2536] The title compound was prepared by substituting EXAMPLE 215D
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 215F
[2537] A mixture of EXAMPLE 215E (0.13 g) and lithium iodide (0.534
g) in pyridine (2 mL) was heated in a CEM Discover microwave
reactor (130.degree. C., 30 minutes). The pyridine was removed
under vacuum, and the residue was partitioned between ethyl acetate
and water. The aqueous layer was extracted with additional ethyl
acetate. The combined organic layers were washed with brine, dried
over MgSO.sub.4, filtered, and concentrated. The residue was then
purified by reverse phase Prep HPLC to give the desired
product.
EXAMPLE 215G
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-{[2-(trifluoromethyl)-1H-indol-4-yl]oxy}benzamide
[2538] The title compound was prepared by substituting EXAMPLE 215F
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.29 (s,
1H), 8.39 (d, 1H), 8.12 (d, 1H), 7.69 (dd, 1H), 7.59 (d, 1H), 7.34
(d, 2H), 7.00-7.12 (m, 5H), 6.85 (s, 1H), 6.71 (dd, 1H), 6.34 (d,
1H), 6.29 (d, 1H), 3.93 (dd, 1H), 3.06-3.09 (m, 6H), 2.76 (s, 2H),
2.62-2.64 (m, 2H), 2.16-2.19 (m, 6H), 2.03-2.05 (m, 2H), 1.96 (s,
2H), 1.79-1.82 (m, 2H), 1.66-1.68 (m, 2H), 1.49-1.57 (m, 2H), 1.96
(t, 2H), 0.93 (s, 6H).
EXAMPLE 216
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
EXAMPLE 216A
2-(2-chloro-4-(methoxymethoxy)phenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(1-tetrahydro-2
H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonyl)benzamide
[2539] The title compound was prepared by substituting EXAMPLE 207E
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 216B
2-(2-chloro-4-hydroxyphenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran--
4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
[2540] The title compound was prepared by substituting EXAMPLE 216A
for EXAMPLE 158E in EXAMPLE 159. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 9.83 (br, s, 1H), 8.47 (s, 1H),
8.17 (br. s, 1H), 7.76 (d, 1H), 7.50 (d, 1H), 7.35 (d, 2H), 7.08
(m, 3H), 6.83 (m, 2H), 6.67 (m, 2H), 6.22 (d, 1H), 3.93 (m, 2H),
3.81 (m, 1H), 3.07 (m, 6H), 2.75 (s, 2H), 2.19 (m, 8H), 1.97 (s,
2H), 1.68 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 217
(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6--
(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide
EXAMPLE 217A
4-nitro-2-(trifluoromethyl)phenol
[2541] The title compound was prepared as described in EXAMPLE 200A
by replacing 2,3-difluoro-4-nitroanisole with
2-tnfluoromethyl-4-nitroanisole.
EXAMPLE 217B
6-(trifluoromethyl)-1H-indol-5-ol
[2542] The title compound was prepared analogously to that of
2-fluoro-4-nitrophenol in WO 02/12227 (page 78).
EXAMPLE 217C
methyl
4-fluoro-2-(6-(trifluoromethyl)-1H-indol-5-yloxy)benzoate
[2543] The title compound was prepared as described in EXAMPLE 3A
by replacing 2-methyl-5-indolol with EXAMPLE 217B.
EXAMPLE 217D
methyl
4-(piperazin-1-yl)-2-(6-(trifluoromethyl)-1H-indol-5-yloxy)benzoate
[2544] The title compound was prepared as described in EXAMPLE 3G
by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE
217C, respectively.
EXAMPLE 217E
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(6-(trifluoromethyl)-1H-indol-5-yloxy)benzoate
[2545] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 217D and
EXAMPLE 60D, respectively.
EXAMPLE 217F
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(6-(trifluoromethyl)-1H-indol-5-yloxy)benzoic acid
[2546] The title compound was prepared as described in EXAMPLE 38 H
by replacing EXAMPLE 38G with EXAMPLE 217E.
EXAMPLE 217G
(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-
-1-yl)-N-({4[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-{[6--
(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide
[2547] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 217F and
EXAMPLE 3I, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.38 (s, 1H), 8.43 (d, 1H),
8.09 (d, 1H), 7.77 (dd, 1H), 7.67 (s, 1H), 7.55 (m, 2H), 7.33 (d,
2H), 7.02 (m, 4H), 6.67 (dd, 1H), 6.38 (s, 1H), 3.71 (m, 1H), 3.05
(m, 7H), 2.72 (s, 3H), 2.25 (m, 7H), 1.98 (m, 5H), 1.72 (m, 3H),
1.38 (t, 3H), 0.92 (s, 6H).
EXAMPLE 218
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl-
}sulfonyl)-2-{[6-(trifluoromethyl)-1H-indol-5-yl]oxy}benzamide
[2548] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 217F and
EXAMPLE 49C, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.42 (s, 1H), 8.46 (d, 1H),
8.16 (d, 1H), 7.77 (dd, 1H), 7.70 (s, 1H), 7.56 (m, 2H), 7.33 (m,
3H), 7.03 (m, 5H), 6.69 (dd, 1H), 6.40 (s, 1H), 6.14 (d, 1H), 3.91
(m, 3H), 3.72 (m, 1H), 3.02 (m, 8H), 2.72 (s, 2H), 2.25 (m, 10H),
1.95 (m, 4H), 1.48 (m, 5H), 0.92 (s, 6H).
EXAMPLE 219
2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2-
H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 219A
methyl 2-((2-aminothiazol-4-yl)methoxy)-4-fluorobenzoate
[2549] A mixture of methyl 4-fluoro-2-hydroxybenzoate (552 mg),
4-(chloromethyl)thiazol-2-amine hydrochloric acid (600 mg) and
Cs.sub.2CO.sub.3 (2.64 g) in 15 mL. N,N-dimethylformamide was
stirred at room temperature for 24 hours. Water was added and the
mixture was extracted with ethyl acetate (2.times.), washed with
water (2.times.) and brine, dried over MgSO.sub.4, filtered and
concentrated. The residue was chromatographed on silica gel using
10-50% ethyl acetate in hexanes as eluent.
EXAMPLE 219B
methyl
2-((2-aminothiazol-4-yl)methoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2550] The title compound was prepared by substituting EXAMPLE 219A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 219C
methyl
2-((2-(tert-butoxycarbonylamino)thiazol-4-yl)methoxy)-4-(4-((2-(4-c-
hlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2551] To a solution of EXAMPLE 219B (280 mg),
4-(dimethylamino)pyridine (2.94 mg), triethylamine (81 .mu.L) in 10
mL tetrahydrofuran at room temperature was added a solution of
di-tert-butyl dicarbonate (134 .mu.L) in 3 mL tetrahydrofuran via a
cannula. The mixture was stirred at room temperature overnight, and
partitioned between water and ethyl acetate. The aqueous phase was
extracted with ethyl acetate and the combined organics were washed
with brine and dried over MgSO.sub.4, filtered and concentrated.
The oil residue was chromatographed on silica gel with 25-60% ethyl
acetate in hexanes.
EXAMPLE 219D
2-((2-(tert-butoxycarbonylamino)thiazol-4-yl)methoxy)-4-(4-((2-(4-chloroph-
enyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic
acid
[2552] The title compound was prepared by substituting EXAMPLE 219C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 219E
tert-butyl
4-((5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methy-
l)piperazin-1-yl)-2-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yl-
amino)phenylsulfonylcarbamoyl)phenoxy)methyl)thiazol-2ol-2-ylcarbamate
[2553] The title compound was prepared by substituting EXAMPLE 219D
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G respectively in
EXAMPLE 1H.
EXAMPLE 219F
2-((2-aminothiazol-4-yl)methoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-
-yl)piperidin-4-ylamino)phenylsulfonyl)benzamide
[2554] This EXAMPLE was prepared by substituting EXAMPLE 219E for
EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 0.96 (s, 6H) 1.36-1.78 (m, 8H)
1.99 (m, 2H) 2.14-2.31 (m, 7H) 2.40-2.64 (m, 3H) 2.78 (m, 2H) 2.92
(d, 2H) 3.16-3.43 (m, 10H) 3.75 (m, 1H) 3.84-3.96 (m, 2H) 5.01 (s,
2H) 6.51 (d, 1H) 6.57 (s, 1H) 6.63 (s, 1H) 6.93 (s, 2H) 7.06 (d,
2H) 7.28 (d, 1H) 7.37 (d, 2H) 7.45 (d, 1H) 7.93 (dd, 1H) 8.28 (d,
1H) 8.62 (d, 1H).
EXAMPLE 220
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)a-
mino]-3-nitrophenyl}sulfonyl)benzamide
[2555] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 200F and
EXAMPLE 184A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.72 (s, 1H), 9.14 (s, 1H),
8.47 (d, 1H), 7.82 (m, 1H), 7.54 (dd, 2H), 7.41 (t, 1H), 7.34 (d,
2H), 7.04 (d, 1H), 6.92 (d, 1H), 6.66 (d, 1H), 6.42 (d, 1H), 6.21
(s, 1H), 2.98 (m, 11H), 2.73 (s, 2H), 2.40 (s, 4H), 2.17 (m, 7H),
1.95 (s, 3H), 1.38 (t, 2H), 0.93 (s, 6H).
EXAMPLE 221
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
[2556] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.19 (s,
1H), 9.17 (s, 1H), 8.52 (d, 1H), 7.89 (dd, 1H), 7.59 (d.1H), 7.53
(d, 1H), 7.34 (m, 4H), 7.23 (d, 1H), 7.04 (d, 2H), 6.62 (dd, 1H),
6.39 (m, 1H), 6.07 (m, 1H), 2.94 (m, 10H), 2.71 (s, 2H), 2.36 (s,
3H), 2.15 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (m, 6H).
EXAMPLE 222
tert-butyl
4-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}-
sulfonyl)amino]carbonyl}phenoxy)methyl]-1,3-thiazol-2-ylcarbamate
[2557] The title compound was prepared by substituting EXAMPLE 219D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G respectivelyin EXAMPLE
1H. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 0.96
(s, 6H) 1.37-1.54 (m, 12H) 1.60-1.79 (m, 2H) 1.97-2.08 (m, 3H)
2.15-2.30 (m, 7H) 2.38 (s, 3H) 2.78 (s, 2H) 2.91 (d, 2H) 3.17-3.26
(m, 5H) 3.69-3.84 (m, 1H), 5.08 (s, 2H) 6.48 (d, 1H) 6.53 (s, 1H)
7.07 (d, 2H) 7.17 (s, 1H) 7.23 (d, 1H) 7.37 (d, 2H) 7.43 (d, 1H)
7.90 (dd, 1H) 8.22 (d, 1H) 8.58 (d, 1H) 10.39 (s, 1H), 11.35 (s,
1H).
EXAMPLE 223
2-[(2-amino-1,3-thiazol-4-yl)methoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl-
)amino]-3-nitrophenyl}sulfonyl)benzamide
[2558] The title compound was prepared by substituting EXAMPLE 222
for EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 0.96 (s, 6H) 1.42 (t, 2H)
1.59-1.76 (m, 2H) 1.92-2.06 (m, 3H) 2.16-2.42 (m, 11H) 2.78 (s, 4H)
3.20-3.26 (m, 5H) 3.67-3.82 (m, 1H) 4.99 (s, 2H) 6.50 (d, 1H) 6.55
(s, 1H) 6.62 (s, 1H) 6.91 (s, 2H) 7.08 (d, 2H) 7.26 (d, 1H) 7.37
(d, 2H) 7.45 (d, 1H) 7.93 (dd, 1H) 8.24 (d, 1H) 8.60 (d, 1H).
EXAMPLE 224
2-[3-(acetylamino)phenoxy]-(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
EXAMPLE 224A
methyl
2-(3-acetamidophenoxy-(4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperaz-
in-1-yl)benzoate
[2559] The title compound was prepared by substituting
3-acetamidophenol for EXAMPLE 1D in EXAMPLE 1E.
EXAMPLE 224B
2-(3-acetamidophenoxy)-4-(4-((4'-chlorobiphenyl-2-yl)methyl)piperazin-1-yl-
)benzoic acid
[2560] The title compound was prepared by substituting EXAMPLE 224A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 224C
2-[3-(acetylamino)phenoxy]-(4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3--
nitrophenyl}sulfonyl)benzamide
[2561] The title compound was prepared by substituting EXAMPLE 224B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.48 (s, 1H), 9.89 (s, 1H),
8.59 (m, 1H), 8.50 (d, 1H), 7.71 (dd, 1H), 7.47 (m, 6H), 7.36 (m,
2H), 7.24 (m, 2H), 7.14 (m, 3H), 6.75 (dd, 1H), 6.50 (dd, 1H), 6.39
(d, 1H), 3.86 (dd, 2H), 3.37 (m, 2H), 3.30 (m, 6H), 3.16 (m, 4H),
2.35 (s, 4H), 2.00 (s, 3H), 1.89 (m, 1H), 1.63 (dd, 2H), 1.27 (m,
2H).
EXAMPLE 225
2-[3-(acetylamino)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-y-
lpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
[2562] The title compound was prepared by substituting EXAMPLE 224B
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.86 (s,
1H), 8.45 (d, 1H), 8.15 (d, 1H), 7.70 (dd, 1H), 7.54 (d, 1H), 7.36
(d, 2H), 7.29 (d, 1H), 7.09 (m, 4H), 6.98 (m, 1H), 6.70 (dd, 1H),
6.45 (dd, 1H), 6.33 (d, 1H), 3.95 (dd, 2H), 3.83 (m, 1H), 3.36 (m,
3H), 3.24 (m, 2H), 3.11 (m, 4H), 2.77 (m, 4H), 2.17 (m, 8H), 1.98
(m, 5H), 1.66 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 226
2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-yl-
piperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
EXAMPLE 226A
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(2-chlorophenylamino)benzoate
[2563] A solution of EXAMPLE 214A (500 mg), cesium carbonate (429
mg), palladium(II) acetate (21 mg), rac-BINAP
(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (58.5 mg) and toluene
(6.4 mL) was degassed with N.sub.2. The solution was stirred at
115.degree. C. for 5 minutes. After cooling to room temperature,
2-chloroaniline (144 mg) was added and the reaction mixture was
degassed again with N.sub.2 and was stirred at 115.degree. C. for
45 minutes. The solution was cooled to room temperature, diluted
with ethyl acetate and was washed with water and brine, dried
(MgSO.sub.4), filtered and concentrated. The crude material was
purified by flash chromatography on silica gel, eluting with
dichloromethane/1% methanol.
EXAMPLE 226B
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(2-chlorophenylamino)benzoic acid
[2564] The title compound was prepared by substituting EXAMPLE 226A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 226C
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(2-chlorophenylamino)-N-(3-nitro-4-(1-tetrahydro-2H-pyran-4-yl)piperi-
din-4-ylamino)phenylsulfonyl)benzamide
[2565] The title compound was prepared by substituting EXAMPLE 226B
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.11 (br
s, 1H), 9.16 (br s, 1H), 8.53 (d, 1H), 7.97-8.20 (m, 1H), 7.93 (d,
1H), 7.81 (d, 1H), 7.47 (d, 1H), 7.42 (dd, 1H), 7.36 (d, 2H), 7.22
(t, 1H), 7.15 (d, 1H), 7.07 (d, 2H), 6.89 (t, 1H), 6.52 (d, 1H),
6.34 (dd, 1H), 3.96 (d, 2H), 3.46-3.78 (m, 2H), 3.33-3.40 (m, 2H),
3.23-3.28 (m, 2H), 2.96-3.14 (m, 6H), 2.13-2.31 (m, 8H), 1.98 (br
s, 6H), 1.65 (br s, 4H), 1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 227
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyr-
an-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
EXAMPLE 227A
6-Methoxy-1H-indol-5-ol
[2566] 5-(benzyloxy)-6-methoxy-1H-indole (3.00 g) was added to
methanol (100 mL) and ethyl acetate (100 mL) in a pressure bottle.
Palladium hydroxide on carbon (0.832 g,) was added and the solution
was shaken under 30 psi of hydrogen at room temperature for 40
minutes. The mixture was filtered through a nylon membrane, the
solvent removed under vacuum, the residue taken up in ethyl
acetate, the solution was filtered over a pad of silica gel, and
the solvent was removed from the filtrate under vacuum.
EXAMPLE 227B
4-Fluoro-2-(6-methoxy-1H-indol-5-yloxy)-benzoic acid methyl
ester
[2567] The title compound was prepared by substituting methyl
2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and EXAMPLE
227A for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 227C
2-(6-Methoxy-1H-indol-5-yloxy)-4-piperazin-1-yl-benzoic acid methyl
ester
[2568] The title compound was prepared by substituting piperazine
for EXAMPLE 3F and EXAMPLE 227B for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 227D
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(6-methoxy-1H-indol-5-yloxy)-benzoic acid methyl ester
[2569] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 227C for
tert-butyl piperazrae-1-carboxylate in EXAMPLE 1A.
EXAMPLE 227E
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(6-methoxy-1H-indol-5-yloxy)-benzoic acid
[2570] The title compound was prepared by substituting EXAMPLE 227D
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 227F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-methoxy-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(1-tetrahydro-2H-pyr-
an-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
[2571] The title compound was prepared by substituting EXAMPLE 227E
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.02 (br
s, 1H), 8.60 (d, 1H), 8.25 (d, 1H), 7.89 (dd, 1H), 7.54 (d, 1H),
7.33 (d, 2H), 7.29-7.26 (m, 2H), 7.21 (d, 1H), 7.09 (s, 1H), 7.04
(d, 2H), 6.59 (dd, 1H), 6.36 (t, 1H), 6.03 (d, 1H), 3.96-3.87 (m,
3H), 3.74 (s, 3H), 3.73 (m, 1H), 2.97 (m, 8H), 2.70 (br s, 2H),
2.13 (br s, 8H), 2.05-1.92 (m, 4H), 1.74 (m, 2H), 1.63 (m, 2H),
1.49 (m, 2H), 1.37 (t, 2H), 0.92 (s, 6H).
EXAMPLE 229
2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 229A
methyl 2-(2-aminobenzo[d]thiazol-6-yloxy)-4-fluorobenzoate
[2572] The title compound was prepared by substituting
2-aminobenzo[d]thiazol-6-ol for 2-methyl-5-indolol in EXAMPLE
3A.
EXAMPLE 229B
methyl
2-(2-aminobenzo[d]thiazol-6-yloxy)-4(4-((2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2573] The title compound was prepared by substituting EXAMPLE 229A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 229C
methyl
2-(2-(tert-butoxycarbonylamino)benzo[d]thiazol-6-yl)-4-(4-((2-(4-ch-
lorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2574] The title compound was prepared by substituting EXAMPLE 229B
for EXAMPLE 219B in EXAMPLE 219C.
EXAMPLE 229D
2-(2-(tert-butoxycarbonylamino)benzo[d]thiazol-6-yloxy)-4-(4-((2-(4-chloro-
phenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic
acid
[2575] The title compound was prepared by substituting EXAMPLE 229C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 229E
tert-butyl
6-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl-
)piperazin-1-yl)-2-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonylc-
arbamoyl)phenoxy)benzo[d]thiazol-2-ylcarbamate
[2576] The title compound was prepared by substituting EXAMPLE 229D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G respectivelyin EXAMPLE
1H.
EXAMPLE 229F
2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-y-
l)amino]-3-nitrophenyl}sulfonyl)benzamide
[2577] The title compound was prepared by substituting EXAMPLE 229E
for EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 0.93 (s, 6H) 1.39 (t, 2H)
1.62-1.80 (m, 2H) 1.91-2.24 (m, 10H) 2.50-2.62 (m, 4H) 2.74 (s, 4H)
2.97-3.18 (m, 5H) 3.66-3.82 (m, 1H) 6.24 (d, 1H) 6.64 (dd, 1H) 6.75
(dd, 1H) 6.92 (d, 1H) 7.01-7.12 (m, 3H) 7.20 (d, 1H) 7.31 (s, 2H)
7.35 (d, 2H) 7.52 (d, 1H) 7.61-7.71 (m, 1H) 8.09 (d, 1H) 8.44 (d,
1H).
EXAMPLE 230
2-[(2-chlorophenyl)amino]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-
-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-ni-
trophenyl}sulfonyl)benzamide
[2578] The title compound was prepared by substituting EXAMPLE 226B
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.11 (br s, 1H),
8.53 (d, 1H), 7.02 (br s, 1H), 7.94 (dd, 1H), 7.81 (d, 1H), 7.46
(dd, 1H), 7.42 (dd, 1H), 7.36 (d, 2H), 7.18-7.25 (m, 1H), 7.14 (d,
1H), 7.07 (d, 2H), 6.85-6.92 (m, 1H), 6.52 (d, 1H), 6.33 (dd, 1H),
3.88 (br s, 1H), 3.01-3.09 (m, 7H), 2.66-2.83 (m, 6H), 2.07-2.32
(m, 8H), 1.97 (br s, 3H), 1.78 (br s, 2H), 1.41 (t, 2H), 0.94 (s,
6H).
EXAMPLE 231
tert-butyl
5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl-
)sulfonyl]amino}carbonyl)phenoxy]-1H-indole-1-carboxylate
EXAMPLE 231A
ethyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate
[2579] The title compound was prepared by substituting
5-hydroxyindole for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 231B
ethyl
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-enyl)methyl)piperazin-1-yl)benzoate
[2580] The title compound was prepared by substituting EXAMPLE 231A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 231C
2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-
)methyl)piperazin-1-yl)benzoic acid
[2581] The title compound was prepared by substituting EXAMPLE 231B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 231D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-
-indol-5-yloxy)benzamide
[2582] The title compound was prepared by substituting EXAMPLE 231C
for EXAMPLE 1F and EXAMPLE 11A for EXAMPLE 1G in EXAMPLE 1H, except
2-10% methanolin CH.sub.2C.sub.2 was used for the
chromatography.
EXAMPLE 231E
tert-butyl
5-[5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-({[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl-
)sulfonyl]amino}carbonyl)phenoxy]-1H-indole-1-carboxylate
bis(2,2,2-trifluoroacetate)
[2583] The title compound was prepared by substituting EXAMPLE 231D
for EXAMPLE 202D in EXAMPLE 202E. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.63 (v br s, 1H), 9.40 (v br
s, 2H), 8.61 (br t, 1H), 8.33 (d, 1H), 8.00 (d, 1H), 7.85 (dd, 1H),
7.70 (d, 1H), 7.54 (d, 1H), 7.40 (d, 2H), 7.10 (m, 4H), 6.97 (dd,
1H), 6.76 (dd, 1H), 6.43 (d, 1H), 6.33 (d, 1H), 3.60, 3.50, 3.30
(all v br m, total 10H), 3.10 (br m, 4H), 2.79 2.77 (both s, total
6H), 2.20 (br m, 2H), 2.04 (s, 2H), 1.85 (br m, 2H), 1.66 (s, 9 H),
1.45 (br t, 2H), 0.95 (s, 6H).
EXAMPLE 232
2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro--
2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
EXAMPLE 232A
tert-butyl
6-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl-
)piperazin-1-yl)-2-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yla-
mino)phenylsulfonylcarbamoyl)phenoxy)benzo[d]thiazol-2-ylcarbamate
[2584] The title compound was prepared by substituting EXAMPLE 229D
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G respectivelyin
EXAMPLE 1H.
EXAMPLE 232B
2-[(2-amino-1,3-benzothiazol-6-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro--
2H-pyran-4-ylpiperidin-4-yl)amino]-phenyl}sulfonyl)benzamide
[2585] The title compound was prepared by substituting EXAMPLE 232A
for EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 0.95 (s, 6H) 1.44 (br. s, 2H)
1.61-1.89 (m, 3H) 1.90-2.12 (m, 5H) 2.13-2.32 (m, 4H) 2.36-2.63 (m,
2H) 2.97 -3.78 (m, 16H) 4.01 (dd, 2H) 6.30 (s, 1H) 6.72 (d, 1H)
6.84 (d, 1H) 7.11 (m, 3H) 7.18-7.32 (m, 2H) 7.33-7.55 (m, 5H)
7.68-7.89 (m, 1H) 8.17 (d, 1H) 8.57 (d, 1H) 9.25 (br. s, 1H) 11.62
(br. s, 1H).
EXAMPLE 233
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1--
yl)propyl]amino}phenyl)sulfonyl]benzamide
[2586] The title compound was prepared by susbtituting EXAMPLE 154E
for EXAMPLE 122C and EXAMPLE 254A for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (br
s, 1H), 8.62 (br t, 1H), 8.57 (d, 1H), 7.83 (dd, 1H), 7.75 (s, 1H),
7.51 (d, 1H), 7.37 (dd, 1H), 7.34 (m, 3H), 7.26 (d, 1H), 7.08 (d,
1H), 7.04 (d, 2H), 6.63 (dd, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 3.43
(dd, 2H), 3.18 (br m, 2H), 3.04 (br m, 4H), 2.95 (s, 2H), 2.70 (s,
2H), 2.55 (t, 2H), 2.45 (t, 2H), 2.17 (br m, 6H), 1.95 (s, 2H),
1.79 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 234
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2587] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 122C and EXAMPLE 205A for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.54 (s, 1H), 8.17 (br d, 1H), 7.84 (d, 1H), 7.52 (d, 1H),
7.34 (m, 4H), 7.24 (br d, 1H), 7.11 (br d, 1H), 7.04 (d, 2H), 6.64
(d, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 3.62 (br m, 4H), 3.58 (v br s,
1H), 3.00 (br m, 4H), 2.73 (s, 2H), 2.65 (br m, 4H), 2.47 (v br s,
1H), 2.18 (br m, 6H), 2.06 (br m, 2H), 1.93 (br m, 4H), 1.40 (m,
6H), 0.92 (s, 6H).
EXAMPLE 235
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcy-
clohexyl)amino]-3nitrophenyl}sulfonyl)benzamide
[2588] The title compound was prepared by substituting EXAMPLE 200F
for EXAMPLE 122C and EXAMPLE 205A for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.72 (s,
1H), 8.46 (s, 1H), 8.15 (br d, 1H), 7.78 (d, 1H), 7.52 (d, 1H),
7.40 (dd, 1H), 7.34 (d, 2H), 7.06 (br d, 1H), 7.05 (d, 2H), 6.91
(br d, 1H), 6.66 (br d, 1H), 6.40 (s, 1H), 6.25 (d, 1H), 3.62 (br
m, 4H), 3.58 (v br s, 1H), 3.00 (br m, 4H), 2.73 (s, 2H), 2.65 (br
m, 4H), 2.47 (v br s, 1H), 2.18 (br m, 6H), 2.06 (br m, 2H), 1.93
(br m, 4H), 1.40 (m, 6H), 0.92 (s, 6H).
EXAMPLE 236
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 236A
tert-butyl 1-(cyclopropylmethyl)piperidin-4-ylcarbamate
[2589] The title compound was prepared by substituting
cyclopropanecarbaldehyde for 4'-chlorobiphenyl-2-carboxaldehyde and
tert-butyl piperidin-4-ylcarbamate for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 236B
1-(cyclopropylmethyl)piperidin-4-amine
bis(2,2,2-trifluoroacetate)
[2590] The title compound was prepared by substituting EXAMPLE 236A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 236C
4-(1-(cyclopropylmethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide
[2591] The title compound was prepared by substituting EXAMPLE 236B
for 4-(1-isopropylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide in
EXAMPLE 41A.
EXAMPLE 236D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2592] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 236C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 12.39 (s, 1H), 9.31
(d, 1H), 8.49 (d, 1H), 8.45 (dd, 1H), 8.15 (d, 1H), 7.47-7.52 (m,
3H), 7.41-7.45 (m, 3H), 7.04 (d, 2H), 6.98 (d, 1H), 6.71 (dd, 1H),
6.57 (dd, 2H), 3.48-3.55 (m, 1H), 3.01-3.07 (m, 4H), 2.86 (d, 2H),
2.74 (s, 2H), 2.21-2.26 (m, 2H), 2.19 (d, 4H), 2.07-2.13 (m, 4H),
1.93-2.00 (m, 4H), 1.63-1.71 (m, 2H), 1.38 (t, 2H), 0.93 (s, 6H),
0.84-0.91 (m, 1H), 0.45-0.49 (m, 2H), 0.11 (q, 2H).
EXAMPLE 237
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sul-
fonyl]-2-[(6,7-difluoro-1H-indol-5-yl)oxy]benzamide
[2593] The title compound was prepared by substituting EXAMPLE 200F
for EXAMPLE 1F and EXAMPLE 236C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 13.12 (s, 1H), 9.29
(d, 1H), 8.49 (d, 1H), 8.46 (dd, 1H), 8.11 (d, 1H), 7.42 (d, 2H),
7.19 (s, 1H), 7.04 (d, 2H), 6.98 (d, 1H), 6.75 (dd, 1H), 6.66 (d,
1H), 6.51-6.54 (m, 1H), 3.50-3.55 (m, 1H), 3.07-3.13 (m, 4H),
2.83-2.87 (m, 2H), 2.76 (s, 2H), 2.25 (t, 2H), 2.11-2.23 (s, 8H),
1.93-2.00 (m, 4H), 1.63-1.71 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H),
0.84-0.90 (m, 1H), 0.44-0.49 (m, 2H), 0.08-0.12 (m, 2H).
EXAMPLE 238
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran--
4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2594] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.23 (s, 1H), 8.63 (t, 1H),
8.60 (d, 1H), 7.87 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.30-7.34
(m, 4H), 7.17 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.41 (s, 1H),
6.09 (s, 1H), 3.85 (dd, 2H), 3.26 (t, 2H), 3.03 (s, 4H), 2.74 (s,
2H), 2.12-2.19 (m, 6H), 1.94 (s, 2H), 1.87-1.90 (m, 1H), 1.62 (d,
2H), 1.38 (t, 2H), 1.22-1.30 (m, 2H), 0.92 (s, 6H).
EXAMPLE 239
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazi-
n-1-yl)propyl]amino}phenyl)sulfonyl]benzamide
[2595] The title compound was prepared by substituting EXAMPLE 200F
for EXAMPLE 122C and EXAMPLE 254A for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.68 (br
s, 1H), 8.70 (v br s, 1H), 8.46 (s, 1H), 7.74 (s, 1H), 7.73 (br s,
1H), 7.52 (d, 1H), 7.37 (dd, 1H), 7.34 (d, 2H), 7.05 (d, 2H), 7.95
(v br s, 1H), 6.83 (v br s, 1H), 6.67 (dd, 1H), 6.39 (s, 1H), 6.25
(d, 1H), 3.44 (q, 2H), 3.18 (br m, 2H), 3.04 (br m, 4H), 2.97 (s,
2H), 2.73 (s, 2H), 2.57 (t, 2H), 2.47 (t, 2H), 2.18 (br m, 6H),
1.95 (s, 2H), 1.88 (m, 2H), 1.37 (t, 2H), 0.91 (s, 6H).
EXAMPLE 240
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-py-
ran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 240A
N-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-enyl)methyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzami-
de
[2596] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 122C and 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE
11A in EXAMPLE 137.
EXAMPLE 240B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-hydroxy-1-tetrahydro-2H-py-
ran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2597] EXAMPLE 240A (150 mg) was dissolved in dioxane (1.8 mL),
then 2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol (35 mg) and
triethylamine (0.078 mL) were added. The reaction was heated at
110.degree. C. for 20 hours. The reaction was concentrated and the
crude was purified by preparative HPLC using a C18 column,
250.times.50 mm, 10.mu., and eluting with a gradient of 20-100%
CH.sub.3CN vs. 0.1% trifluoroacetic acid in water, giving the
product as a trifluoroacetate salt. The salt was dissolved in
dichloromethane (6 mL) and washed with 50% aqueous NaHCO.sub.3. The
organic layer was dried over anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated to give the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.23 (s, 1H), 8.60 (d, 1H),
8.58 (d, 1H), 7.84 (dd, 1H), 7.52 (d, 1H), 7.39 (dd, 1H), 7.33 (m,
4H), 7.29 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.42 (s, 1H), 6.08
(s, 1H), 5.03 (t, 1H), 3.85 (m, 2H), 3.74 (m, 1H), 3.63 (m, 1H),
3.57 (m, 1H), 3.26 (dd, 2H), 3.02 (br m, 4H), 2.73 (s, 2H), 2.18
(br m, 6H), 1.95 (s, 2H), 1.94 (m, 1H), 1.61 (br m, 2H), 1.38 (m,
3H), 1.30 (m, 1H), 0.92 (s, 6H).
EXAMPLE 241
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydro-
-2H-pyran-4-yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide
EXAMPLE 241A
4-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenes-
ulfonamide
[2598] The title compound was prepared by substituting
(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 241B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-({[4-(hydroxymethyl)tetrahydro-
-2H-pyran-4-yl]methyl}amino-3-nitrophenyl]sulfonyl}benzamide
[2599] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 241A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.22 (s,
2H), 9.10 (t, 1H), 8.59 (d, 1H), 7.87 (dd, 1H), 7.51 (d, 1H),
7.30-7.39 (m, 5H), 7.24 (d, 1H), 7.02-7.05 (m, 2H), 6.68 (dd, 1H),
6.41 (s, 1H), 6.08 (s, 1H), 5.22 (t, 1H), 3.51-3.62 (m, 6H), 3.41
(d, 2H), 3.03 (s, 4H), 2.73 (s, 2H), 2.09-2.18 (m, 6H), 1.95 (s,
2H), 1.45-1.51 (m, 4H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 242
2-[(6-chloro-1H-indol-5-yl)oxy]4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 242A
ethyl 2-(4-amino-2-chlorophenoxy)-4-fluorobenzoate
[2600] To a solution of ethyl 2,4-difluorobenzoate (6.48 g) and
4-amino-2-chlorophenol (5.0 g) in diglyme (40 mL) was added
K.sub.3PO.sub.4 (7.39 g). The mixture was stirred at 110.degree. C.
overnight. The mixture was diluted with ethyl acetate (300 mL) and
washed with water, brine and dried over Na.sub.2SO.sub.4. The
mixture was filtered, and the solvent was evaporated and the
residue was loaded on a column and eluted with 10% ethyl acetate in
hexane to give the product.
EXAMPLE 242B
ethyl 2-(4-amino-2-chloro-5-iodophenoxy)-4-fluorobenzoate
[2601] To a solution of EXAMPLE 242A (8.15 g) is dichloromethane
(60 mL) was added bis(pyridine)iodonium tetrafluoroborate (9.79 g).
The mixture was stirred at room temperature for 4 hours. The
mixture was diluted with ethyl acetate (200 mL) and washed with
aqueous Na.sub.2S.sub.2O.sub.3, water, brine and dried over
Na.sub.2SO.sub.4. The mixture was filtered, and the solvent was
evaporated and the residue was loaded on a column and eluted with
10% ethyl acetate in hexane to give the pure product.
EXAMPLE 242C
ethyl
2-(4-amino-2-chloro-5-((trimethylsilyl)ethynyl)phenoxy)-4-fluorobenz-
oate
[2602] To a mixture of EXAMPLE 242B (3.0 g),
bis(triphenylphosphine)palladium(II) dichloride (242 mg), CuI (66
mg) in triethylamine (30 mL) was added trimethylsilylacetylene (2.2
g). The mixture was stirred at room temperature overnight. The
mixture was diluted with ethyl acetate (200 mL) and washed with
aqueous NH.sub.4Cl, water, brine and dried over Na.sub.2SO.sub.4.
The mixture was filtered, and the solvent was evaporated and the
residue was loaded on a column and eluted with 10% ethyl acetate in
hexane to give the pure product.
EXAMPLE 242D
ethyl 2-(4-amino-2-chloro-5-ethynylphenoxy)-4-fluorobenzoate
[2603] To a solution of EXAMPLE 242C (2.69 g) in methanol (20 mL)
was added CsF (5 g). The mixture was stirred at room temperature
overnight. The solvent was evaporated and the residue was dissolved
in ethyl acetate (200 mL) and washed with water, brine and dried
over Na.sub.2SO.sub.4. The mixture was filtered, and the solvent
was evaporated.
EXAMPLE 242E
ethyl 2-(6-chloro-1H-indol-5-yloxy)-4-fluorobenzoate
[2604] To a solution of EXAMPLE 242D (1.0 g) in ethanol (20 mL) was
added NaAuCl.sub.4 2H.sub.2O (60 mg). The mixture was stirred at
room temperature for 4 hours. The mixture was diluted with ethyl
acetate (200 mL) and washed with water, brine and dried over
Na.sub.2SO.sub.4. The mixture was filtered, and the solvent was
evaporated and the residue was loaded on a column and eluted with
10% ethyl acetate in hexane to give the pure product.
EXAMPLE 242F
ethyl 2-(6-chloro-1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate
[2605] The title compound was prepared as described in EXAMPLE 3G
by replacing EXAMPLE 3F and EXAMPLE 3A with piperazine and EXAMPLE
242E respectively.
EXAMPLE 242G
ethyl
2-(6-chloro-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2606] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38F and EXAMPLE 38E with EXAMPLE 242F and
EXAMPLE 60D.
EXAMPLE 242H
2-(6-chloro-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2607] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 242G.
EXAMPLE 242I
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyra-
n-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2608] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and
EXAMPLE 49C, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.20 (s, 1H), 8.52 (m, 1H),
8.18 (d, 1H), 7.83 (dd, 1H), 7.53 (m, 2H), 7.40 (m, 1H), 7.33 (d,
3H), 7.18 (m, 1H), 7.04 (m, 4H), 6.62 (m, 1H), 6.38 (s, 1H), 6.01
(d, 1H), 3.92 (m, 2H), 3.77 (m, 1H), 3.13 (m, 8H), 2.71 (s, 2H),
2.24 (m, 8H), 1.95 (m, 6H), 1.52 (m, 6H), 0.94 (s, 6H).
EXAMPLE 243
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6,7-difluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-py-
ran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2609] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F with EXAMPLE 200F. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.75 (s, 1H), 8.59 (t, 1H),
8.53 (d, 1H), 7.82 (dd, 1H), 7.49 (d, 1H), 7.41 (m, 1H), 7.34 (d,
3H), 7.12 (d, 1H), 7.04 (d, 2H), 6.98 (d, 1H), 6.69 (dd, 1H), 6.43
(d, 1H), 6.24 (d, 1H), 3.85 (m, 2H), 3.07 (m, 5H), 2.74 (m, 2H),
2.23 (m, 6H), 1.92 (m, 5H), 1.60 (m, 3H), 1.30 (m, 4H), 0.94 (s,
6H).
EXAMPLE 244
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
[2610] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and
EXAMPLE 184A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.24 (s, 1H), 9.19 (s, 1H),
8.52 (d, 1H), 7.88 (dd, 1H), 7.56 (m, 3H), 7.42 (t, 1H), 7.31 (m,
3H), 7.03 (d, 2H), 6.63 (dd, 1H), 6.41 (s, 1H), 5.98 (d, 1H), 2.94
(m, 10H), 2.70 (s, 3H), 2.37 (m, 3H), 2.14 (m, 6H), 1.94 (s, 2H),
1.37 (t, 2H), 0.91 (s, 6H).
EXAMPLE 245
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylm-
ethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide
EXAMPLE 245A
tert-butyl 1-(thiazol-4-ylmethyl)piperidin-4-ylcarbamate
[2611] The title compound was prepared by substituting
thiazole-4-carbaldehyde 4'-chlorobiphenyl-2-carbaldehyde and
tert-butylpiperidin-4-ylcarbamate for tert-butyl
piperazine-1-carboxylate in EXAMPLE 1A
EXAMPLE 245B
[2612] The title compound was prepared by substituting EXAMPLE 245A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 245C
3-nitro-4-1-(thiazol-4-ylmethyl)piperidin-4-ylamino)benzenesulfonamide
[2613] The title compound was prepared by substituting EXAMPLE 243B
for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 245D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylm-
ethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide
[2614] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 245C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (s,
1H), 9.08 (s, 1H), 8.20 (s, 1H), 7.91 (s, 1H), 7.82 (d, 1H),
7.29-7.34 (m, 4H), 7.18 (d, 1H), 7.15 (m, 1H), 7.04 (d, 2H), 6.60
(dd, 1H), 6.37 (s, 1H), 6.08 (s, 1H), 4.28 (s, 2H), 2.90-2.98 (m,
8H), 2.72 (s, 2H), 2.14-2.17 (m, 6H), 2.01 (m, 2H), 1.95 (s, 2H),
1.53-1.55 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 246
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)a-
mino]phenyl}sulfonyl)benzamide
[2615] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.60 (t, 1H), 8.42 (d, 1H), 7.71
(dd, 1H), 7.51 (d, 1H), 7.36 (d, 2H), 7.19 (t, 1H), 7.10 (d, 1H),
7.07 (d, 2H), 6.93 (dd, 1H), 6.79 (dd, 1H), 6.72 (dd, 1H), 6.69 (t,
1H), 6.47 (d, 1H), 3.87 (dd, 2H), 3.21-3.32 (m, 4H), 3.20 (s, 4H),
2.81 (s, 2H), 2.27 (s, 4H), 2.16 (br s, 2H), 1.90-1.98 (m, 3H),
1.63-1.66 (m, 2H), 1.41 (t, 2H), 1.27-1.30 (m, 2H), 0.94 (s,
6H).
EXAMPLE 247
2-(4-amino-3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
[2616] The title compound was prepared by substituting EXAMPLE 40C
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.12 (s, 1H), 8.50 (d, 2H),
7.84 (dd, 1H), 7.58 (d, 1H), 7.32-7.34 (m, 2H), 7.28 (d, 1H), 7.15
(d, 1H), 7.10 (d, 1H), 7.04 (d, 2H), 6.58 (dd, 1H), 6.34 (s, 1H),
6.07 (d, 1H), 3.63-3.70 (m, 6H), 2.96 (s, 4H), 2.71 (s, 2H),
2.12-2.16 (m, 6H), 1.95 (s, 2H), 1.72-1.76 (m, 2H), 1.55-1.60 (m,
2H), 1.38 (t, 2H), 0.94 (s, 6H).
EXAMPLE 248
N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfo-
nyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2617] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 191A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.12 (s,
1H), 8.50 (d, 1H), 7.84 (dd, 1H), 7.32-7.34 (m, 3H), 7.28 (d, 1H),
7.15 (d, 1H), 7.11 (d, 1H), 7.04 (d, 2H), 6.58 (dd, 1H), 6.34 (s,
1H), 6.07 (d, 1H), 3.85-3.89 (m, 4H), 3.61-3.63 (m, 2H), 3.66-3.69
(m, 4H), 3.48-3.51 (m, 2H), 2.96 (s, 4H), 2.71 (s, 2H), 2.14-2.18
(m, 6H), 1.95 (s, 2H), 1.72-1.76 (m, 2H), 1.57-1.70 (m, 2H), 1.38
(t, 2H), 0.92 (s, 6H).
EXAMPLE 249
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3S,4R)-3-hydroxy-1-(1,3-thi-
azol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 249A
[2618] A mixture of tert-butyl
(3S,4R)-1-benzyl-3-hydroxypiperidin-4-ylcarbamate (0.42 g) and
palladium hydroxide on carbon (0.095 g) in ethanol (15 mL) was
hydrogenated with a balloon of H.sub.2. The reaction mixture was
stirred for 16 hours. The solid was filtered off, and the filtrate
was concentrated to give the title compound.
EXAMPLE 249B
tert-butyl
(3R,4S)-3-hydroxy-1-(thiazol-4-ylmethyl)piperidin-4-ylcarbamate
[2619] The title compound was prepared by substituting
thiazole-4-carhaldehyde for 4-chlorobiphenyl-2-carbaldehyde and
EXAMPLE 249A for tert-butylpiperazine-1-carboxylate in EXAMPLE
1A.
EXAMPLE 249C
(3R,4S)-4-amino-1-(thiazol-4-ylmethyl)piperidin-3-ol
[2620] The title compound was prepared by substituting EXAMPLE 249B
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 249D
4-((3R,4S)-3-hydroxy-1-(thiazol-4-ylmethyl)piperidin-4-ymamino)-3-nitroben-
zenesulfonamide
[2621] The title compound was prepared by substituting EXAMPLE 249C
for (tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 249E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(3R,4S)-3-hydroxy-1-(1,3-thi-
azol-4-ylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2622] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 249D for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.64 (t, 1H), 9.07-9.09 (m, 1H), 8.60 (s, 1H), 8.57 (s, 1H),
7.82 (d, 1H), 7.80 (s, 1H), 7.51 (d, 2H), 7.19-7.32 (m, 6H), 7.04
(d, 2H), 6.62-6.64 (m, 2H), 6.39 (s, 1H), 6.08 (s, 1H), 3.82 (m,
2H), 3.01 (s, 4H), 2.77 (s, 2H), 2.12-2.16 (m, 6H), 1.81 (m, 2H),
1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 250
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4--
yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
EXAMPLE 250A
4-((4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenes-
ulfonamide
[2623] The title compound was prepared by substituting
(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol for
(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 250B
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4--
yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide
[2624] The title compound was prepared by substituting EXAMPLE 34C
for EXAMPLE 1F and EXAMPLE 250A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.11 (s,
1H), 8.44 (d, 1H), 7.72 (dd, 1H), 7.50 (d, 1H), 7.36 (d, 2H),
7.17-7.20 (m, 2H), 7.07 (d, 2H), 6.95 (dd, 2H), 6.78 (dd, 1H), 6.72
(dd, 1H), 6.69 (t, 1H), 6.48 (d, 1H), 5.24 (t, 1H), 3.54-3.65 (m,
6H), 3.42 (d, 2H), 3.21 (s, 4H), 2.84 (s, 2H), 2.26-2.34 (m, 4H),
2.17-2.19 (m, 2H), 1.48-1.55 (m, 4H), 0.95 (s, 6H).
EXAMPLE 251
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-
-ylamino)phenyl]sulfonyl}benzamide
[2625] The title compound was prepared by substituting tetrahydro
2H-pyran-4-amine for 2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol
EXAMPLE 240B. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.21 (s, 1H), 8.58 (d, 1H), 8.24 (d, 1H), 7.84 (dd, 1H),
7.52 (d, 1H), 7.38 (dd, 1H), 7.33 (m, 3H), 7.29 (d, 1H), 7.23 (d,
1H), 7.03 (d, 2H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.08 (s, 1H), 3.90
(m, 3H), 3.47 (m, 2H), 3.03 (br m, 4H), 2.73 (s, 2H), 2.19 (br m,
6H), 1.95 (s, 2H), 1.91 (br m, 2H), 1.60 (m, 2H), 1.38 (t, 2H),
0.92 (s, 6H).
EXAMPLE 252
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitrop-
henyl]sulfonyl}benzamide
EXAMPLE 252A
4-(morpholinoamino)-3-nitrobenzenesulfonamide
[2626] The title compound was prepared by substituting
morpholin-4-amine for
4-(1-isopropylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide in
EXAMPLE 41A.
EXAMPLE 252B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[4-(morpholin-4-ylamino)-3-nitrop-
henyl]sulfonyl}benzamide
[2627] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 252A for EXAMPLE 1G is EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 12.38 (s, 1H),
9.26-9.30 (m, 2H), 8.48 (dd, 1H), 8.14 (d, 1H), 7.71 (d, 1H), 7.51
(t, 1H), 7.46-7.50 (m, 2H), 7.41-7.45 (m, 3H), 7.04 (d, 2H), 6.71
(dd, 1H), 6.54-6.58 (m, 2H), 3.86 (s, 2H), 3.71 (s, 2H), 3.01-3.07
(m, 4H), 2.89 (d, 4H), 2.74 (s, 2H), 2.23 (t, 2H), 2.07-2.13 (m,
4H), 1.96 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 253
2-(3-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfon-
yl}benzamide
[2628] The title compound was prepared by substituting EXAMPLE 36C
for EXAMPLE 1F and EXAMPLE 252A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 9.26 (s, 1H), 9.13
(d, 1H), 8.31 (dd, 1H), 8.09 (d, 1H), 7.67 (d, 1H), 7.46 (d, 2H),
7.10-7.16 (m, 3H), 7.08 (t, 1H), 7.02 (d, 1H), 6.93 (dd, 1H), 6.82
(dd, 1H), 6.69 (d, 1H), 3.88 (s, 2H), 3.77 (s, 2H), 3.27 (s, 2H),
3.13-3.19 (m, 4H), 2.93 (s, 4H), 2.84 (s, 2H), 2.31 (t, 2H),
2.23-2.28 (m, 4H), 2.00 (s, 2H), 1.42 (t, 2H), 0.97 (s, 6H).
EXAMPLE 254
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]am-
ino}phenyl)sulfonyl]benzamide
EXAMPLE 254A
3-Nitro-4-[3-(3-oxo-piperazin-1-yl)-propylamino]-benzenesulfonamide
[2629] The title compound was prepared by substituting
4-(3-aminopropyl)-piperazine-2-one for tert-butyl
4-aminopiperidine-1-carboxylate in EXAMPLE 140A.
EXAMPLE 254B
2-(2-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1--
yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]am-
ino}phenyl)sulfonyl]benzamide
[2630] The title compound was prepared by susbtituting EXAMPLE 5B
for EXAMPLE 1F and EXAMPLE 254A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.85 (t,
1H), 8.47 (d, 1H), 7.80-7.72 (m, 2H), 7.51 (d, 1H), 7.41 (dd, 1H),
7.36 (d, 2H), 7.18-7.03 (m, 4H), 7.00 (td, 1H), 6.75 (dd, 1H), 6.71
(d, 1H), 6.30 (d, 1H), 3.46 (q, 2H), 3.22-3.11 (m, 6H), 2.97 (s,
2H), 2.79 (br s, 2H), 2.59 (t, 2H), 2.47 (t, 2H), 2.31-2.12 (m,
6H), 1.97 (br s, 2H), 1.82 (m, 2H), 1.46 9t, 2H), 0.94 (s, 6H).
EXAMPLE 255
2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
n-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpi-
peridin-4-yl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 255A
methyl 2-(6-aminopyridin-3-yloxy)-4-fluorobenzoate
[2631] A mixture of
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine
(1.039 g), CsF (1.956 g),
bis(triphenylphosphine)palladium(II)dichloride (0.301 g), and
methyl 2-bromo-4-fluorobenzoate (1.0 g) in 50 mL
dimethoxyethane-methanol (1:1) was heated at 80.degree. C. for 2.5
hours. The reaction mixture was partitioned between water and ethyl
acetate. The organic phase was washed with brine, dried over
MgSO.sub.4, filtered, ad concentrated. The residue was
chromatographed on silica gel with 25-80% ethyl acetate in
hexanes.
EXAMPLE 255B
methyl
2-(6-aminopyridin-3-yloxy)-4-(4-((2-(4-chlorphenyl)-4,4-dimethylcyc-
lohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2632] The title compound was prepared by substituting EXAMPLE 255A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 255C
methyl
2-(6-butyoxycarbonylamino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl-
)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2633] The title compound was prepared by substituting EXAMPLE 255B
for EXAMPLE 219B in EXAMPLE 219C.
EXAMPLE 255D
2-(6-(tert-butoxycarbonylamino)pyridin-3-yloxy))-4-(4-((2-(4-chlorophenyl)-
-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2634] The title compound was prepared by substituting EXAMPLE 255C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 255E
tert-butyl
5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl-
)piperazin-1-yl)-2-(3-nitro-4(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylam-
ino)phenylsulfonylcarbamoyl)phenoxy)pyridin-2-ylcarbamate
[2635] The title compound was prepared by substituting EXAMPLE 255D
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G respectivelyln
EXAMPLE 1H.
EXAMPLE 255F
2-(6-aminopyridin-3-yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
n-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpi-
peridin-4-yl)amino]phenyl}sulfonyl)benzamide
[2636] The title compound was prepared by substituting EXAMPLE 255E
for EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 0.96 (s, 6H) 1.42 (t, 2H)
1.61-1.75 (m, 2H) 1.92-2.05 (m, 6H) 2.21 (s, 5H) 2.28-2.42 (m, 3H)
2.80-3.57 (m, 14H) 3.95-4.00 (m, 2H) 6.31 (d, 1H) 6.68 (d, 1H) 6.82
(dd, 1H) 7.08 (d, 2H) 7.15 (s, 1H) 7.28-7.41 (m, 4H) 7.68 (d, 1H)
7.85 (dd, 1H) 8.22 (s, 1H) 8.50 (d, 1H).
EXAMPLE 256
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 256A
methyl
4-(4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piper-
azin-1-yl)-2-(6-fluoro-1H-indol-5-yloxyl)benzoate
[2637] The title compound was prepared as described EXAMPLE 110D by
replacing EXAMPLE 34A with EXAMPLE 154B.
EXAMPLE 256B
4-(4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piperazin-1--
yl)-2-(6-fluoro-1H-indol-5-yloxyl)benzoic acid
[2638] The title compound was prepared as described in EXAMPLE 110E
by replacing EXAMPLE 110D with EXAMPLE 256A.
EXAMPLE 256C
4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-
-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2639] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E with EXAMPLE 256B. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.29 (s, 1H), 11.22 (s, 1H),
8.60 (s, 1H), 8.57 (s, 1H), 7.86 (d, 1H), 7.52 (d, 1H), 7.27-7.40
(m, 5H), 7.15 (d, 1H), 7.02 (d, 2H), 6.60-6.68 (m, 1H), 6.40 (s,
1H), 6.08 (d, 1H), 3.84 (dd, 2H), 3.20-3.32 (m, 4H), 3.01 (s, 4H),
2.59-2.72 (m, 1H), 2.16-2.31 (m, 4H), 1.75-2.12 (m, 5H), 1.58-1.65
(m, 2H), 1.31-1.41 (m, 2H), 1.20-1.29 (m, 2H), 1.01 (d, 3H), 0.91
(s, 3H), 0.90 (s, 3H).
EXAMPLE 257
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-[(3-nitro-4-{[3-(3-oxopiperazin-1--
yl)propyl]amino}phenyl)sulfonyl]benzamide
[2640] The title compound was prepared by substituting EXAMPLE 209G
for EXAMPLE 1F and EXAMPLE 254A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.23 (br
s, 1H), 8.75 (t, 1H), 8.43 (d, 1H), 7.74 (br s, 1H), 7.61 (dd, 1H),
7.51 (d, 1H), 7.35(d, 2H), 7.24 (t, 1H), 7.05 (d, 2H), 6.95 (d,
1H), 6.85 (dd, 1H), 6.76 (dd, 1H), 6.42 (d, 1H), 6.26 (t, 1H), 6.06
(dd, 1H), 3.43 (q, 2H), 3.20-3.08 (m, 6H), 2.97 (br s, 2H), 2.76
(br s, 2H), 2.57 9t, 2H), 2.47 (t, 2H), 2.27-2.12 (m, 6H), 1.97 (br
s, 2H), 1.80 (m, 2H), 1.40 (t, 2H), 0.93 (s, 6H).
EXAMPLE 258
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-p-
yran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide
EXAMPLE 258A
[2641] The title compound was prepared by substituting
(tetrahydro-2H-pyran-3-yl)methanamine for
1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 258B
(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide
[2642] The racemic mixture of EXAMPLE 258A was resolved by chiral
SFC on an AD column (21 mm i.d..times.250 mm in length) using a
gradient of 10-30% 0.1% diethylamine methanol in CO.sub.2 over 15
minutes (oven temperature: 40.degree. C.; flow rate: 40 mL/minute)
to provide the title compound.
EXAMPLE 258C
(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylzmino)benzenesulfonamide
[2643] The racemic mixture of EXAMPLE 258A was resolved by chiral
SFC on an AD column (21 mm i.d..times.250 mm in length) using a
gradient of 10-30% 0.1% diethylamine methanol in CO.sub.2 over 15
minutes (oven temperature: 40.degree. C.; flow rate: 40 mL/minute)
to provide the title compound.
EXAMPLE 258D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-p-
yran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide
[2644] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and
EXAMPLE 258B, respectively. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.22 (s, 2H), 8.50-8.65 (m,
2H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.28-7.35 (m, 4H),
7.13 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.41 (s, 1H), 6.09 (d,
1H), 3.79 (dd, 1H), 3.68-3.74 (m, 1H), 3.14-3.32 (m, 4H), 3.03 (s,
4H), 2.73 (s, 2H), 2.08-2.25 (m, 6H), 1.78-1.97 (m, 4H), 1.55-1.66
(m, 1H), 1.41-1.52 (m, 1H), 1.23-1.40 (m, 3H), 0.92 (s, 6H).
EXAMPLE 259
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-p-
yran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide
[2645] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and
EXAMPLE 258C, respectively. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.22 (s, 2H), 8.50-8.65 (m,
2H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.28-7.35 (m, 4H),
7.13 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.41 (s, 1H), 6.09 (d,
1H), 3.79 (dd, 1H), 3.68-3.74 (m, 1H), 3.14-3.32 (m, 4H), 3.03 (s,
4H), 2.73 (s, 2H), 2.08-2.25 (m, 6H), 1.78-1.97 (m, 4H), 1.55-1.66
(m, 1H), 1.41-1.52 (m, 1H), 1.23-1.40 (m, 3H), 0.92 (s, 6H).
EXAMPLE 260
tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)amino]carbonyl}phenoxy)-3,4-dihydro
isoquinoline-2(1H)-carboxylate
EXAMPLE 260A
tert-butyl 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate
[2646] A mixture of 1,2,3,4-tetrahydroisoquinolin-5-ol,
hydrochloric acid (1.0 g), di-tert-butyl dicarbonate (1.27 g) and
1.0 N aqueous NaOH (14.5 mL) in dioxane (20 mL) was stirred at room
temperature for 16 hours. The reaction mixture was partitioned
between water and ethyl acetate. The aqueous layer was neutralized
with 5% aqueous HCl. The combined organic layers were washed with
brine, dried (MgSO.sub.4), filtered, and concentrated. The residue
was purified by flash chromatography on silica gel to give the
title compound.
EXAMPLE 260B
tert-butyl
5-(2-(ethoxycarbonyl)-5-fluorophenoxy)-3,4-(dihydroisoquinoline-
-2(1H)-carboxylate
[2647] The title compound was prepared by ssubstituting EXAMPLE
260A for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 260C
tert-butyl
5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl-
)piperazin-1-yl)-2-(ethoxycarbonyl)phenoxy)-3,4-dihydroisoquinolin-2(1H)-c-
arboxylate
[2648] The title compound was prepared by substituting EXAMPLE 260B
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 260D
2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-4-(4-((2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoi-
c acid
[2649] The title compound was prepared by substituting EXAMPLE 260C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 260E
2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-4-(4-((2-
-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoi-
c 3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonic
anhydride
[2650] The title compound was prepared by substituting EXAMPLE 260D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.63 (s, 1H), 8.45 (s, 1H), 7.70
(d, 1H), 7.50 (d, 1H), 7.35 (d, 1H), 7.15 (d, 1H), 7.06 (d, 2H),
6.97 (t, 1H), 6.80 (d, 1H), 6.73 (dd, 1H), 6.37 (d, 1H), 6.31 (d,
1H), 4.48 (s, 2H), 3.86 (dd, 2H), 3.53 (t, 2H), 3.14 (s, 4H),
2.67-2.75 (m, 2H), 2.16-2.30 (m, 6H), 1.63 (d, 2H), 1.43 (s, 9H),
0.94 (s, 6H).
EXAMPLE 261
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 261A
4-Fluoro-2-(6-nitro-pyridin-3-yloxy)-benzoic acid methyl ester
[2651] Methyl 4-fluoro-2-hydroxybenzoate (3.00 g), 5-chloro
2-nitropyridine (3.08 g), and potassium carbonate (4.87 g) were
added to dimethylsulfoxide (50 mL), heated to 110.degree. C. for
one hour, cooled, added to water, and extracted with ethyl ether.
The ether was washed with brine and dried on anhydrous sodium
sulfate. The solution was filtered and concentrated and purified by
flash column chromatography on silica gel using 10% ethyl acetate
in hexanes increasing to 20% ethyl acetate in hexanes and
increasing again to 30% ethyl acetate in hexanes.
EXAMPLE 261B
2-(6-Amino-pyridin-3-yloxy)-4-fluoro-benzoic acid methyl ester
[2652] EXAMPLE 261A (1015 mg), cyclohexene (3.52 mL, 2853 mg), and
10% palladium on carbon (100 mg) were added to ethanol (12 mL)and
ethyl acetate (4 mL) and heated at 75.degree. C. for three hours.
The solution was cooled and vacuum filtered over diatomaceous
earth. The solvent was removed under vacuum.
EXAMPLE 261C
2-(6-Amino-pyridin-3-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohe-
x-1-enylmethyl]-piperazin-1-yl}-benzoic acid methyl ester
[2653] The title compound was prepared by substituting EXAMPLE 261B
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 261D
2-(6-Amino-pyridin-3-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohe-
x-1-enylmethyl]-piperazin-1-yl}-benzoic acid
[2654] The title compound was prepared by substituting EXAMPLE 261C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 261E
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2655] The title compound was prepared by substituting EXAMPLE 261D
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.53 (br
s, 1H), 8.19 (br s, 1H), 7.85 (dd, 1H), 7.66 (br s, 1H), 7.47 (d,
1H), 7.36 (d, 2H), 7.25-7.14 (m, 1H), 7.10 (m, 1H), 7.07 (d, 2H),
6.58 (dd, 1H), 6.43 (d, 1H), 6.10 (br s, 1H), 5.81 (m, 2H), 3.94
(d, 2H), 3.03 (br s, 6H), 2.73 (m, 2H), 2.24-2.12 (m, 8H),
2.09-2.00 (m, 2H), 1.97 (br s, 2H), 2.09-2.00 (m, 2H), 1.84-1.74
(m, 2H), 1.70-1.60 (m, 2H), 1.58-1.47 (m, 4H), 1.40 (t, 2H), 0.94
(s, 6H).
EXAMPLE 262
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran--
4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 262A
methyl
5,5-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylat-
e
[2656] The title compound was prepared by substituting
4,4-dimethyl-2-methoxycarbonylcyclohexanone for
5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 3B.
EXAMPLE 262B
methyl 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate
[2657] The title compound was prepared by substituting EXAMPLE 262A
for EXAMPLE 3B in EXAMPLE 3C.
EXAMPLE 262C
(2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methanol
[2658] The title compound was prepared by substituting EXAMPLE 262B
for EXAMPLE 3C in EXAMPLE 3D.
EXAMPLE 262D
2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde
[2659] The title compound was prepared as described in EXAMPLE 53F
by replacing EXAMPLE 53E with EXAMPLE 262C.
EXAMPLE 262E
tert-butyl
4-((2-(4-chlorphenyl)-5,5-dimethylcyclohex-1-enyl)methyl)pipera-
zine-1-carboxylate
[2660] The title compound was prepared as described in EXAMPLE 1A
by replacing 4'-chlorobiphenyl-2-carboxaldehyde with EXAMPLE
262D.
EXAMPLE 262F
1-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazine
[2661] The title compound was prepared as described in EXAMPLE 110C
by replacing EXAMPLE 110B with EXAMPLE 262E.
EXAMPLE 262G
methyl
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl0methyl)pipera-
zin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoate
[2662] The title compound was prepared as described in EXAMPLE 110D
by replacing EXAMPLE 34A and EXAMPLE 110C with EXAMPLE 154B and
EXAMPLE 262F, respectively.
EXAMPLE 262H
4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(6-fluoro-1H-indol-5-yloxy)benzoic acid
[2663] The title compound was prepared as described in EXAMPLE 110E
by replacing EXAMPLE 110D with EXAMPLE 262G.
EXAMPLE 262I
4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran--
4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2664] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E with EXAMPLE 262H. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.27 (s, 1H), 11.22 (s, 1H),
8.61 (t, 1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.38 (t,
1H), 7.31-7.36 (m, 3H), 7.30 (d, 1H), 7.16 (d, 1H), 7.07 (d, 2H),
6.65 (dd, 1H), 6.41 (s, 1H), 6.08 (d, 1H), 3.84 (dd, 2H), 3.22-3.32
(m, 4H), 3.02 (s, 4H), 2.68 (s, 2H), 2.17 (s, 6H), 1.84 -1.96 (m,
3H), 1.57-1.65 (m, 2H), 1.39 (t, 2H), 1.20-1.31 (m, 2H), 0.92 (s,
6H).
EXAMPLE 263
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
EXAMPLE 263A
4-(2-methoxyethylamino)-3-nitrobenzenesulfonamide
[2665] The title compound was prepared by substituting
2-methoxyethanamine for 3-(N-morpholinyl)-1-propylamine in EXAMPLE
4A.
EXAMPLE 263B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
[2666] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 263A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (4600 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.28 (s,
1H), 11.21 (s, 1H), 8.58 (m, 2H), 7.87 (dd, 1H), 7.50 (d, 1H), 7.32
(m, 5H), 7.15 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.40 (m, 1H),
6.10 (m, 1H), 3.58 (m, 4H), 3.30 (s, 3H), 3.04 (m, 4H), 2.73 (s,
2H), 2.17 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 264
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-
-ylmethyloxy)phenyl]sulfonyl}benzamide
EXAMPLE 264A
3-nitro-4((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
[2667] Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran
(20 mL) was treated with 60% NaH (1.377 g). The solution was
stirred for 20 minutes at room temperature. To this solution was
added 4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-wise. The
reaction was stirred for another 2 hours. The mixture was poured
into water, neutralized with 10% HCl, and extracted with ethyl
acetate three times. The combined organic layers were washed with
brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified with flash column chromatography on silica gel
eluting with 20%-60% ethyl acetate in hexanes.
EXAMPLE 264B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-
-ylmethyloxy)phenyl]sulfonyl}benzamide
[2668] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 264A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.12 (s,
1H), 8.10 (d, 1H), 7.52 (d, 1H), 7.45 (d, 1H), 7.38 (d, 1H),
7.33-7.35 (m, 3H), 7.28 (d, 1H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.41
(s, 1H), 6.10 (s, 1H), 4.09 (d, 2H), 3.88 (dd, 2H), 3.05 (s, 4H),
2.80 (br s, 2H), 2.03-2.20 (m, 6H), 1.63-1.65 (m, 2H), 1.33-1.40
(m, 4H), 0.92 (s, 6H).
EXAMPLE 265
2-[(3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran--
4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 265A
ethyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate
[2669] The title compound was prepared by substituting 5-indolol
for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 265B
ethyl 2-(3-chloro-1H-indol-5-yloxy)-4-fluorobenzoate
[2670] V-Chloro-succinimide (160 mg) was added portionwise to a
solution of EXAMPLE 265A (300 mg) in toluene (10 mL) and the
mixture was stirred at room temperature for about two hours. The
mixture was chromatographed on a silica gel column with 30% ethyl
acetate in hexane to give the title compound.
EXAMPLE 265C
ethyl
2-(3-chloro-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2671] The title compound was prepared by substituting EXAMPLE 265B
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 265D
2-(3-chloro-1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2672] The title compound was prepared by substituting EXAMPLE 265C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 265E
2-(3-chloro-1H-indol-5-yloxy-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-ylmet-
hyl)amino)phenylsulfonyl)benzamide
[2673] The title compound was prepared by substituting EXAMPLE 265D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.42 (s, 1H), 11.30 (br s, 1H),
8.60 (t, 1H), 8.54 (d, 1H), 7.78 (dd, 1H), 7.55 (d, 1H), 7.50 (d,
1H), 7.42 (d, 1H), 7.34 (d, 2H), 7.09 (d, 1H), 7.04 (d, 2H), 7.00
(d, 1H), 6.92 (dd, 1H), 6.68 (dd, 1H), 6.16 (d, 1H), 3.85 (dd, 2H),
3.28 (dd, 2H), 3.07 (m, 4H), 2.75 (m, 2H), 2.25-2.15 (m, 6H), 1.95
(br. s, 2H), 1.90 (m, 1H), 1.61 (dd, 2H), 1.38 (t, 2H), 1.27 (m,
2H), 0.92 (s, 6H).
EXAMPLE 266
2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran--
4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 266A
ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate
[2674] The title compound was prepared by substituting 4-indolol
for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 266B
ethyl 2-(3-chloro-1H-indol-4-yloxy)-4-fluorobenzoate
[2675] The title compound was prepared by substituting EXAMPLE 266A
for EXAMPLE 265A in EXAMPLE 265B.
EXAMPLE 266C
ethyl
2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2676] The title compound was prepared by substituting EXAMPLE 266B
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 266D
2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2677] The title compound was prepared by substituting EXAMPLE 266C
for EXAMPLE 1E in EXAMPLE 1P.
EXAMPLE 266E
2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)m-
ethylamino)phenyl)sulfonyl)benzamide
[2678] The title compound was prepared by substituting EXAMPLE 266D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.56 (s, 1H), 11.00 (br s, 1H),
8.64 (t, 1H), 8.54 (d, 1H), 7.81 (dd, 1H), 7.58 (d, 1H), 7.45 (d,
1H), 7.34 (d, 2H), 7.26 (d, 1H), 7.16 (d, 2H), 7.10 (t, 1H), 7.03
(d, 2H), 6.68 (dd, 1H), 6.62 (d, 1H), 6.10 (d, 1H), 3.85 (dd, 2H),
3.26 (t, 2H), 3.02 (br.s, 4H), 2.73 (br.s, 2H), 2.20-2.10 (m, 6H),
1.95 (br.s, 2H), 1.90 (m, 1H), 1.61 (dd, 2H), 1.38 (t, 2H), 1.27
(m, 2H), 0.92 (s, 6H).
EXAMPLE 267
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-[(2-oxo-2,3-dihydro-1H-indol-5-yl)oxy]benzamide
[2679] A solution of EXAMPLE 265E (38 mg) in ethanol (5 mL) and 1 N
aqueous HCl (5 mL) was stirred at 85.degree. C. for 7 hours. The
mixture was cooled to ambient temperture and concentrated. The
residue was purified on reverse-phase HPLC on a C18 column using a
water-acetonitrile gradient with ammonium acetate buffer to give
the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.30 (br s, 1H), 10.33 (s, 1H),
8.61 (t, 1H), 8.54 (d, 1H), 7.84 (dd, 1H), 7.47 (d, 1H), 7.35 (d,
2H), 7.18 (d, 1H), 7.06 (d, 2H), 6.84 (s, 1H), 6.80 (d, 1H), 6.74
(d, 1H), 6.67 (dd, 1H), 6.20 (d, 1H), 3.85 (dd, 2H), 3.43 (s, 2H),
3.27 (t, 2H), 3.10 (br.s, 4H), 2.77 (br.s, 2H), 2.25-2.10 (m, 6H),
1.97 (br.s, 2H), 1.90 (m, 1H), 1.62 (dd, 2H), 1.40 (t, 2H), 1.27
(m, 2H), 0.94 (s, 6H).
EXAMPLE 268
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
[2680] The title compound was prepared by substituting EXAMPLE 266E
for EXAMPLE 265E in EXAMPLE 267. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.50 (br s, 1H), 10.40 (s, 1H),
8.59 (t, 1H), 8.54 (d, 1H), 7.72 (d, 1H), 7.47 (d, 1H), 7.35 (d,
2H), 7.12 (d, 1H), 7.06 (d, 2H), 6.96 (t, 1H), 6.75 (dd, 1H), 6.46
(d, 1H), 6.44 (d, 1H), 6.13 (d, 1H), 3.86 (dd, 2H), 3.28 (t, 2H),
3.25 (s, 2H), 3.19 (br.s, 4H), 2.82 (br.s, 2H), 2.28 (br.s, 4H),
2.18 (m, 2H), 1.98 (br.s, 2H), 1.90 (m, 1H), 1.63 (d, 2H), 1.41 (t,
2H), 1.27 (m, 2H), 0.94 (s, 6H).
EXAMPLE 269
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-4-yl)oxy]-N-({4-[(2-methoxyethyl)amino]-3-nitr-
ophenyl}sulfonyl)benzamide
[2681] The title compound was prepared by substituting EXAMPLE 209G
for EXAMPLE 1F and EXAMPLE 263A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.22 (br
s, 1H), 8.55 (t, 1H), 8.43 (d, 1H), 7.61 (dd, 1H), 7.51 (d, 1H),
7.35 (d, 2H), 7.24 (t, 1H), 7.05 (d, 2H), 7.00 (d, 1H), 6.89 (dd,
1H), 6.77 (dd, 1H), 6.43 (d, 1H), 6.26 (t, 1H), 6.06 (t, 1H),
3.63-3.51 (m, 4H), 3.32 (s, 3H), 3.13 (br s, 4H), 2.78 (br s, 2H),
2.31-2.12 (m, 6H), 1.97 (br s, 2H), 1.40 (t, 2H), 0.93 (s, 6H).
EXAMPLE 270
tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate
EXAMPLE 270A
methyl
2-(6-(bis(tert-butoxycarbonyl)amino)pyridin-3-yloxy)-4-(4-((2-(4-ch-
lorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2682] EXAMPLE 261C (1080 mg) was dissolved in acetonitrile (12 mL)
and 4-dimethylaminopyridine (47 mg) and di-tert-butyl dicarbonate
(462 mg) were added. The solution was mixed at room temperature for
16 hours, the volume of solvent reduced, and the material purified
by flash column chromatography on silica gel using 30% ethyl
acetate in hexanes.
EXAMPLE 270B
2-(6-tert-Butoxycarbonylamino-pyridin-3-yloxy)-4-{4-[2-(4-chloro-phenyl)-4-
,4-dimethyl-cyclohex-1-enylmethyl]-piperazia-1-yl}-benzoic acid
[2683] The title compound was prepared by substituting EXAMPLE 270A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 270C
tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]p-
henyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate
[2684] The title compound was prepared by substituting EXAMPLE 270B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 9.72 (s, 1H), 8.61 (t, 1H), 8.55
(d, 1H), 7.95 (d, 1H), 7.82 (dd, 1H), 7.74 (d, 1H), 7.47 (d, 1H),
7.36 (d, 2H), 7.32 (dd, 1H), 7.19 (d, 1H), 7.06 (d, 2H), 6.70 (dd,
1H), 6.27 (d, 1H), 3.86 (dd, 2H), 3.13 (br s, 4H), 2.78 (br s, 2H),
2.54 (m, 1H), 2.45 (m, 1H), 2.29-2.13 (m, 6H), 1.97 (br s, 2H),
1.91 (m, 1H), 1.63 (d, 2H), 1.48 (s, 9H), 1.40 (t, 2H), 1.34-1.20
(m, 4H), 0.94 (s, 6H).
EXAMPLE 271
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin--
4-ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbam-
ate
EXAMPLE 271A
2-(2-Amino-pyridin-4-yloxy)-4-fluoro-benzoic acid methyl ester
[2685] The title compound was prepared by substituting methyl
2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and
2-aminopyridin-4-ol for 2-methyl-5-indolol in EXAMPLE 3A, except
here heating was at 130.degree. C.
EXAMPLE 271B
2-(2-Amino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohe-
x-1-enylmethyl]-piperazin-1-yl}-benzoic acid methyl ester
[2686] The title compound was prepared by substituting EXAMPLE 271A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 271C
methyl
2-(2-(bis(tert-butoxycarbonyl)amino)pyridin-4-yloxy)-4-(4-((2-(4-ch-
lorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2687] The title compound was prepared by substituting EXAMPLE 271B
for EXAMPLE 261C in EXAMPLE 270A.
EXAMPLE 271D
2-(2-tert-Butoxycarbonylamin-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phenyl)-4,-
4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoic acid
[2688] The title compound was prepared by substituting EXAMPLE 271C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 271E
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin--
4-yl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate
[2689] The title compound was prepared by substituting EXAMPLE 271D
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 9.33 (br
s, 1H ), 8.42 (m, 1H), 8.21 (d, 1H), 8.02 (m, 1H), 7.76 (m, 1H),
7.58 (d, 1H), 7.40-7.34 (m, 2H), 7.26 (m, 1H), 7.20-6.95 (m, 4H),
6.67 (d, 1H), 6.30 (br s, 1H), 3.99-3.90 (m, 3H), 3.89 (m, 1H),
3.07 (br s, 4H), 2.76 (br s, 2H), 2.42-2.32 (m, 1H), 2.30-2.14 (m,
8H), 2.13-2.03 (m, 2H), 20.2-1.95 (m, 3H), 1.90-1.65 (m, 6H),
1.60-1.49 (m, 2H), 1.40 (t, 2H), 1.31 (t, 9H), 0.94 (s, 6H).
EXAMPLE 272
2-[(6-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide
[2690] The title compound was prepared by substituting EXAMPLE 270C
for EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.64 (t, 1H), 8.60 (d, 1H), 7.89
(dd, 1H), 7.73 (d, 1H), 7.46 (d, 1H), 7.36 (d, 2H), 7.24 (d, 1H),
7.18 (dd, 1H), 7.06 (d, 2H), 6.61 (dd, 1H), 6.47 (d, 1H), 6.07 (d,
1H), 5.90 (br s, 2H), 3.85 (dd, 2H), 3.07 (br s, 4H), 2.75 (br s,
2H), 2.28-2.11 (m, 10H), 1.97 (br s, 2H), 1.92 (m, 1H), 1.63 (dd,
2H), 1.40 (t, 2H), 1.26 (m, 2H), 0.94 (s, 6H).
EXAMPLE 273
2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-
-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2691] The title compound was prepared by substituting EXAMPLE 271E
for EXAMPLE 1A is EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.49 (br s, 1H), 8.16-8.06 (m,
1H), 7.86 (dd, 1H), 7.70 (dd, 1H), 7.44 (d, 1H), 7.40-7.35 (m, 2H),
7.16-7.09 (m, 2H), 7.07 (d, 2H), 6.59 (d, 1H), 6.45 (dd, 1H), 6.19
(d, 1H), 3.96-3.89 (m, 3H), 3.81 (m, 1H), 3.00 (br s, 4H),
2.93-2.77 (ro, 2H), 2.74 (br s, 2H), 2.29-2.11 (m, 8H), 2.09-1.95
(m, 4H), 1.90-1.46 (m, 8H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 274
2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 274A
methyl 2-(5-bromopyridin-3-yloxy)-4-fluorobenzoate
[2692] To a solution of 5-bromopyridin-3-ol (1.060 g) in
2-methyltetrahydrofuran (15 mL) was added potassium tert-butoxide
(6.09 mL, 1.0M in tetrahydrofuran) dropwise. After stirring for 5
minutes, methyl 2,4-difluorobenzoate (1.049 g) was added as a
solution in 2-methyltetrahydrofuran (2 mL) and the reaction was
heated to 75.degree. C. N,N-Dimethylformamide (2 mL) was added to
the reaction and the reaction was stirred overnight. The reaction
was cooled, diluted with ethyl acetate (100 mL) and washed with
water (50 mL), brine (50 mL), dried over magnesium sulfate,
filtered, and concentrated. Silica gel chromatography (SF40-80)
eluting with a gradient of 5% to 35% ethyl acetate/hexanes gave the
product.
EXAMPLE 274B
methyl
2-(5-bromopyridin-3-yloxy)-(4-((2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2693] The title compound was prepared by substituting EXAMPLE 274A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 274C
2-(5-bromopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex--
1-enyl)methyl)piperazin-1-yl)benzoic acid
[2694] The title compound was prepared by substituting EXAMPLE 274B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 274D
2-[(5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide
[2695] The title compound was prepared by substituting EXAMPLE 274C
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.99-11.42 (m, 1H), 8.62 (s,
1H), 8.42 (d, 1H), 8.17 (d, 1H), 8.10 (d, 1H), 7.71 (dd, 1H), 7.54
(d, 1H), 7.37 (d, 2H), 7.19 (t, 1H), 7.09 (t, 3H), 6.81 (dd, 1H),
6.59 (d, 1H), 3.87 (dd, 2H), 3.44-3.15 (m, 8H), 2.88 (s, 2H), 2.33
(s, 4H), 2.19 (s, 2H), 1.97 (d, 3H), 1.66 (d, 2H), 1.5-1.20 (m,
4H), 0.97 (d, 6H).
EXAMPLE 275
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-
-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2-
H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 275A
ethyl
2-(6-chloro-1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-
-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
[2696] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38F with EXAMPLE 242F.
EXAMPLE 275B
2-(6-chloro-1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-d-
ihydro)-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoic acid
[2697] The title compound was prepared as described in EXAMPLE 38 H
by replacing EXAMPLE 38G with EXAMPLE 275A.
EXAMPLE 275C
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-
-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2-
H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2698] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 275B and
EXAMPLE 1G, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.27 (s, 1H), 11.19 (m, 1H),
8.62 (t, 1H), 8.58 (d, 1H), 7.84 (dd, 1H), 7.54 (m, 3H), 7.43 (m,
1H), 7.36 (m, 3H), 7.14 (m, 3H), 6.66 (dd, 1H), 6.43 (s, 1H), 6.00
(d, 1H), 4.10 (s, 2H), 3.85 (dd, 1H), 3.24 (m, 2H), 3.02 (m, 4H),
2.85 (m, 2H), 2.16 (m, 6H), 1.90 (m, 1H), 1.62 (m, 2H), 1.28 (m,
4H), 1.18 (s, 6H).
EXAMPLE 276
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran--
4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2699] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F with EXAMPLE 242H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.27 (s, 1H), 11.12 (m, 1H),
8.60 (m, 2H), 7.85 (dd, 1H), 7.54 (m, 2H), 7.44 (m, 1H), 7.33 (d,
3H), 7.16 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.43 (s, 1H), 6.00
(d, 1H), 3.85 (m, 2H), 3.28 (m, 4H), 3.02 (m, 4H), 2.73 (s, 2H),
2.15 (m, 4H), 1.93 (m, 4H), 1.61 (m, 3H), 1.29 (m, 4H), 0.92 (s,
6H).
EXAMPLE 277
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2-
H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 277A
methyl
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)me-
thyl)piperazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoate
[2700] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38E with EXAMPLE 154C.
EXAMPLE 277B
4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)pi-
perazin-1-yl)-2-(6-fluoro-1H-indol-5-yloxy)benzoic acid
[2701] The title compound was prepared as described in EXAMPLE 38H
by replacing EXAMPLE 38G with EXAMPLE 277A.
EXAMPLE 277C
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2-
H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2702] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F with EXAMPLE 277B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.30 (m, 1H), 11.21 (s, 1H),
8.61 (m, 2H), 7.86 (dd, 1H), 7.51 (d, 1H), 7.37 (m, 3H), 7.30 (m,
1H), 7.15 (m, 3H), 6.66 (dd, 1H), 6.41 (m, 1H), 6.00 (d, 1H), 4.10
(s, 2H), 3.84 (dd, 2H), 3.28 (m, 4H), 3.03 (m, 4H), 2.82 (s, 2H),
2.23 (m, 5H), 1.89 (m, 1H), 1.62 (m, 2H), 1.26 (m, 4H), 1.19 (s,
6H).
EXAMPLE 278
tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate
EXAMPLE 278A
methyl
2-(5-(tert-butoxycarbonylamino)pyridin-3-yloxy)-4-(4-((2-(4-chlorop-
henyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2703] EXAMPLE 274B (0.135 g) tert-butylcarbamate (0.028 g) and
cesium carbonate (0.106 g) were mixed together in dioxane (2 mL).
Diacetoxypalladium (2.425 mg) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.012
g,) were added and the reaction was degassed with nitrogen then
sealed and heated to 85.degree. C. The reaction was stirred for 16
hours, cooled, loaded onto silica gel (40 g) and eluted using a
gradient of 0.5% to 7.5% methanol/dichlormethane to yield the
product.
EXAMPLE 278B
2-(5-(tert-butoxycarbonylamino)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)--
4,4-dimethylcyclohex-1-enyl)methylpiperazin-1-yl)benzoic acid
[2704] The title compound was prepared by substituting EXAMPLE 278A
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 278C
tert-butyl
5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-3-ylcarbamate
[2705] The title compound was prepared by substituting EXAMPLE 278B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 9.75 (s, 1H), 8.84 (d, 1H), 8.51 (d, 1H), 8.32 (d, 1H),
8.13 (dd, 1H), 8.08 (d, 1H), 7.92 (d, 1H), 7.87 (s, 1H), 7.24 (d,
2H), 6.92 (dd, 3H), 6.65 (s, 1H), 6.58 (dd, 1H), 6.06 (d, 1H), 4.02
(dd, 2H), 3.42 (dd, 2H), 3.32-3.21 (m, 2H), 3.14 (s, 4H), 2.77 (s,
2H), 2.22 (d, 6H), 1.98 (s, 3H), 1.70 (t, 2H), 1.56-1.36 (m, 13H),
0.95 (s, 6H).
EXAMPLE 279
2-[5-aminopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
[2706] To EXAMPLE 278C (0.050 g) in dichloromethane (2 mL) was
added trifluoroacetic acid (0.061 mL) and the reaction stirred at
room temperature. After stirring for 19 hours, the reaction was
concentrated then dried under high vacuum. The residue was
dissolved in dichloromethane (1 mL) and neutralized with
N,N-diisopropylethylamine (0.208 mL). The solution was loaded onto
silica gel (GraceResolv 12 g) and the product eluted using a
gradient of 0.5% methanol/dichloromethane to 5%
methanol/dichloromethane over 30 minutes (Flow=30 mL/min) to give
the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.82
(d, 1H), 8.50 (s, 1H), 8.11 (dd, 1H), 7.98 (d, 1H), 7.91 (d, 1H),
7.82 (d, 1H), 7.30-7.14 (m, 2H), 7.01-6.83 (m, 3H), 6.69 (t, 1H),
6.58 (dd, 1H), 6.10 (d, 1H), 4.10-3.98 (m, 2H), 3.88 (s, 2H), 3.42
(dd, 2H), 3.34-3.20 (m, 2H), 3.14 (d, 4H), 2.78 (s, 2H), 2.22 (d,
6H), 1.99 (s, 3H), 1.73 (d, 2H), 1.62-1.10 (m, 4H), 0.95 (s,
6H).
EXAMPLE 280
tert-butyl
4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]met-
hyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino-
]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate
[2707] The title compound was prepared by substituting EXAMPLE 271D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 9.33 (br s, 1H), 8.65 (t, 1H),
8.55 (br s, 1H), 8.16 (br s, 1H), 7.82 (d, 1H), 7.57 (d, 1H), 7.44
(t, 1H), 7.35 (d, 2H), 7.32-7.13 (m, 2H), 7.11 (d, 1H), 7.06 (d,
2H), 6.71 (d, 1H), 3.86 (dd, 2H), 3.09 (br s, 4H), 2.73 (d, 2H),
2.25-2.12 (m, 8H), 1.97 (br s, 2H), 1.91 (m, 1H), 1.66-1.47 (m,
4H), 1.40 (t, 2H), 1.31 (s, 9H), 1.24 (t, 2H), 0.94 (s, 6H).
EXAMPLE 281
2-[3-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-
-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2708] The title compound was prepared by substituting EXAMPLE 265D
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1H.
(.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.34 (s,
1H), 8.48 (d, 1H), 8.15 (d, 1H), 7.74 (dd, 1H), 7.53-7.51 (m, 2H),
7.37 (d, 1H), 7.34 (d, 2H), 7.04 (d, 2H), 7.00 (d, 1H), 6.87-6.85
(m, 2H), 6.64 (dd, 1H), 6.19 (d, 1H), 3.94 (dd, 2H), 3.75 (m, 1H),
3.28 (dd, 2H), 3.02 (m, 6H), 2.72 (m, 2H), 2.62 (m, 1H), 2.25-2.10
(m, 6H), 2.00 (m, 2H), 1.95 (br.s, 2H), 1.91 (m, 2H), 1.77 (d, 2H),
1.70-1.60 (m, 2H), 1.55-1.45 (m, 2H), 1.38 (m, 2H), 0.92 (s,
6H).
EXAMPLE 282
2-[(2-aminopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohe-
x-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pryan-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide
[2709] The title compound was prepared by substituting EXAMPLE 280
for EXAMPLE 1A in EXAMPLE 1B. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.59 (t, 1H), 8.54 (d, 1H), 7.84
(dd, 1H), 7.73 (m, 1H), 7.46 (d, 1H), 7.36 (d, 2H), 7.16 (d, 1H),
7.14-7.10 (m, 1H), 7.06 (d, 2H), 6.95 (d, 1H), 6.66 (d, 2H), 6.46
(m, 1H), 6.15 (d, 1H), 3.86 (dd, 2H), 3.07 (br s, 4H), 2.76 (br s,
2H), 2.30-2.12 (m, 6H), 1.97 (br s, 2H), 1.90 (m, 1H), 1.63 (d,
2H), 1.40 (t, 2H), 1.35-1.15 (m, 6H), 0.94 (s, 6H).
EXAMPLE 283
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-hydroxypyridin-3-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2-H-pyran--
4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 283A
methyl 2-(6-(benzyloxy)pyridin-3-yloxy)-4-fluorobenzoate
[2710] To 6-(benzyloxy)pyridin-3-ol (1.10 g) in
2-methyltetrahydrofuran (20 mL) was added potassium t-butoxide
(5.47 mL, 1.0M in tetrahydrofuran). After stirring for 15 minutes,
methyl 2,4-difluorobenzoate (1.035 g) in 2-methyltetrahydrofuran (2
mL) was added and the reaction heated to 75.degree. C. for 1 hour.
The reaction was cooled, diluted with ethyl acetate (150 mL),
washed with water (50 mL), brine (50 mL), dried over magnesium
sulfate, filtered and concentrated. Silica gel chromatography
(SF40-80g) eluting with a gradient of 5% to 20% ethyl
acetate/hexanes gave the title compound.
EXAMPLE 283B
methyl
2-(6-(benzyloxy)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2711] The title compound was prepared by substituting EXAMPLE 283A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 283C
2-(6-(benzyloxy)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyc-
lohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2712] The title compound was prepared by substituting EXAMPLE 283B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 283D
2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyr-
an-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2713] The title compound was prepared by substituting EXAMPLE 283C
for EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 283E
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(6-hydroxypyridin-3-yloxy)-N-(3-nitro-4-((tetrahydro-2-H-pyran-4-yl)m-
ethylamino)phenylsulfonyl)benzamide
[2714] To
2-(6-(benzyloxy)pyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-
-pyran-4-yl)methylamino)phenylsulfonyl)benzamide (0.132 g) in
dichloromethane (1 mL) was added trifluoroacetic acid (0.33 mL) and
the reaction was sealed in a vial under nitrogen and heated to
40.degree. C. After stirring for 16 hours, the reaction was cooled,
diluted with dichloromethane (50 mL) and washed with sodium
carbonate (2.times.25 mL). The organic layer was dried over
magnesium sulfate, filtered, and concentrated. Silica gel
chromatography (GraceResolv 12 g) eluting with a gradient of 0.3%
to 3% methanol/dichloromethane (Flow=36 mL/minute) over 30 minutes
gave the title compound. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
12.51-11.38 (m, 1H), 9.78 (s, 1H), 8.89 (d, 1H), 8.52 (t, 1H), 8.19
(dd, 1H), 7.92 (d, 1H), 7.43-7.33 (m, 2H), 7.24 (d, 2H), 7.00-6.89
(m, 3H), 6.74-6.67 (m, 1H), 6.35 (dd, 1H), 6.00 (d, 1H), 4.00 (d,
2H), 3.42 (dd, 2H), 3.34-3.23 (m, 2H), 3.16 (s, 4H), 2.79 (s, 2H),
2.24 (d, 6H), 1.99 (s, 3H), 1.72 (s, 2H), 1.55-1.33 (m, 4H), 0.96
(s, 6H).
EXAMPLE 284
2-{[6-(benzyloxy)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pry-
an-4ylmethyl)amino]phenyl}sulfonyl)benzamide
[2715] The title compound was prepared as described in EXAMPLE
283D. .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.93 (s, 1H), 8.88
(d, 1H), 8.52 (t, 1H), 8.17 (dd, 1H), 8.05 (d, 1H), 7.92 (d, 1H),
7.49 (d, 2H), 7.45-7.34 (m, 4H), 7.24 (d, 2H), 6.97-6.85 (m, 4H),
6.54 (dd, 1H), 5.95 (d, 1H), 5.41 (s, 2H), 4.02 (dd, 2H), 3.48-3.35
(m, 2H), 3.30-3.23 (m, 2H), 3.15-3.02 (m, 4H), 2.77 (s, 2H), 2.23
(dd, 6H), 1.95 (d, 3H), 1.71 (s, 2H), 1.59-1.33 (m, 4H), 1.03-0.89
(m, 6H).
EXAMPLE 285
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro--
1H-indol-5-yl)oxy]benzamide
EXAMPLE 285A
4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide
[2716] (1,4-Dioxan-2-yl)methanol (380 mg) in tetrahydrofuran (30
mL) was treated with sodium hydride (60%, 245 mg) at room
temperature for 30 minutes. The reaction mixture was cooled in an
ice bath and 4-fluoro-3-nitrobenzenesulfonamide (675 mg) was added.
The resulting mixture was stirred at room temperature for 2 hours
and another portion of sodium hydride (60%, 245 mg) was added. The
reaction mixture was stirred overnight and quenched with ice water
(3 mL). The cloudy mixture was filtered and the filtrate was
concentrated. The residue was triturated with methanol to give the
title compound.
EXAMPLE 285
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-[(6-fluoro--
1H-indol-5-yl)oxy]benzamide
[2717] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and
EXAMPLE 285A, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.21 (s, 2H), 8.38 (d, 1H),
8.10 (d, 1H), 7.52 (d, 1H), 7.47 (d, 1H), 7.38 (t, 1H), 7.32-7.36
(m, 3H), 7.27 (d, 1H), 7.04 (d, 2H), 6.65 (dd, 1H), 6.40 (s, 1H),
6.10 (d, 1H), 4.20-4.29 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd, 1H),
3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.06 (s,
4H), 2.82 (s, 2H), 2.26 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.39
(t, 2H), 0.92 (s, 6H).
EXAMPLE 286
2-[(3-chloro-1H-indol-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino-
]-3-nitrophenyl}sulfonyl)benzamide
[2718] The title compound was prepared by substituting EXAMPLE 266D
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.51 (s,
1H), 9.17 (s, 1H), 8.48 (s, 1H), 7.83 (d, 1H), 7.58 (d, 2H), 7.43
(s, 1H), 7.33 (d, 2H), 7.20 (d, 1H), 7.07-7.03 (m, 3H), 6.66 (d,
1H), 6.52 (m, 1H), 6.10 (s, 1H), 3.00 (m, 3H), 2.90 (m, 6H), 2.71
(br.s, 2H), 2.50 (s, 3H), 2.32 (m, 3H), 2.15 (m, 6H), 1.95 (br.s,
2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 287
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2--
oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
[2719] The title compound was prepared by substituting EXAMPLE 286
for EXAMPLE 265E in EXAMPLE 267. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.31 (s, 1H), 8.86 (s, 1H),
8.29 (s, 1H), 7.54 (m, 2H), 7.42 (d, 1H), 7.36 (d, 2H), 7.08 (d,
2H), 6.91 (t, 1H), 6.68 (d, 1H), 6.39 (m, 2H), 6.06 (d, 1H), 3.34
(m, 4H), 3.27 (s, 2H), 3.08 (br.s, 4H), 2.86 (m, 4H), 2.76 (s, 2H),
2.28 (s, 3H), 2.25-2.10 (m, 6H), 1.97 ((br.s, 2H), 1.40 (t, 2H),
0.94 (s, 6H).
EXAMPLE 288
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2--
oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
EXAMPLE 288A
2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitr-
ophenylsulfonyl)benzamide
[2720] The title compound was prepared by substituting EXAMPLE 266D
for EXAMPLE 1F and EXAMPLE 3I for EXAMPLE 1G is EXAMPLE 1H.
EXAMPLE 288B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-methylpiperazin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-[(2--
oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
[2721] The title compound was prepared by substituting EXAMPLE 288A
for EXAMPLE 265E in EXAMPLE 267. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.29 (s, 1H), 8.34 (s, 1H),
8.05 (br. d, 1H), 7.64 (d, 1H), 7.54 (d, 1H), 7.36 (d, 2H), 7.07
(d, 2H), 7.01 (d, 1H), 6.91 (t, 1H), 6.68 (d, 1H), 6.38 (m, 2H),
6.08 (d, 1H), 3.80 (br. s, 1H), 3.34 (m, 2H), 3.23 (s, 2H), 3.09
(br.s, 4H), 2.84 (m, 2H), 2.76 (s, 2H), 2.62 (br.s, 2H), 2.24 (s,
3H), 2.25-2.05 (m, 6H), 1.98 ((br.s, 2H), 1.76 (m, 2H), 1.40 (t,
2H), 0.94 (s, 6H).
EXAMPLE 289
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pheny-
l}sulfonyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
EXAMPLE 289A
2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl-
)piperidin-4-ylamino)phenylsulfonyl)benzamide
[2722] The title compound was prepared by substituting EXAMPLE 266D
for EXAMPLE 1F and EXAMPLE 49C for EXAMPLE 1G in EXAMPLE 1B.
EXAMPLE 289B
4-(4-((2-(4-chloropbenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-N-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsul-
fonyl-2-(2-oxoindolin-4-yloxy)benzamide
[2723] The title compound was prepared by substituting EXAMPLE 289A
for EXAMPLE 265E in EXAMPLE 267. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.32 (s, 1H), 8.37 (s, 1H),
8.12 (br.s, 1H), 7.68 (d, 1H), 7.52 (d, 1H), 7.36 (d, 2H), 7.07 (m,
3H), 6.93 (t, 1H), 6.69 (d, 1H), 6.40 (m, 2H), 6.09 (d, 1H), 3.94
(m, 2H), 3.83 (br.s, 1H), 3.34 (m, 7H), 3.23 (s, 2H), 3.12 (br.s,
4H), 2.77 (s, 2H), 2.62 (s, 2H), 2.30-2.00 (m, 8H), 1.98 ((br.s,
2H), 1.85 (m, 2H), 1.73 (m, 2H), 1.54 (m, 2H), 1.40 (t, 2H), 0.94
(s, 6H).
EXAMPLE 290
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nit-
rophenyl]sulfonyl}benzamide
[2724] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and
EXAMPLE 285A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.25 (s, 1H), 8.37 (d, 1H),
8.09 (m, 1H), 7.48 (m, 4H), 7.33 (m, 3H), 7.05 (m, 3H), 6.65 (dd,
1H), 6.42 (m, 1H), 6.01 (d, 1H), 4.25 (m, 2H), 3.83 (m, 3H), 3.63
(m, 3H), 3.45 (m, 2H), 3.04 (m, 4H), 2.74 (m, 2H), 2.24 (m, 5H),
1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 291
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-
-3-nitrophenyl}sulfonyl)benzmide
EXAMPLE 291A
4-((1,4-dioxan-2-yl)methylamino-3-nitrobenzenesulfonamide
[2725] The title compound was prepared as described in EXAMPLE 4A
by replacing 3-(N-morpholinyl)-1-propylamine with
C-[1,4]dioxan-2-yl-methylamine.
EXAMPLE 291B
2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcycl-
ohex-1-en-1-yl]methyl}piperazin-1-yl-N-({4-[(1,4-dioxan-2-ylmethyl)amino]--
3-nitrophenyl}sulfonyl)benzamide
[2726] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and
EXAMPLE 291A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.25 (s, 1H), 8.37 (d, 1H),
8.09 (dd, 1H), 7.54 (m, 2H), 7.44 (m, 2H), 7.33 (m, 3H), 7.05 (m,
2H), 6.65 (dd, 1H), 6.42 (s, 1H), 6.01 (d, 1H), 3.83 (m, 3H), 3.63
(m, 2H), 3.45 (m, 2H), 3.04 (m, 4H), 2.74 (m, 2H), 2.24 (m, 5H),
1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 292
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide
[2727] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and
EXAMPLE 291A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.20 (s, 1H), 8.58 (d, 2H),
7.95 (s, 1H), 7.88 (dd, 1H), 7.51 (d, 1H), 7.34 (m, 5H), 7.15 (d,
1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.40 (s, 1H), 3.78 (m, 3H), 3.61
(m, 2H), 3.46 (m, 3H), 3.03 (m, 4H), 2.89 (s, 3H), 2.73 (m, 2H),
2.15 (m, 4H), 1.95 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 293
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2728] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 242H and
EXAMPLE 205A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.23 (s, 1H), 8.53 (d, 1H),
8.17 (d, 1H), 7.82 (dd, 1H), 7.53 (t, 2H), 7.41 (t, 1H), 7.33 (d,
2H), 7.24 (s, 1H), 7.11 (d, 1H), 7.03 (d, 2H), 6.64 (dd, 1H), 6.40
(s, 1H), 6.01 (d, 1H), 3.60 (m, 5H), 3.02 (m, 4H), 2.71 (s, 2H),
2.57 (m, 6H), 2.03 (m, 12H), 1.39 (m, 6H), 0.92 (s, 6H).
EXAMPLE 294
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimeth-
yl-5,6-dihydro
2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)a-
mino]-3-nitrophenyl}sulfonyl)benzamide
[2729] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 275B and
EXAMPLE 205A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.20 (s, 1H), 8.50 (d, 1H),
8.14 (d, 1H), 7.79 (dd, 1H), 7.54 (m, 2H), 7.38 (m, 3H), 7.12 (m,
4H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.02 (d, 1H), 4.10 (s, 2H), 3.59
(m, 6H), 3.31 (m, 4H), 3.01 (m, 4H), 2.81 (s, 2H), 2.68 (s, 2H),
2.54 (m, 3H), 2.03 (m, 5H), 1.39 (m, 4H), 1.20 (s, 6H).
EXAMPLE 295
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcycl-
ohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2730] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 277B and
EXAMPLE 205A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.17 (s, 1H), 8.53 (d, 1H),
8.16 (d, 1H), 7.83 (dd, 1H), 7.52 (d, 1H), 7.34 (m, 4H), 7.20 (dd,
1H), 7.13 (m, 3H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.09 (d, 1H), 4.10
(s, 2H), 4.01 (s, 1H), 3.61 (m, 4H), 3.02 (m, 4H), 2.81 (s, 2H),
2.59 (m, 3H), 2.12 (m, 12H), 1.39 (m, 4H), 1.18 (s, 6H).
EXAMPLE 296
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran--
4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 296A
1,6-dioxaspiro[2.5]octane-2-carbonitrile
[2731] A mixture of dihydro-2H-pyran- 4(3H)-one (10.0 g) and
2-chloroacetonitrile (7.5 g) in tert-butanol (10 mL) was treated
with 1.0 N potassium tert-butoxide (100 mL) drop-wise over 20
minutes. The reaction mixture was stirred at room temperature for
16 hours. It was diluted with water (10 mL) and 10% aqueous HCl (20
mL). The reaction mixture was concentrated to one-third of its
original volume, and extracted with diethyl ether four times. The
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified
with flash column chromatography on silica gel eluting with 20-40%
ethyl acetate in hexanes.
EXAMPLE 296B
2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile
[2732] EXAMPLE 296A (11.5 g) was dissolved in dichloromethane (40
mL) in a polypropylene bottle. The bottle was cooled to 0.degree.
C. To this solution was added 70% hydrogen fluoride-pyridine (10.3
mL) slowly. The solution was allowed to warm to room temperature
over 3 hours, and stirred for 24 hours. The reaction mixture was
diluted with ethyl acetate (200 mL) and poured into saturated
aqueous NaHCO.sub.3. Additional solid NaHCO.sub.3 was used to
neutralize the solution carefully until bubbling ceased. The
organic layer was isolated, and the aqueous layer was extracted
with additional ehtyl acetate three times (150 mL each). The
combined organic layers were washed with 1% aqueous HCl, brine,
dried (MgSO.sub.4), filtered and concentrated to give the desired
compound which was used directly in the next reaction.
EXAMPLE 296C
(4-fluorotetrahydro-2H-pyran-4-yl)methanol
[2733] EXAMPLE 296B (11.8 g) in 2-propanol (150 mL) and water (37
mL) was cooled to 0.degree. C. To this solution was added sodium
borohydride (4.2 g). The solution was stirred and allowed to warm
to room temperature over 3 hours. The reaction was quenched with
acetone, and stirred for another 1 hour. The clear liquid was
separated from the solid by decanting. Additional ethyl acetate was
used to wash the solid, and was decanted. The combined organic
solutions were concentrated. The residue was purified with flash
column chromatography on silica gel eluting with 20-40% ethyl
acetate-hexanes.
EXAMPLE 296D
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide
[2734] EXAMPLE 296C (2.0 g) in tetrahydrofuran (20 mL) was treated
with 60% NaH (1.3 g). The solution was stirred for 20 minutes at
the room temperature. To this solution was added
4-fluoro-3-nitrobenzenesulfonamide (2.8 g) portion-wise. The
reaction was stirred for another 2 hours. The mixture was poured
into water, neutralized with 10% aqueous HCl, and extracted with
ethyl acetate three times. The combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified with flash column chromatography on silica gel
eluting with 20%-60% ethyl acetate in hexanes.
EXAMPLE 296E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2H-pyran--
4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide
[2735] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 122C and EXAMPLE 296D for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.40 (s, 1H), 8.13 (br d, 1H), 7.54 (d, 1H), 7.49 (br d, 1H),
7.38 (dd, 1H), 7.33 (d, 3H), 7.28 (br d, 1H), 7.04 (d, 2H), 6.64
(d, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 4.38 (d, 2H), 3.78 (m, 2H),
3.60 (m, 2H), 3.06 (v br s, 4H), 2.82 (br s, 2H), 2.27 (v br s,
4H), 2.15 (br m, 2H), 1.95 (s, 2H), 1.85 (m, 4H), 1.40 (t, 2H),
0.92 (s, 6H).
EXAMPLE 297
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-fluorotetrahydro-2-
H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide
[2736] The title compound was prepared by substituting EXAMPLE 277B
for EXAMPLE 122C and EXAMPLE 296D for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.43 (s, 1H), 8.16 (br d, 1H), 7.52 (d, 2H), 7.38 (m, 4H),
7.30 (br d, 1H), 7.11 (d, 2H), 6.64 (d, 1H), 6.40 (s, 1H), 6.09 (s,
1H), 4.40 (d, 2H), 4.10 (s, 2H), 3.78 (m, 2H), 3.60 (m, 2H), 3.07
(v br s, 4H), 2.84 (br s, 2H), 2.24 (v br s, 4H), 2.16 (s, 2H),
1.85 (m, 4H), 1.18 (s, 6H).
EXAMPLE 298
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]-
sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2737] The title compound was prepared by susbtituting EXAMPLE 277B
for EXAMPLE 122C and EXAMPLE 301B for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.83 (d, 1H), 8.60 (s, 1H), 7.54 (d, 1H), 7.38 (d, 2H), 7.37
(m, 1H), 7.33 (d, 1H), 7.21 (br d, 1H), 7.13 (d, 2H), 6.66 (dd,
1H), 6.38 (s, 1H), 6.12 (s, 1H), 4.30 (d, 2H), 4.10 (s, 2H), 3.85
(dd, 2H), 3.33 (m, 2H), 3.07 (v br s, 4H), 2.95 (br s, 2H), 2.31 (v
br s, 4H), 2.16 (s, 2H), 2.05 (m, 1H), 1.63 (br m, 2H), 1.38 (ddd,
2H), 1.18 (s, 6H).
EXAMPLE 299
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 299A
tert-butyl 2-(5-hydroxy-1H-indol-3-yl)ethylcarbamate
[2738] To a suspension of 3-(2-aminoethyl)-1H-indol-5-ol,
hydrochloride (5 g) in dichloromethane (100 mL) was added
N-ethyl-N-isopropylpropan-2-amine (3.19 g) followed by a solution
of di-tert-butyl dicarbonate (5.64 g) in dichloromethane (10 mL).
The mixture was stirred at ambient temperature under nitrogen 18
hours. The resulting solution was washed with brine, dried over
sodium sulfate, filtered and concentrated. The crude material was
purified on silica gel with 1-5% methanol in methylene
chloride.
EXAMPLE 299B
ethyl
2-(3-(2-(tert-butoxycarbonylamino)ethyl)-1H-indol-5-yloxy)-4-fluorob-
enzoate
[2739] The title compound was prepared by substituting EXAMPLE 299A
for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 299C
ethyl
2-(3-(2-(tert-butoxycarbonylamino)ethyl)-1H-indol-5-yloxy)-4-(4-((2--
(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoat-
e
[2740] The title compound was prepared by substituting EXAMPLE 299B
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 299D
2-(3-(2-(tert-butoxycarbonylamino)ethyl)-1H-indol-5-yloxy)-4-(4-((2-(4-chl-
orophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic
acid
[2741] The title compound was prepared by substituting EXAMPLE 299C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 299E
tert-butyl
2-(5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)met-
hyl)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)ph-
enylsulfonylcarbamoyl)phenoxy)-1H-indol-3-yl)ethylcarbamate
[2742] The title compound was prepared by substituting EXAMPLE 299D
for EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 299F
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[-(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2743] A solution of EXAMPLE 299E (146.6 mg) in dichloromethane (10
mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (5 mL)
was added dropwise over 5 minutes. The reaction mixture was stirred
15 minutes under nitrogen, the ice bath was removed and the
reaction was allowed to come to ambient temperature. The reaction
was stirred 1.5 hours and then concentrated. The crude material was
purified by reverse phase chromatography with ammonium acetate
buffer in acetonitrile to give the title compound. .sup.1H NMR (300
MHz, dimethylsulfoxide-d.sub.6) .delta. 10.86 (d, 1H), 8.39 (d,
1H), 8.33 (t, 1H), 8.06 (br s, 1H), 7.71 (dd, 1H), 7.53 (d, 1H),
7.34 (d, 2H), 7.26 (d, 1H), 7.19 (d, 1H), 7.05 (m, 3H), 6.89 (d,
1H), 6.70 (dd, 1H), 6.52 (dd, 1H), 6.15 (d, 1H), 3.83 (dd, 2H),
3.22 (m, 3H), 2.82-3.00 (m, 8H), 2.72 (s, 2H), 2.16 (m, 6H), 1.96
(s, 2H), 1.88 (m, 4H), 1.60 (d, 2H), 1.38 (m, 2H), 1.24 (m, 2H),
0.93 (s, 6H).
EXAMPLE 300
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 300A
tert-butyl
2-(5-(5-(4-((2-(4-chlorophenyl)-4-dimethylcyclohex-1-enyl)methy-
l)piperazin-1-yl)-2-(4-(4-methylpiperazin
4-ylamino)-3-nitrophenylsulfonylcarbamoyl)phenoxy)-1H-indol-3-yl)ethylcar-
bamate
[2744] The title compound was prepared by substituting EXAMPLE 299D
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 300B
2-{[3-(2-aminoethyl)-1H-indol-5-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2745] The title compound was prepared by substituting EXAMPLE 300A
for EXAMPLE 299E in EXAMPLE 299F. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.88 (d, 1H), 8.78 (s, 1H),
8.61 (br s, 1H), 8.38 (d, 1H), 7.76 (dd, 1H), 7.52 (d, 1H), 7.42
(d, 1H), 7.34 (d, 2H), 7.27 (d, 1H), 7.20 (d, 1H), 7.05 (m, 3H),
6.71 (dd, 1H), 6.51 (dd, 1H), 6.14 (dm, 1H), 3.02-2.80 (m, 12H),
2.71 (s, 2H), 2.20-2.11 (m, 9H), 1.95 (s, 2H), 1.90 (s, 6H), 1.38
(m, 2H), 0.93 (s, 6H).
EXAMPLE 301
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-
-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 301A
[2746] (Tetrahydro-2H-pyran-4-yl)methanol (0.65 g) in
tetrahydrofuran (20 mL) was treated with 60% sodium hydride (0.895
g). The reaction mixture was stirred for 10 minutes. To this
solution was added EXAMPLE 305A (1.519 g). The reaction mixture was
stirred overnight. It was poured into water, neutralized with 10%
aqueous HCl, and extracted with ethyl acetate three times. The
combined organic layers were washed with brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified
with flash column chromatography on silica gel eluting with 20%-60%
ethyl acetate in hexanes to give the title compound.
EXAMPLE 301B
[2747] A mixture of EXAMPLE 301A (0.702 g), dicyanozinc (0.129 g),
and tetrakis(triphenylphosphine)palladium(0) (0.231 g) in
N,N-dimethylformamide (2 mL) was degassed via vacuum/nitrogen cycle
three times. The reaction mixture was heated at 120.degree. C. for
3 hours. After cooling, it was poured into water and extracted with
ethyl acetate three times. The combined organic layers were washed
with brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified with flash column chromatography on silica gel
eluting with 20%-60% tetrakis(triphenylphosphine)palladium(0) in
hexanes to give the title compound.
EXAMPLE 301C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-
-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2748] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1E and EXAMPLE 301B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.14 (s,
1H), 8.75 (s, 1H), 8.51 (s, 1H), 7.55 (d, 1H), 7.32-7.34 (m, 3H),
7.28 (d, 1H), 7.12 (d, 1H), 7.04 (d, 2H), 6.62 (dd, 1H), 6.33 (s,
1H), 6.11 (s, 1H), 4.28 (d, 2H), 3.86 (dd, 2H), 2.92-3.06 (m, 4H),
2.35-2.38 (m, 2H), 1.95-2.15 (m, 5H), 1.61-1.64 (m, 2H), 1,34-1.40
(m, 4H), 0.91 (s, 6H).
EXAMPLE 302
2-[(6-amino-5-fluoropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 302A
methyl 2-(6-chloro-5-fluoropyridin-3-yloxy)-4-fluorobenzoate
[2749] To a solution of 6-chloro-5-fluoropyridin-3-ol (0.977 g) in
2-methyltetrahydrofuran (12 mL) was added potassium
2-methylpropan-2-olate (1.0 M) in tetrahydrofuran, 7.28 mL). After
stirring for 15 minutes at room temperature, methyl
2,4-difluorobenzoate (1.710 g) was added as a solution
2-methyltetrahydrofuran (2 mL) followed by N,N-dimethylformamide (2
mL) then the reaction was heated to 75.degree. C. under a nitrogen
atmosphere. After stirring overnight the reaction was cooled,
diluted with ethyl acetate (100 mL) and washed with water (50 mL)
and brine (50 mL), dried over magnesium sulfate, filtered, and
concentrated. Silica gel chromatography (GraceResolv 40 g) eluting
with a gradient 2% to 15% ethyl acetate/hexanes gave the title
compound.
EXAMPLE 302B
methyl
2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-fluorobe-
nzoate
[2750] Methyl 2-(6-chloro-5-fluoropyridin-3-yloxy)-4-fluorobenzoate
(0.875 g), tert-butyl carbamate (0.410 g), cesium carbonate (1.427
g), diacetoxypalladium (0.033 g) and
(9.9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphise) (0.169 g)
were added to dioxane (10 mL). The reaction was degassed with
nitrogen then sealed. The reaction was then heated to 85.degree. C.
After stirring for 16 hours the reaction was cooled, diluted with
water (25 mL) and the product was extracted into dichloromethane
(2.times.25 mL). The organic layer was dried over magnesium
sulfate, filtered, and concentrated. Silica gel chromatography
(GraceResolv 40 g) eluting with a gradient of 5% to 25% ethyl
acetate/hexanes gave the title compound.
EXAMPLE 302C
methyl
2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-(piperaz-
in-1-yl)benzoate
[2751] Methyl
2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-fluorobenzoate
(0.170 g) and piperazine (0.154 g) were dissolved in
dimethylsulfoxide (2 mL) and heated to 85.degree. C. After 1 hour,
the reaction was cooled, poured into dichloromethane (75 mL), and
washed with water (30 mL). The organic layer was dried over
magnesium sulfate, filtered, and concentrated to give the title
compound.
EXAMPLE 302D
methyl
2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-(4-((2-(-
4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2752] The title compound was prepared by substituting EXAMPLE 302C
for tert-butyl piperazine-1-carboxylate and EXAMPLE 60D for
4'-chlorobiphenyl-5-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 302E
2-(6-(tert-butoxycarbonylamino)-5-fluoropyridin-3-yloxy)-4-(4-((2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic
acid
[2753] The title compound was prepared by substituting EXAMPLE 302D
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 302F
tert-butyl
5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl-
)piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)pheny-
lsulfonylcarbamoyl)phenoxy)-3-fluoropyridin-2-ylcarbamate
[2754] The title compound was prepared by substituting EXAMPLE 302E
for EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 302G
2-(6-amino-5-fluoropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran--
4-yl)methylamino)phenylsulfonyl)benzamide
[2755] To EXAMPLE 302F (0.115 g) in dichloromethane (2 mL) was
added TFA (0.276 mL). After stirring for 3 hours the reaction was
concentrated, dissolved in dichloromethane (50 mL) and washed with
aqueous saturated NaHCO.sub.3 (30 mL), dried over magnesium
sulfate, filtered, and concentrated. Silica gel chromatography
(GraceResolv 12 g) eluting with a gradient of 0.5% to 3%
methanol/dichloromethane gave the title compound. .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 9.86 (s, 1H), 8.88 (d, J=2.2, 1H), 8.52
(s, 1H), 8.17 (dd, 1H), 7.92 (d, 1H), 7.83 (d, 1H), 7.26 (s, 1H),
7.11 (dd, 1H), 6.93 (dd, 3H), 6.54 (dd, 1H), 5.98 (d, 1H), 4.69 (s,
2H), 4.02 (dd, 2H), 3.42 (d, 2H), 3.31-3.23 (m, 2H), 3.12 (s, 4H),
2.78 (s, 2H), 2.25 (s, 6H), 1.99 (s, 3H), 1.72 (s, 2H), 1.55-1.34
(m, 4H), 0.96 (s, 6H).
EXAMPLE 303
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 303A
5,6-dichloropyridine-3-sulfonamide
[2756] The title compound was prepared by substituting
5,6-dichloropyridine-3-sulfonyl chloride for
5-bromo-6-chloropyridine-3-sulfonyl chloride is EXAMPLE 305A.
EXAMPLE 303B
5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[2757] The title compound was prepared by substituting EXAMPLE 303A
for EXAMPLE 305A and (tetrahydro-2H-pyran-4-yl)methanol for
(1,3-dioxan-4-yl)methanol in EXAMPLE 305B.
EXAMPLE 303C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl-
}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2758] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 122C and EXAMPLE 303B for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.57 (d, 1H), 8.23 (s, 1H), 7.54 (d, 1H), 7.37 (dd, 1H), 7.35
(m, 3H), 7.26 (br d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.40 (s,
1H), 6.10 (s, 1H), 4.25 (d, 2H), 3.86 (dd, 2H), 3.33 (m, 2H), 3.06
(v br s, 4H), 2.86 (br s, 2H), 2.30 (v br s, 4H), 2.05 (m, 1H),
2.15 (br m, 2H), 1.95 (s, 2H), 1.63 (br d, 2H), 1.40 (t, 2H), 1.33
(ddd, 2H), 0.92 (s, 6H).
EXAMPLE 304
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfon-
yl)-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]benzamide
EXAMPLE 304A
4-Fluoro-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-benzoic
acid methyl ester
[2759] The title compound was prepared by substituting methyl
2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and
5-hydroxy-3,4-dihydro-2H-isoquinolin-1-one for 2-methyl-5-indolol
in EXAMPLE 3A, except here the heating was at 130.degree. C.
EXAMPLE 304B
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-pieprazin-1--
yl}-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-benzoic acid
methyl ester
[2760] The title compound was prepared by substituting EXAMPLE 304A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 304C
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmeithyl]-piperazin-1-
-yl}-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-5-yloxy)-benzoic
acid
[2761] The title compound was prepared by substituting EXAMPLE 304B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 304D
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfon-
yl)-2-[(1-oxo-1,2,3,4-tetrahydroisoquinolin-5-yl)oxy]benzamide
[2762] The title compound was prepared by substituting EXAMPLE 304C
for EXAMPLE 1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.37 (br
s, 1H), 8.22-8.18 (m, 2H), 7.93-7.84 (m, 2H), 7.57-7.52 (m, 1H),
7.45 (d, 1H), 7.36 (d, 2H), 7.12-7.02 (m, 3H), 6.72 (d, 1H), 6.59
(d, 1H), 6.36 (d, 1H), 3.62 (br s, 4H), 3.13 (br s, 4H), 2.95-2.69
(m, 6H) 2.68-2.35 (m, 4H), 2.32-3.03 (m, 10H), 2.02-1.84 (m, 4H),
1.42 (m, 6H), 0.94 (t, 6H)
EXAMPLE 305
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fl-
uoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 305A
5-bromo-6-chloropyridine-3-suIfonamide
[2763] 5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in
methanol (20 mL) was cooled to 0.degree. C. To this solution was
added 7N NH.sub.3 in methanol (80 mL). The reaction mixture was
stirred overnight. The solvent was removed at low temperature, and
the residue was partitioned between ethyl acetate and water. The
aqueous layer was extracted with ethyl acetate three times. The
combined organic layers were washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. The residue was purified by flash
column chromatography on silica gel to give the product.
EXAMPLE 305B
6-((1,4-dioxan-2-yl)methoxy-5-bromopyridine-3-sulfonamide
[2764] (1,4-Dioxan-2-yl)methanol (211 mg) in tetrahydrofuran (10
mL) was treated with 60% sodium hydride (125 mg). The reaction
mixture was stirred for 10 minutes. To this solution was added
EXAMPLE 305A (211 mg). The reaction mixture was stirred overnight.
It was poured into water, neutralized with 10% aqueous HCl, and
extracted with ethyl acetate three times. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated to afford the product.
EXAMPLE 305C
6-((1,4-dioxan-2-yl)methoxy)-5-cyanopyridine-3-sulfonamide
[2765] A mixture of EXAMPLE 305B (100 mg), dicyanozinc (20 mg), and
tetrakis(triphenylphosphine)palladium(0) (40 mg) in
N,N-dimethylformamide (0.5 mL) was degassed via vacuum/nitrogen
cycle three times. The reaction mixture was heated at 120.degree.
C. for 3 hours. After cooling, it was poured into water and
extracted with ethyl acetate three times. The combined organic
layers were washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified with flash column
chromatography on silica gel eluting with 2%-5%
methanol/dichloromethane to give the title compound.
EXAMPLE 305D
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5cyano-6-(1,4-dioxan-2-ylmethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fl-
uoro-1H-indol-5-yl)oxy]benzamide
[2766] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 305C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.14 (s,
1H), 8.76 (s, 1H), 8.55 (s, 1H), 7.57 (d, 1H), 7.33 (m, 4H), 7.12
(d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.34 (s, 1H), 6.14 (s, 1H),
4.44 (d, 2H), 3.91 (m, 1H), 3.80 (m, 2H), 3.63 (m, 2H), 3.46 (m,
2H), 3.33 (m, 4H), 3.09 (m, 4H), 2.35 (m, 2H), 2.17 (m, 2H), 1.98
(m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 306
N-({[5-bromo-6-(1,4-dioxan-2ylmethoxy)pyridino-3-yl]sulfonyl}-4-(4-{[2-(4--
chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6--
fluoro-1H-indol-5-yl)oxy]benzamide
[2767] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 305B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.19 (s,
1H), 8.58 (dd, 1H), 8.37 (d, 1H), 7.55 (d, 1H), 7.35 (m, 4H), 7.26
(d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.10 (d, 1H),
4.37 (m, 2H), 3.89 (m, 1H), 3.79 (m, 2H), 3.63 (m, 2H), 3.47 (m,
2H), 3.31 (m,2H), 3.06 (m, 4H), 2.85 (m, 2H), 2.32 (m, 2H), 2.14
(s, 2H), 1.96 (s, 2H), 1.38 (m, 2H), 0.91 (s, 6H).
EXAMPLE 307
Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfon-
yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 307A
Trans-5-bromo-6-((1r,4
r)-4-morpholinocyclohexylamino)pyridine-3-sulfonamide
[2768] A mixture of EXAMPLE 305A (1.0 g) trans
4-morpholinocyclohexanamine (0.95 g) and triethylamine (3.08 mL) in
anhydrous dixoane (20 mL) was heated at 110.degree. C. overnight.
The organic solvent was removed under vacuum. The residue was
purified with flash column chromatography on silica gel eluting
with 2%-8% methanol/dichloromethane to give the title compound.
EXAMPLE 307B
Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)amino]pyridin-3-yl}sulfon-
yl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipera-
zin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2769] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 307A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (m,
1H), 8.43 (d, 1H), 8.05 (d, 1H), 7.55 (d, 1H), 7.35 (m, 4H), 7.27
(d, 1H), 7.03 (d, 2H), 6.61 (dd, 1H), 6.49 (dd, 1H), 6.40 (dd, 1H),
3.93 (m, 1H), 3.60 (m, 4H), 3.38 (m, 2H), 2.98 (m, 4H), 2.70 (s,
2H), 2.60 (m, 4H), 2.34 (m, 1H), 2.15 (m, 6H), 1.92(d, 6H), 1.37
(m, 6H), 0.92 (s, 6H).
EXAMPLE 308
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl-
}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 308A
5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamid-
e
[2770] The title compound was prepared by substituting EXAMPLE 296C
for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 301A.
EXAMPLE 308B
5-cyano-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamid-
e
[2771] The title compound was prepared by substituting EXAMPLE 308A
for EXAMPLE 301A in EXAMPLE 301B.
EXAMPLE 308C
4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-y-
l)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}s-
ulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2772] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 308B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.15 (s,
1H), 8.79 (s, 1H), 8.59 (s, 1H), 7.57 (d, 1H), 7.34-7.37 (m, 3H),
7.30 (d, 1H), 7.13 (d, 1H), 7.05 (d, 2H), 6.64 (dd, 1H), 6.35 (s,
1H), 6.13 (s, 1H), 4.25 (d, 2H), 3.75-3.80 (m, 2H), 3.56-3.62 (m,
2H), 3.09 (s, 4H), 2.15-2.60 (m, 4H), 1.80-21.83 (m, 2H), 1.41 (d,
2H), 0.93 (s, 6H).
EXAMPLE 309
2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-yl-
methyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 309A
2-(3-chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
[2773] 1-Bromo-3-chloro-5-nitrobenzene (0.51 g),
bis(pinacolato)diboron (0.60 g), potassium acetate (0.63 g), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.09
g) were combined with dimethylformamide (5.3 mL), flushed with
nitrogen, heated at 60.degree. C. overnight, diluted with ethyl
acetate, washed with water and brine, dried (MgSO.sub.4), filtered,
concentrated and chromatographed on silica gel with 5-10% ethyl
acetate in hexanes as eluent to give the product.
EXAMPLE 309B
3-chloro-5-nitrophenol
[2774] EXAMPLE 309A (0.5 g) in tetrahydrofuran (10 mL) was treated
with a 4 N aqueous solution of sodium hydroxide (2.65 mL), heated
at 50.degree. C. for 4 hours, cooled to 0.degree. C., treated
dropwise with a 30% aqueous hydrogen peroxide solution (0.65 mL),
stirred overnight while warming to room temperature and then
quenched with saturated aqueous sodium thiosulfate solution. The
resulting mixture was partitioned between ethyl acetate and 1N
aqueous sodium hydroxide solution and the organic portion was set
aside. The aqueous layer was acidified to pH 4 with 2N aqueous HCl
solution and extracted with ethyl acetate (2.times.100 mL). These
extracts were combined, washed with brine, dried (MgSO.sub.4),
filtered, concentrated and chromatographed on silica gel with 5-10%
ethyl acetate in hexanes as eluent to give the product.
EXAMPLE 309C
methyl 2-(3-chloro-5-nitrophenoxy)-4-fluorobenzoate
[2775] The title compound was prepared by substituting methyl
2,4-difluorobenzoate for ethyl 2,4-difluorobenzoate and EXAMPLE
309B for 2-methyl-5-indolol in EXAMPLE 3A.
EXAMPLE 309D
methyl 2-(3-amino-5-chlorophenoxy)-4-fluorobenzoate
[2776] EXAMPLE 309C (0.31 g) in a 1:1 mixture of methanol and
tetrahydrofuran (9.5 mL) was treated with tin(II) chloride
dihydrate (1.06 g), heated at 65.degree. C. for 4 hours and
filtered through a pad of celite rinsing with ethyl acetate. The
filtrate was washed with water and brine, dried (MgSO.sub.4),
filtered, concentrated and chromatographed on silica gel with
10-20% ethyl acetate in hexanes as eluent to give the product.
EXAMPLE 309E
methyl 2-(3-amino-5-chlorophenoxy)-4-(piperazin-1-yl)benzoate
[2777] The title compound was prepared by substituting piperazine
for EXAMPLE 3F and EXAMPLE 309D for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 309F
1-chloro-4-(2-(chloromethyl)-5,5-dimethylcyclohex-1-enyl)benzene
[2778] EXAMPLE 3D (0.251 g) in tetrahydrofuran (5 mL) at 0.degree.
C. was treated sequentially with N,N-diisopropylethylamine (0.524
mL) and methanesulfonyl chloride (0.086 mL) and then stirred for
1.5 hours. Additional N,N-diisopropylethylamine (0.524 mL) and
methanesulfonyl chloride (0.086 mL) were added and stirring was
continued for another hour. The reaction mixture was diluted with
ethyl acetate, washed with water and brine, dried (MgSO.sub.4),
filtered and concentrated. The concentrate was slurried in a 1:1
mixture of diethyl ether and dichloromethane and unreacted EXAMPLE
3D was removed by filtration. The filtrate was concentrated. The
mixture was swirled with diethyl ether and the liquid decanted
three times. The decanted diethyl ether mixture was concentrated
and dried under vacuum to give the product.
EXAMPLE 309G
methyl
2-(3-amino-5-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2779] EXAMPLE 309F (0.109 g) in N,N-dimethylformamide (2 mL) was
treated with EXAMPLE 309E (0.15 g) and cesium carbonate (0.264 g),
stirred at ambient temperature over two nights, diluted with ethyl
acetate, washed with water and brine, dried (MgSO.sub.4), filtered,
concentrated and chromatographed on silica gel with 0 to 5% acetone
in dichloromethane as eluent to give the product.
EXAMPLE 309H
2-(3-amino-5-chlorophenoxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2780] The title compound was prepared by substituting EXAMPLE 309G
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 309I
2-(3-amino-5-chlorophenoxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-
-1-en-1-yl]methyl})piperazin-1-yl)-N-({3-nitro-4-[(tetrahydra-2H-pyran-4-y-
lmethyl)amino]phenyl}sulfonyl)benzamide
[2781] The title compound was prepared by substituting EXAMPLE 309H
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.42 (s, 1H), 8.62 (t, 1H),
8.52 (d, 1H), 7.74 (dd, 1H), 7.48 (d, 1H), 7.36 (d, 2H), 7.13 (d,
1H), 7.07 (d, 2H), 6.74 (dd, 1H), 6.41 (d, 1H), 6.22 (t, 1H), 5.92
(m, 2H), 5.47 (s, 2H), 3.86 (dd, 2H), 3.32 (m, 4H), 3.18 (m, 4H),
2.80 (m, 2H), 2.21 (m, 6H), 1.98 (s, 2H), 1.89 (m, 1H), 1.64 (dd,
2H), 1.41 (t, 2H), 1.26 (m, 2H), 0.95 (s, 6H).
EXAMPLE 310
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-f-
luoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 310A
5-bromo-6-(2-morpholinoethoxy)pyridine-3-sulfonamide
[2782] The title compound was prepared by substituting
2-morpholinoethanol for (tetrahydro-2H-pyran-4-yl)methanol in
EXAMPLE 301A.
EXAMPLE 310B
5-cyano-6-(2-morpholinoethoxy)pyridine-3-sulfonamide
[2783] The title compound was prepared by substituting EXAMPLE 310A
for EXAMPLE 301A in EXAMPLE 301B.
EXAMPLE 310C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-[(6-fl-
uoro-1H-indol-5-yl)oxy]benzamide
[2784] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 310B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.14 (s,
1H), 8.75 (d, 1H), 8.52 (d, 1H), 7.58 (d, 1H), 7.33-7.36 (m, 3H),
7.28 (d, 1H), 7.09 (d, 1H), 7.05 (d, 2H), 6.62 (dd, 1H), 6.34 (s,
1H), 6.12 (s, 1H), 4.62 (t, 2H), 3.25-3.61 (m, 4H), 3.05 (s, 4H),
2.93 (s, 4H), 2.68 (s, 4H), 2.32-2.36 (m, 4H), 2.15 (s, 2H), 1.96
(s, 2H), 1.40 (d, 2H), 0.93 (s, 6H).
EXAMPLE 311
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylcycloh-
exyl)oxy]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 311A
Trans-4-(4-aminocyclohexyloxy)-3-nitrobenzenesulfonamide
[2785] to a solution of tert-butyl 4-hydroxycyclohexylcarbamate
(0.250 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.186
g). After stirring for 15 minutes,
4-fluoro-3-nitrobenzensulfonamide (0.256 g) was added as a solution
in tetrahydrofuran (1 mL). The reaction was heated to 60.degree. C.
for 1.5 hours, cooled and poured into a mixture of dichloromethane
(100 mL) and water (25 mL). The aqueous layer was adjusted to
pH.about.4 with 1N aqueous HCl and the organic layer was separated,
washed with brine (50 mL), dried over magnesium sulfate and
concentrated. The residue was loaded onto silica gel (GraceResolve
40 g) and eluted using a gradient of 0.5% to 7.5%
methanol/dichloromethane over 30 minutes. This solid was
immediately treated with HCl (4.0 M in dioxane, 5 mL) at room
temperature for 1 hours and concentrated to give the title
compound.
EXAMPLE 311B
[2786]
Trans-4-(4-morpholinocyclohexyloxy-3-nitrobenzenesulfonamide
[2787] To EXAMPLE 311A (0.220 g) and
1-bromo-2-(2-bromoethoxy)ethane (0.177 g) in N,N-dimethylformamide
(3 mL) was added triethylamine (0.338 mL) and the reaction heated
to 70.degree. C. for 5 hours. The reaction was cooled and the
resulting precipitate removed by filtration. The reaction was
concentrated and loaded onto silica gel and eluted using a gradient
of 0.5% to 7.5% methanol/dichloromethane to give the title
compound.
EXAMPLE 311C
Trans-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-morpholinocyclohexyl-
oxy)-3-nitrophenylsulfonyl)benzamide
[2788] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 311B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.21-11.09 (m, 1H), 8.29-8.13 (m, 2H), 8.03-7.88 (m, 1H), 7.54 (s,
1H), 7.33 (d, 4H), 7.21-7.11 (m, 1H), 7.04 (d, 2H), 6.97-6.89 (m,
1H), 6.66-6.51 (m, 1H), 6.43-6.31 (m, 1H), 6.08 (s, 1H), 4.62-4.49
(m, 1H), 3.62 (s, 4H), 2.98 (s, 4H), 2.68 (d, 7H), 2.19 (s, 8H),
1.95 (s, 4H), 1.38 (s, 6H), 0.92 (s, 6H).
EXAMPLE 312
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-y-
l}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methy-
l}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 312A
5-bromo-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)pyridine-3-sulf-
onamide
[2789] The title compound was prepared by substituting EXAMPLE 49B
for trans 4-morpholinocyclohexanamine in EXAMPLE 307A.
EXAMPLE 312B
N-({5-bromo-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]pyridin-3-y-
l}sulfonyl-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl-
}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2790] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 312A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.16 (s,
1H), 8.40 (d, 1H), 8.05 (d, 1H), 7.56 (d, 1H), 7.32 (m, 4H), 7.19
(m, 1H), 7.04 (d, 2H), 6.58 (d, 1H), 6.38 (s, 1H), 6.05 (s, 1H),
4.05 (m, 1H), 3.93 (d, 2H), 3.24 (m, 8H), 2.96 (m, 4H), 2.72 (m,
3H), 2.15 (m, 6H), 1.93 (m, 2H), 1.85 (m, 4H), 1.55 (m, 2H), 1.38
(t, 2H), 1.17 (t, 2H), 0.91 (s, 6H).
EXAMPLE 313
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
EXAMPLE 313A
2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)-N-(4-((4-fluorotetrahydro-2H-pyran-4-yl)m-
ethoxy)-3-nitrophenylsulfonyl)benzamide
[2791] The title compound was prepared by substituting EXAMPLE 266D
for EXAMPLE 1F and EXAMPLE 296D for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 313B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulf-
onyl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
[2792] The title compound was prepared by substituting EXAMPLE 313A
for EXAMPLE 265E in EXAMPLE 267. .sup.1H NMR (500 MHz, methylene
chloride-d.sub.2) .delta. 8.44 (d, 1H), 8.24 (dd, 1H), 7.86 (d,
1H), 7.71 (s, 1H), 7.24 (m, 3H), 7.19 (d, 1H), 6.97 (d, 2H), 6.77
(d, 1H), 6.62 (d, 2H), 6.14 (d, 1H), 4.19 (d, 2H), 3.84 (m, 2H),
3.75 (m, 2H), 3.39 (s, 2H), 3.14 (br.s, 4H), 2.77 (s, 2H),
2.30-2.10 (m, 6H), 1.99 ((br.s, 2H), 1.95-1.87 (m, 4H), 1.55 (m,
2H), 1.43 (t, 2H), 0.95 (s, 6H).
EXAMPLE 314
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-te-
trahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohe-
xyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
EXAMPLE 314A
oxepan-4-one
[2793] Tetrahydro-2H-pyran-4-one (5 g) was placed in methanol (30
mL) in the presence of barium oxide (0.85 g). Nitrosomethylurethane
(6.6 g) was added slowly to the reaction mixture. During the
addition, barium oxide (1.0 g) was added by small portions. The
reaction mixture was stirred 3 hours at room temperature and then
filtrated. The methanol was evaporated, diethyl ether was then
added to the residue, and a precipitate was formed. The mixture was
filtrated and diethyl ether evaporated to afford the product.
EXAMPLE 314B
(Z)-5-chloro-2,3,6,7-tetrahydrooxepine-4-carbaldehyde
[2794] Phosphorus oxychloride (3.45 mL) was added dropwise to a
cooled (0.degree. C.) solution of EXAMPLE 314A (4.2 g) in
N,N-dimethylformamide (12 mL) and dichloromethane (30 mL). The
mixture was then stirred at room temperature overnight before it
was diluted with ethyl acetate (300 mL) and washed with aqueous
sodium acetate, water (3.times.), brine and dried over
Na.sub.2SO.sub.4. After filtration and concentration, the crude
product was used directly in the next reaction without further
purification.
EXAMPLE 314C
(Z)-5-(4-chlorophenyl)-2,3,6,7-tetrahydrooxepine-4-carbaldehyde
[2795] To a mixture of 4-chlorophenylboronic acid (6.10 g), EXAMPLE
314B (5.2 g), palladium(II) acetate (146 mg, 0.65 mmol),
K.sub.2CO.sub.3 (13.5 g) and tetrabutylammonium bromide (10.5 g)
was added water (200 mL). The mixture was stirred at 50.degree. C.
for 4 hours. The mixture was diluted with ethyl acetate (400 mL)
and washed with water (3.times.) and brine and dried over
Na.sub.2SO.sub.4. After filtration and concentration, the residue
was loaded on a column and eluted with 5 to 20% ethyl acetate in
hexane to give the pure product.
EXAMPLE 314D
(Z)-ethyl
2-(6-chloro-1H-indol-5-yloxy)-4-(4-((5-(4-chlorophenyl)-2,3,6,7--
tetrahydrooxepin-4-yl)methyl)piperazin-1-yl)benzoate
[2796] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 38E and EXAMPLE 38E with EXAMPLE 242F and
EXAMPLE 314C.
EXAMPLE 314E
(Z)-2-(6-chloro-1H-indol-5-yoxy)-4-(4-((5-(4-chlorophenyl)-2,3,6,70tetrahy-
drooxepin-4-yl)methyl)piperazin-1-yl)benzoic acid
[2797] The title compound was prepared as described in EXAMPLE 38G
by replacing EXAMPLE 34B with EXAMPLE 314D.
EXAMPLE 314F
Trans-4-(4-morpholinocyclohexylamino)-3-(trifluoromethylsulfonyl)benzenesu-
lfonamide
[2798] The title compound was prepared by substituting trans
4-morpholinocyclohexanamine for 3-(N-morpholinyl)-1-propylamine and
EXAMPLE 131C for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE
4A.
EXAMPLE 314G
Trans-2-[(6-chloro)-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-t-
etrahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcycloh-
exyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
[2799] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 314E and
EXAMPLE 314F, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.38 (s, 1H), 8.20 (m, 1H),
7.98 (dd, 1H), 7.53 (m, 4H), 7.38 (m, 3H), 7.13 (m, 3H), 6.98 (m,
1H), 6.72 (m, 3H), 6.45 (d, 1H), 3.86 (m, 12H), 3.36 (m, 3H), 3.02
(m, 6H), 2.74 (d, 8H), 2.18 (m, 4H), 1.65 (m, 2H).
EXAMPLE 315
Trans-2-[(6-chloro-1H-indol-5-yl)oxy]-4-(4-{[5-(4-chlorophenyl)-2,3,6,7-te-
trahydrooxepin-4-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohe-
xyl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2800] The title compound was prepared in EXAMPLE 1H by replacing
EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 314E and EXAMPLE 205A,
respectively. .sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6)
.delta. 11.09 (s, 1H), 8.38 (d, 1H), 8.01 (d, 1H), 7.70 (dd, 1H),
7.57 (d, 1H), 7.46 (s, 1H), 7.34 (m, 3H), 7.07 (d, 2H), 6.91 (m,
2H), 6.57 (m, 2H), 6.30 (s, 1H), 6.02 (d, 1H), 3.61 (m, 10H), 2.98
(m, 12H), 2.28 (m, 8H), 1.95 (m, 4H), 1.36 (m, 2H).
EXAMPLE 316
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-methylpiperazin-1--
yl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2801] The title compound was prepared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 277B and
EXAMPLE 184A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.18 (s, 1H), 9.16 (s, 1H),
8.52 (d, 1H), 7.89 (dd, 1H), 7.56 (m, 2H), 7.31 (m, 5H), 7.13 (d,
2H), 6.62 (dd, 1H), 6.39 (s, 1H), 6.07(d, 1H), 4.09 (m, 2H), 2.95
(m, 9H), 2.81 (s, 2H), 2.35 (s, 3H), 2.16 (m, 6H), 1.18 (s,
6H).
EXAMPLE 317
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)o-
xy]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 317A
4-morpholinobut-2-yn-1-ol
[2802] To a solution of morpholine (4.36 g) in toluene (15 mL) was
added 4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 mL). The
solution was stirred at 85.degree. C. for 3 hours. After cooling,
the solid was filtered off. The filtrate was subjected to vacuum
distillation to give the title compound.
EXAMPLE 317B
4-(4-morpholinobut-2-ynyloxy)-3-nitrobenzenesulfonamide
[2803] The title compound was prepared by substituting EXAMPLE 317A
for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 264A.
EXAMPLE 317C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({4-[(4-morpholin-4-ylbut-2-ynyl)o-
xy]-3-nitrophenyl}sulfonyl)benzamide
[2804] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 317B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.12 (s,
1H), 8.39 (d, 1H), 8.14 (dd, 1H), 7.52-7.54 (m, 2H), 7.34-7.39 (m,
3H), 7.32-7.35 (m, 3H), 7.29 (d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H),
6.41 (s, 1H), 6.09 (d, 1H), 5.16 (s, 2H), 3.52-3.55 (m, 4H), 3.05
(s, 4H), 2.82 (s, 4H), 2.37-2.39 (m, 4H), 2.26 (s, 4H), 1.95 (s,
2H), 1.39 (d, 2H), 0.92 (s, 6H).
EXAMPLE 318
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 318A
methyl 4-fluoro-2-(6-nitropyridin-3-yloxy)benzoate
[2805] To a solution of methyl 4-fluoro-2-hydroxybenzoate (23.5 g)
and 2-nitro-5-chloropyridine (21.9 g) in N,N-dimethylformamide (120
mL) was added cesium carbonate (45 g). The mixture was stirred at
50.degree. C. overnight. The mixture was diluted with ethyl acetate
(800 mL) and washed with water (3.times.) and brine. After drying
over Na.sub.2SO.sub.4 and filtration, the solvent was evaporated
under vacuum and the residue was purified by silica gel
chromatography (2% ethyl acetate in dichloromethane) to give the
title compound.
EXAMPLE 318B
methyl 2-(6-aminopyridin-3-yloxy)-4-fluorobenzoate
[2806] EXAMPLE 318A (12.995 g) and methanol (150 mL) were added to
Ra--Ni, water wet A-7000 (6.50 g) in a 250 mL SS pressure bottle
and stirred for 2 hours at 30 psi and room temperature. The mixture
was filtered through a nylon membrane and concentrated to give the
title compound.
EXAMPLE 318C
Methyl 2-(6-amino-5-chloropyridin-3-yloxy)-4-fluorobenzoate
[2807] EXAMPLE 318B (3.0 g) and 1-chloropyrrolidine-2,5-dione
(1.680 g) were stirred together in N,N-dimethylformamide (30 mL) at
room temperature under nitrogen for 16 hours. The reaction was
diluted with ethyl acetate (200 mL) and washed with water (75 mL),
brine (75 mL), dried over magnesium sulfate, filtered and
concentrated. Silica gel chromatography (GraceResolv 80 g) eluting
with a gradient of 5% to 35% ethyl acetate/hexanes over 40 minutes
(Flow=40 mL/min) gave the title compound.
EXAMPLE 318D
methyl
2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2808] The title compound was prepared by substituting EXAMPLE 318C
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 318E
2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2809] The title compound was prepared by substituting EXAMPLE 318D
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 318F
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2810] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 9.86 (s, 1H), 8.89 (d, 1H), 8.52 (t, 1H), 8.17 (dd, 1H),
7.96-7.83 (m, 2H), 7.36 (d, 1H), 7.23 (s, 1H), 6.99-6.86 (m, 3H),
6.54 (dd, 1H), 5.97 (d, 1H), 4.95 (s, 2H), 4.01 (d, 2H), 3.42 (d,
2H), 3.32-3.22 (m, 2H), 3.12 (s, 4H), 2.78 (s, 2H), 2.22 (d, 6B),
1.99 (s, 2H), 1.72 (s, 2H), 1.50-1.34 (m, 5H), 0.96 (s, 6H).
EXAMPLE 319
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin--
4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 319A
4-(1-Methanesulfonyl-piperidin-4-ylamino)-
3-nitro-benzenesulfonamide
[2811] The title compound was prepared by substituting
1-(methylsulfonyl)piperidin-4-amine for tert-butyl
4-aminopiperidine-1-carboxylate in EXAMPLE 140A.
EXAMPLE 319B
4-(4-{[2-(4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-[(6-fluoro-
-1H-indol-5-yl)oxy]-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitr-
ophenyl)sulfonyl]benzamide
[2812] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 319A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.21 (br
s, 1H), 8.59 (d, 1H), 8.26 (d, 1H), 7.89 (dd, 1H), 7.50 (d, 1H),
7.38 (t, 1H), 7.34 (d, 2H), 7.31 (t, 1H), 7.28 (d, 1H), 7.22 (d,
1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.40 (t, 1H), 6.10 (d, 1H), 3.82
(m, 1H), 3.56 (dt, 2H), 3.09 (br s, 4H), 2.96 (dd, 2H), 2.92 (s,
3H), 2.73 (m, 2H), 2.25-2.08 (m, 6H), 2.02 (dd, 2H), 1.95 (br s,
2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 320
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfon-
yl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
EXAMPLE 320A
Trans-2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(4-morpholinocyclohexylamino)--
3-nitrophenylsulfonyl)benzamide
[2813] The title compound was prepared by substituting EXAMPLE 266D
for EXAMPLE 1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 320B
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfon-
yl)-2-[(2-oxo-2,3-dihydro-1H-indol-4-yl)oxy]benzamide
[2814] The title compound was prepared by substituting EXAMPLE 320A
for EXAMPLE 265E in EXAMPLE 267. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.37 (s, 1H), 8.41 (s, 1H),
8.17 (d, 1H), 7.72 (d, 1H), 7.48 (d, 1H), 7.36 (d, 2H), 7.13 (d,
1H), 7.06 (d, 2H), 6.95 (t, 1H), 6.74 (d, 1H), 6.44 (m, 2H), 6.12
(d, 1H), 3.70-3.58 (m, 4H), 3.34 (m, 2H), 3.24 (s, 2H), 3.16 (br.s,
4H), 2.79 (m, 6H), 2.25 (m, 3H), 2.18 (m, 3H), 2.12 (m, 2H), 1.98
(m, 4H), 1.55-1.40 (m, 4H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 321
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3--
dihydro-1H-indol-4-yl)oxy]benzamide
EXAMPLE 321A
2-(3-chloro-1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcycloh-
ex-1-enyl)methyl)piperazin-1-yl)-N-(4-(2-methoxyethylamino)-3-nitrophenyls-
ulfonyl)benzamide
[2815] The title compound was prepared by substituting EXAMPLE 266D
for EXAMPLE 1F and EXAMPLE 263A for EXAMPLE 1G in EXAMPLE 1H.
EXAMPLE 321B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)-2-[(2-oxo-2,3--
dihydro-1H-indol-4-yl)oxy]benzamide
[2816] The title compound was prepared by substituting EXAMPLE 321A
for EXAMPLE 265E in EXAMPLE 267. .sup.1H NMR (500 MHz, methylene
chloride-d.sub.2) .delta. 9.80 (br.s, 1H), 8.73 (d, 1H), 8.56 (t,
1H), 8.00 (dd, 1H), 7.87 (d, 1H), 7.76 (br.s, 1H), 7.25 (d, 2H),
7.22 (t, 1H), 7.96 (d, 2H), 6.94 (d, 1H), 6.74 (d, 1H), 6.62 (m,
2H), 6.16 (d, 1H), 3.68 (t, 2H), 3.54 (t, 2H), 3.41 (s, 3H), 3.37
(s, 2H), 3.13 (br.s, 4H), 2.77 (m, 2H), 2.30-2.18 (m, 6H), 1.99
(br.s, 2H), 1.43 (t, 2H), 0.95 (s, 6H).
EXAMPLE 322
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ytmethoxy)pyridin-3-yl]sulfon-
yl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 322A
6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-((triisopropylsilyl)ethynyl)pyridi-
ne-3-sulfonamide
[2817] EXAMPLE 301B (0.176 g), bis(triphenylphosphine)palladium(II)
chloride (0.176 g), copper(I) iodide (0.010 g),
N,N-dimethylacetamide (2.5 mL) and triethylamine (0.105 mL) were
combined, flushed with nitrogen and stirred for 2 minutes.
(Triisopropyl)acetylene (0.135 mL) was added and the reaction
mixture was flushed with nitrogen again, heated at 60.degree. C.
overnight, diluted with ethyl acetate, washed with water and brine,
dried (MgSO.sub.4), filtered, concentrated and chromatographed on
silica gel with 10-30% ethyl acetate in hexanes as eluent to give
the product.
EXAMPLE 322B
5-ethynyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide
[2818] EXAMPLE 322A (0.205 g) in tetrahydrofuran (3 mL) at ambient
temperature was treated with tetrabutyl ammonium fluoride (1 M in
tetrahydrofuran) (0.906 mL) and stirred at ambient temperature for
4 hours. Additional tetrabutyl ammonium fluoride (1 M in
tetrahydrofuran) (1.8 mL) was added and the mixture was heated at
40.degree. C. for 45 minutes. Solid tetrabutyl ammonium fluoride
(0.253 g) was added and heating was continued for 30 minutes. The
reaction mixture was concentrated and then chromatographed on
silica gel using 0-2% methanol in dichloromethane as eluent to give
the product.
EXAMPLE 322C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfon-
yl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2819] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 322B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.21 (s,
1H), 8.62 (d, 1H), 8.22 (d, 1H), 7.53 (d, 1H), 7.35 (m, 5H), 7.04
(d, 2H), 6.65 (dd, 1H), 6.41 (m, 1H), 6.08 (s, 1H), 4.56 (s, 1H),
4.25 (d, 2H), 3.86 (dd, 2H), 3.35 (m, 2H), 3.05 (m, 4H), 2.81 (m,
2H), 2.24 (m, 6H), 2.04 (m, 1H), 1.95 (s, 2H), 1.64 (dd, 2H), 1.36
(m, 4H), 0.92 (s, 6H).
EXAMPLE 323
4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}pi-
perazin-1-yl)-N-{[5ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl-
]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2820] The title compound was prepared by substituting EXAMPLE 277B
for EXAMPLE 1F and EXAMPLE 322B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 12.39 (s, 1H), 9.27
(d, 1H), 8.90 (d, 1H), 8.09 (d, 1H), 7.52 (t, 1H), 7.46 (m, 4H),
7.10 (m, 2H), 6.68 (dd, 2H), 6.60 (m, 1H), 6.50 (d, 1H), 4.49 (s,
1H), 4.38 (m, 2H), 4.22 (d, 2H), 3.95 (dd, 2H), 3.29 (td, 2H), 2.98
(m, 4H), 2.82 (s, 2H), 2.21 (m, 2H), 2.09 (m, 4H), 1.98 (m, 1H),
1.63 (dd, 2H), 1.42 (m, 2H), 1.29 (s, 6H).
EXAMPLE 324
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-yl-
cyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2821] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 205A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.45-10.43 (m, 1H), 8.56 (d, 1H), 8.20 (d, 1H), 7.86 (d, 1H), 7.73
(d, 1H), 7.44 (d, 1H), 7.35 (d, 3H), 7.23 (d, 1H), 7.06 (d, 2H),
6.64 (d, 1H), 6.16 (d, 3H), 3.70 (s, 5H), 3.11 (s, 4H), 2.77 (s,
6H), 2.10 (d, 12H), 1.43 (d, 6H), 0.94(s, 6H).
EXAMPLE 325
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-
-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 325A
1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ol
[2822] Piperidin-4-ol (7.8 g) and dihydro-2H-pyran-4(3H)-one (5.0
g) were dissolved in titanium(IV) isopropoxide (30 mL) and the
reaction was stirred at room temperature overnight. Next day
methanol (40 mL) was added and the reaction was cooled to 0.degree.
C. Then NaBH.sub.4 (3.8 g) was added in portions over one hour.
After two hours 1N aqueous NaOH was added, followed by ethyl
acetate addition. After filtration through celite the layers were
separated, the aqueous layer extracted with ethyl acetate, and the
combined organic layers were dried over Na.sub.2SO.sub.4. The crude
material was purified by column chromatography using
CH.sub.2Cl.sub.2 having 5-10% 7N NH.sub.3 in methanol.
EXAMPLE 325B
5-chloro-6-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)pyridine-3-sulfo-
namide
[2823] The title compound was prepared by substituting EXAMPLE 303A
for EXAMPLE 305A and EXAMPLE 325A for (1,3-dioxan-4-yl)methanol in
EXAMPLE 305B.
EXAMPLE 325C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({5-cyano-6-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]pyridin-
-3-yl}sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2824] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 122C and EXAMPLE 325B for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.06 (s,
1H), 8.64 (s, 1H), 8.37 (s, 1H), 7.60 (d, 1H), 7.35 (d, 2H), 7.28
(s, 1H), 7.24 (d, 1H), 7.04 (d, 2H), 6.96 (d, 1H), 6.55 (d, 1H),
6.27 (s, 1H), 6.09 (s, 1H), 5.20 (m, 1H), 3.90 (d, 2H), 3.30 (m,
5H), 2.96 (br m, 6H), 2.72 (s, 2H), 2.19 (br m, 6H), 2.00 (m, 2H),
1.95 (s, 2H), 1.78 (br m, 4H), 1.47 (br m, 2H), 1.39 (t, 2H), 0.92
(s, 6H).
EXAMPLE 326
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 326A
5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonami-
de
[2825] The title compound was prepared by substituting EXAMPLE 303A
for EXAMPLE 305A and EXAMPLE 296C for (1,3-dioxan-4-yl)methanol in
EXAMPLE 305B.
EXAMPLE 326B
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pip-
erazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2826] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 122C and EXAMPLE 326A for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.18 (s,
1H), 8.75 (s, 1H), 8.27 (s, 1H), 7.55 (d, 1H), 7.34 (m, 4H), 7.23
(br d, 1H), 7.04 (d, 2H), 6.84 (dd, 1H), 6.40 (s, 1H), 6.09 (s,
1H), 4.53 (d, 2H), 3.77 (m, 2H), 3.60 (m, 2H), 3.06 (v br s, 4H),
2.82 (br s, 2H), 2.27 (v br s, 4H), 2.15 (br m, 2H), 1.95 (s, 2H),
1.85 (m, 4H), 1.40 (t, 2H), 0.92 (s, 6H).
EXAMPLE 327
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-
-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2827] The title compound was pre3pared as described in EXAMPLE 1H
by replacing EXAMPLE 1F and EXAMPLE 1G with EXAMPLE 154E and
EXAMPLE 65A, respectively. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.21 (s, 1H), 8.57 (d, 1H),
8.24 (d, 1H), 7.87 (dd, 1H), 7.50 (d, 1H), 7.33 (m, 5H), 7.18 (d,
1H), 7.03 (d, 2H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.09 (s, 1H), 3.70
(m, 1H), 2.98 (m, 6H), 2.73 (s, 2H), 2.23 (m, 6H), 1.93 (m, 4H),
1.76 (m, 1H), 1.57 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H), 0.43 (m,
5H).
EXAMPLE 328
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-
-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 328A
(4-ethylmorpholin-3-yl)methanol
[2828] Morpholin-3-ylmethanol (500 mg) and iodoethane (666 mg) in
N,N-dimethylformamide was treated with K.sub.2CO.sub.3 (1.1 g)
overnight. The reaction mixture was diluted with water and
extracted with ethyl acetate. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated to provide the title
compound.
EXAMPLE 328B
4-((4-ethylmorpholin-3-yl)methoxy)-3-nitrobenzenesulfonamide
[2829] The title compound was prepared as described in EXAMPLE 285A
by replacing (1,4-dioxan-2-yl)methanol with EXAMPLE 328A.
EXAMPLE 328C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(4-ethylmorpholin-3-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-[(6-
-fluoro-1H-indol-5-yl)oxy]benzamide
[2830] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 154E and
EXAMPLE 328B, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.21 (s, 2H), 8.37 (d, 1H),
8.10 (dd, 1H), 7.52 (t, 2H), 7.37 (t, 1H), 7.31-7.36 (m, 3H), 7.26
(d, 1H), 7.04 (d, 2H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.09 (d, 1H),
4.43 (dd, 1H), 4.24 (dd, 1H), 3.80 (dd, 1H), 3.64-3.74 (m, 1H),
3.49-3.61 (m, 2H), 3.03 (s, 4H), 2.92 (s, 1H), 2.78 (s, 4H),
2.52-2.60 (m, 1H), 2.45 (s, 1H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95
(s, 2H), 1.38 (t, 2H), 1.00 (t, 3H), 0.92 (s, 6H).
EXAMPLE 329
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-
-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide
EXAMPLE 329A
(S)-tert-butyl
1-(tetrahydro-2H-pyran-4-yl)piperidin-3-ylcarbamate
[2831] The title compound was prepared by substituting
dihydro-2H-pyran-4(3H)-one for 4'-chlorobiphenyl-2-carboxaldehyde
and (S)-tert-butylpiperidin-3-ylcarbamate for tert-butyl
piperazine-1-carboxylate on EXAMPLE 1A.
EXAMPLE 329B
(S)-1-(tetrahydro-2H-pyran-4-yl)piperidin-3-amine
[2832] The title compound was prepared by substituting EXAMPLE 329A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 329C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[(3S)-1-tetrahydro-2H-
-pyran-4-ylpiperidin-3-yl]amino}phenyl)sulfonyl]benzamide
[2833] The title compound was prepared by substituting EXAMPLE 329B
for 2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol in EXAMPLE 240B.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.92 (br
s, 1H), 8.58 (br s, 1H), 7.85 (m, 1H), 7.52 (d, 1H), 7.37 (m, 1H),
7.33 (m, 3H), 7.28 (br s, 1H), 7.10 (br s, 1H), 7.03 (d, 2H), 6.65
(m, 1H), 6.40 (br s, 1H), 6.08 (m, 1H), 3.98 (br s, 1H), 3.90 (m,
2H), 3.27 (m, 2H), 3.01 (m, 4H), 2.77 (m, 4H), 2.60 (m, 2H), 2.16
(m, 6H), 1.94 (m, 2H), 1.64 (m, 5H), 1.50 (m, 3H), 1.38 (m, 2H),
1.23 (m, 1H), 0.94 (s, 6H).
EXAMPLE 330
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide
[2834] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 296D for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.88 (s, 1H), 8.58 (d,
1H), 8.38 (dd, 1H), 7.91 (t, 2H), 7.36 (d, 1H), 7.29-7.11 (m, 3H),
6.94 (d, 2H), 6.62-6.47 (m, 1H), 5.96 (s, 1H), 4.96 (s, 2H), 4.19
(d, 2H), 3.81 (dt, 4H), 3.13 (s, 4H), 2.78 (s, 2H), 2.22 (d, 6H),
2.07-1.78 (m, 6H), 1.44 (s, 2H), 0.97 (d, 6H).
EXAMPLE 331
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-
-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 331A
3-nitro-4-dioxidothiomorpholinoamino)benzenesulfonamide
[2835] The title compound was prepared by substituting
4-aminothiomorpholine-1,1-dioxide for
3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.
EXAMPLE 331B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-
-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2836] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 331A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.22 (s,
1H), 9.65 (s, 1H), 8.56 (d, 1H), 7.88 (m, 2H), 7.51 (d, 1H), 7.35
(m, 5H), 7.03 (d, 2H), 6.64 (dd, 1H), 6.41 (d, 1H), 6.07 (d, 1H),
3.46 (m, 4H), 3.18 (m, 4H), 3.02 (m, 4H), 2.73 (s, 2H), 2.15 (m,
6H), 1.95 (s, 2H), 1.38 (t, J=6.15 Hz, 2H), 0.92 (s, 6H).
EXAMPLE 332
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-yl-
methyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 332A
3-nitro-4-((tetrahydrofuran-3-yl)methylamino)benzenesulfonamide
[2837] The title compound was prepared by substituting
2-aminomethyl-tetrahydrofuran for 3-(N-morpholinyl)-1-propylamine
in EXAMPLE 4A.
EXAMPLE 332B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-({3-nitro-4-[(tetrahydrofuran-3-yl-
methyl)amino]phenyl}sulfonyl)benzamide
[2838] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 332A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.30
(br.s, 1H), 11.23 (s, 1H), 8.66 (t, 1H), 8.59 (d, 1H), 7.87 (dd,
1H), 7.50 (d, 1H), 7.38 (t, 1H), 7.34 (m, 3H), 7.30 (d, 1H), 7.16
(d, 1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.41 (s, 1H), 6.10 (s, 1H),
3.80 (q, 1H), 3.70 (t, 1H), 3.63 (q, 1H), 3.51 (dd, 1H), 3.40 (m,
2H), 3.06 (br.s, 4H), 2.80 (m, 2H), 2.58 (m, 2H), 2.35-2.10 (m,
5H), 2.00-1.90 (m, 3H), 1.65 (m, 1H), 1.39 (t, 2H), 0.94 (s,
6H).
EXAMPLE 333
Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 333A
trans-4-morpholinocyclohexanol
[2839] Trans-4-aminocyclohexanol (0.5 g),
1-bromo-2-(2-bromoethoxy)ethane (1.07 g) and triethylamine (2.42
mL) were dissolved in anhydrous acetonitrile (20 mL). The reaction
mixture was heated at 60.degree. C. overnight. The organic solvent
was removed under vacuum. The residue was purified by flash column
chromatography on silica gel eluting with 7-10% methanol in
dichloromethane to give the title compound.
EXAMPLE 333B
Trans-5-bromo-6-(4-morpholinocyclohexyloxy)pyridine-3-sulfonamide
[2840] The title compound was prepared by substituting EXAMPLE 333A
for (1,4-dioxan-2-yl)methanol in EXAMPLE 305B.
EXAMPLE 333C
Trans-N-({5-bromo-6-[(4-morpholin-4-ylcyclohexyl)oxy]pyridin-3-yl}sulfonyl-
)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazi-
n-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2841] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 333B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.15 (s,
1H), 8.51 (d, 1H), 8.30 (d, 1H), 7.57 (d, 1H), 7.33 (m, 4H), 7.18
(d, 1H), 7.05 (d, 2H), 6.60 (dd, 1H), 8.37 (s, 1H), 6.07 (d, 1H),
5.02 (m, 1H), 3.68 (m, 4H), 2.99 (m, 4H), 2.74 (m, 7H), 2.23 (m,
8H), 1.95 (m, 4H), 1.41 (m, 6H), 0.92 (s, 6H).
EXAMPLE 334
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[4-dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)s-
ulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 334A
tert-butyl (trans)-4-(dicyclopropylamino)cyclohexylcarbamate
[2842] A suspension of tert-butyl
(trans)-4-aminocyclohexylcarbamate (1 g), molecular sieves 3A (1
g), acetic acid (2.67 mL), (1-ethoxycyclopropoxy)trimethylsilane
(3.74 mL) and sodium cyanoborohydride (0.880 g) in dry methanol (10
mL) was heated at reflux for 3 hours. The insolubles were filtered
off, the resulting solution was basified with aqueous NaOH (6 M) to
pH 14, and extracted with ether. The combined extracts were washed
with brine, dried and concentrated. The residue was purified by
flash chromotography (silica gel 80 g, 30-100% acetone/hexanes)
providing the product.
EXAMPLE 334B
(trans)-N',N'-dicyclopropylcyclohexane-1,4-diamine
bis(2,2,2-trifluoroacetate)
[2843] The title compound was prepared by substituting EXAMPLE 334A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 334C
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-N-[(4-{[4-(dicyclopropylamino)cyclohexyl]amino}-3-nitrophenyl)-
sulfonyl]-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2844] A suspension of EXAMPLE 240A (0.14 g), EXAMPLE 334B (0.110
g) and N,N-diisopropylethylamine (0.303 mL) in dioxane (3 mL) was
stirred for 3 days at 100.degree. C. The mixture was concentrated
and purified by RP HPLC (C8, 30%-100% CH.sub.3CN/water/0.1% TFA).
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 12.38 (s, 1H), 9.31
(d, 1H), 8.48 (dd, 1H), 8.38 (d, 1H), 8.15 (d, 1H), 7.47-7.53 (m,
3H), 7.41-7.46 (m, 3H), 7.01-7.08 (m, 3H), 6.72 (dd, 1H), 6.54-6.59
(m, 2H), 3.45 (ddd, 1H), 3.01-3.07 (m, 4H), 2.72-2.79 (m, 3H), 2.24
(t, 2H), 2.10 (d, 6H), 2.00-2.06 (m, 2H), 1.96 (s, 2H), 1.88 (d,
2H), 1.67 (qd, 2H), 1.34-1.40 (m, 2H), 1.20-1.29 (m, 2H), 0.93 (s,
6H), 0.48 (d, 8H).
EXAMPLE 335
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro--
2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide
EXAMPLE 335A
tert-butyl
(trans)-4-(tetrahydro-2H-pyran-4-ylamino)cyclohexylcarbamate
[2845] The title compound was prepared by substituting tert-buty
(trans)-4-aminocyclohexylcarbamate for tert-butyl
piperazine-1-carboxylate and dihydro-2H-pyran-4(3H)-one for
4'-chlorobiphenyl-2-carboxyldehyde in EXAMPLE 1A.
EXAMPLE 335B
(trans)-N'-(tetrahydro-2H-pyran-4-yl)cyclohexane-1,4-diamine
bis(2,2,2-trifluoroacetate)
[2846] The title compound was prepared by substituting EXAMPLE 335A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 335C
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(tetrahydro--
2H-pyran-4-ylamino)cyclohexyl]amino}phenyl)sulfonyl]benzamide
[2847] The title compound was prepared by substituting EXAMPLE 335B
for EXAMPLE 334B in EXAMPLE 334C. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 12.35 (s, 1H), 9.30 (d, 1H), 8.40 (dd,
1H), 8.35 (d, 1H), 8.19 (d, 1H), 7.51 (dd, 2H), 7.46-7.49 (m, 2H),
7.43 (d, 2H), 7.05 (d, 2H), 6.92 (d, 1H), 6.73 (dd, 1H), 6.54-6.59
(m, 2H), 3.99-4.04 (m, 2H), 3.45-3.52 (m, 1H), 3.41 (t, 2H),
3.10(s, 1H), 3.01-3.07 (m, 4H), 2.91 (s, 1H), 2.75 (s, 2H),
2.21-2.26 (m, 2H), 2.11 (d, 5H), 2.08 (d, 3H), 1.96 (s, 4H), 1.59
(s, 2H), 1.54 (d, 2H), 1.30-1.40 (m, 4H), 0.93 (s, 6H).
EXAMPLE 336
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-tetrahydr-
o-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benzamide
EXAMPLE 336A
tert-butyl 4-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate
[2848] To a solutuion of tert-butyl piperazine-1-carboxylate (5.15
g) and dihydro-2H-pyran-4(3H)-one (3.05 g) stirred for 24 hours at
room temperature in titanium (IV) isopropoxide (16.20 mL), methanol
(5 mL) was added followed by careful addition of sodium borohydride
(2.092 g). The reaction mixture was quenched with water/NaOH
solution, extracted with ether, dried over magnesium sulftate,
filtered, and concentrated to yield the product. The crude product
was used in the next step.
EXAMPLE 336B
1-(tetrahydro-2H-pyran-4-yl)piperazine dihydrochloride
[2849] To a solution of EXAMPLE 336A (3.92 g) in ether was added
HCl (25 mL, 2 M in ether) and the reaction mixture was stirred for
16 hours at room temperature. The solid product was filtered off,
dried and used in next step without further purification.
EXAMPLE 336C
Trans-tert-butyl
4-(4-tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexylcarbamate
[2850] To a solution of EXAMPLE 336B (1 g) and tert-butyl
4-oxocyclohexylcarbamate (0.877 g) stirred for 24 hours at room
temperature in titanium (IV) isopropoxide (2.410 mL), methanol (2
mL) was added followed by careful addition of sodium borohydride
(0.311 g). The reaction mixture was quenched with water, extracted
with ether, dried and concentrated. The crude product was purified
by flash chromotography (silica 80 g, 50%-100% acetone/hexanes)
providing the product.
EXAMPLE 336D
trans-4-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)cyclohexanamine
tris(2,2,2-trifluoroacetate)
[2851] The title compound was prepared by substituting EXAMPLE 336C
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 336E
[2852]
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(3-nitro-4-{[4-(4-te-
trahydro-2H-pyran-4-ylpiperazin-1-yl)cyclohexyl]amino}phenyl)sulfonyl]benz-
amide
[2853] The title compound was prepared by substituting EXAMPLE 336D
for EXAMPLE 334B in EXAMPLE 334C. .sup.1H NMR (500 MHz,
pyridine-d.sub.5) .delta. 12.38 (s, 1H), 9.30-9.34 (m, 1H),
8.41-8.46 (m, 1H), 8.37 (d, 1H), 8.13 (d, 1H), 7.48-7.53 (m, 3H),
7.41-7.46 (m, 3H), 7.04 (d, 2H), 6.96 (t, 1H), 6.69-6.74 (m, 1H),
6.54-6.59 (m, 2H), 3.99-4.05 (m, 2H), 3.29 -3.36 (m, 2H), 3.05 (s,
4H), 2.74 (s, 2H), 2.62 (s, 5H), 2.57 (s, 3H), 2.27-2.36 (m, 2H),
2.19 -2.27 (m, 3H), 2.11 (s, 6H), 1.96 (s, 2H), 1.91 (s, 1H), 1.87
(s, 1H), 1.70 (s, 2H), 1.64 (s, 1H), 1.56 (td, 2H), 1.35-1.43 (m,
4H), 1.29 (s, 2H), 0.93 (s, 6H).
EXAMPLE 337
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-
-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 337A
(4-fluorotetrahydro-2H-pyran-4-yl)methy 1 methanesulfonate
[2854] A mixture of EXAMPLE 296C (1.4 g), methanesulfonyl chloride
1.054 mL), triethylamine (2.99 mL), and 4-(dimethylamino)pyridine
(0.051 g)in CH.sub.2Cl.sub.2 (20 mL) was stirred at 0.degree. C.
for 2 hours, concentrated and cromatographed on silica gel with 30%
ethyl acetate in hexanes as eluent to give the product.
EXAMPLE 337B
2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione
[2855] A mixture of EXAMPLE 337A (1.8 g) and potassium phthalimide
(2.356 g) in N,N-dimethylformamide (30 mL) was heated at
150.degree. C. overnight, diluted with ethyl acetate, washed with
water and brine, dried (MgSO.sub.4), filtered, concentrated and
chromatographed on silica gel with 30% ethyl acetate in hexanes as
eluent to give the product.
EXAMPLE 337C
(4-fluorotetrahydro-2H-pyran-4-yl)methanamine
[2856] A mixture of EXAMPLE 337B (1.4 g) and hydrazine (1.548 mL)
in ethanol (40 mL) was heated at 70.degree. C. overnight, cooled to
room temperature, slurried with CH.sub.2Cl.sub.3 (200 mL) and the
solid removed by filtration. The filtrate was concentrated and
chromatographed on silica gel with 100:5:1 ethyl
acetate/methanol/NH.sub.4OH as eluent to give the product.
EXAMPLE 337D
4-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamid-
e
[2857] A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.44 g),
EXAMPLE 337C (0.266 g), and triethylamine (1.11 mL) in
tetrahydrofuran (10 mL) was heated at 70.degree. C. overnight,
diluted with ehtyl acetate, washed with water and brine, dried
(MgSO.sub.4), filtered, concentrated and chromatographed on silica
gel with 50% ethyl acetate in hexanes as eluent to give the
product.
EXAMPLE 337E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-fluorotetrahydro-2H-pyran-
-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2858] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 337D for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.21 (m,
2H), 8.63 (t, 1H), 8.59 (d, 1H), 7.88 (dd, 1H), 7.51 (d, 1H), 7.33
(m, 6H), 7.03 (m, 2H), 6.65 (dd, 1H), 6.40 (m, 1H), 6.09 (d, 1H),
3.74 (m, 4H), 3.52 (m, 2H), 3.03 (m, 4H), 2.74 (m, 2H), 2.16 (m,
6H), 1.95 (s, 2H), 1.80 (m, 4H), 1.38 (t, 2H), 0.92 (s, 6H).
EXAMPLE 338
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]-N-[(4-{[(4-hydroxycyclohexyl)m-
ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2859] A mixture of EXAMPLE 240A (153 mg),
trans-4-(aminomethyl)cyclohexanol (73.5 mg) and
N-ethyl-N-isopropylpropan-2-amine (0.16 mL) in dioxane (2 mL) was
heated at 100.degree. C. for 20 hours and concentrated. The residue
was dissolved in dimcethylsulfoxide-methanol (1:1) and purified by
HPLC, eluting with 40%-65% acetonitrile 0.1% TFA water over 40
minutes to provide the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.22 (s, 2H), 8.56-8.62 (m,
2H), 7.85 (dd, 1H), 7.51 (d, 1H), 7.38 (t, 1H), 7.29-7.36 (m, 4H),
7.12 (d, 1H), 7.03 (d, 2H), 6.66 (dd, 1H), 6.41 (s, 1H), 6.09 (d,
1H), 4.51 (d, 1H), 3.24 (t, 2H), 3.03 (s, 4H), 2.74 (s, 2H), 2.16
(d, 6H), 1.95 (s, 2H), 1.83 (d, 2H), 1.74 (d, 2H), 1.56 (dd, 1H),
1.38 (t, 2H), 0.95-1.16 (m, 4H), 0.92 (s, 6H).
EXAMPLE 339
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(t-
etrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 339A
methyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate
[2860] Methyl 2,4-difluorobenzoate 1.53 g), K.sub.3PO.sub.4 (1.89
g) and 4-hydroxyindole (1.08 Mg) were stirred at 110.degree. C. in
diglyme (12 mL) for 24 hours. The reaction was cooled and poured
into ether. The solution was washed three times with 1 M aqueous
NaOH solution, and brine, and dried over Na.sub.2SO.sub.4. The
solution was then concentrated, and the crude product was
chromatographed on silica gel with 20% ethylacetate/hexanes.
EXAMPLE 339B
methyl 2-(1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate
[2861] EXAMPLE 339A (1425 mg), piperazine (452 mg), and
HK.sub.2PO.sub.4 (958 mg) were stirred in dimethylsuifoxide (20 mL)
at 140.degree. C. for 24 hours. The reaction was diluted with
ethylacetate, washed three times with water, washed with brine,
dried over Na.sub.2SO.sub.4, and concentrated. The crude product
was chromatographed on silica gell with a methanol/methylene
chloride gradient.
EXAMPLE 339C
methyl 2-(3-bromo-1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate
[2862] A solution of EXAMPLE 339B (1 g) in dichloromethane (50 mL)
and N,N-dimethylformamide (5 mL) was cooled in an ice bath,
N-bromosuccmimide (0.582 g) was added and the mixture was stirred
overnight while warming to ambient temperature. The reaction was
concentrated and the crude product was chromatographed on silica
gel with a methanol/methylene chloride gradient
EXAMPLE 339D
tert-butyl
3-bromo-4-(5-(4-(tert-butyloxycarboayl)piperazin-1-yl)-2-(metho-
xycarbonyl)phenoxy)-1H-indol-1-carboxylate
[2863] EXAMPLE 339C (388 mg) and di-tert-buty dicarbonate (590 mg)
were dissolved in a mixture of acetonitrile (20 mL)and
dichloromethane (20 mL) N-ethyl-N-isopropylporpan-2-amine (0.165
mL) was added followed by N, N-dimethylpyridin-4-amine (33.0 mg)
and the mixture wasstirred 18 hours. The reaction was concentrated
and the crude product was purified on a plug of silica gel with 15%
ethyl acetate in hexane.
EXAMPLE 339E
E (E)-tert-butyl
4-(3-(3-(3-(dimethylamino)prop-1-enyl)-1H-indol-4-yloxy)-4-(methoxycarbon-
yl)phenyl)piperizine-1-carboxylate
[2864] A mixture EXAMPLE 339D (175 mg),
(E)-N,N-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-en-
-1-amine (103 mg), sodium carbonate (73.5 mg) and
bis(triphenylphosphine)palladium(Il) dichloride (9.74 mg) in a
mixture of 1,2-dimethoxyethane (3.0 mL) and water (1.5 mL) was
heated in a CEM Discover microwave reactor at 150.degree. C. for 30
minutes. The reaction was partitioned between brine and ethyl
acetate. The organic layer was dried over sodium sulfate, filtered
and concentrated. The crude product was purified on silica gel with
a 7N methanolic ammonia/methylene chloride gradient.
EXAMPLE 339F
tert-butyl
4-(3-(3-(3-(dimethylamino)propyl)-1H-indol-4-yloxy)-4-(methoxyc-
arbonyl)phenyl)piperizine-1-carboxylate
[2865] A mixture of EXAMPLE 339E (715 mg) and 5% palladium on
carbon (143 mg) in methanol (20 mL) was hydrogenated at 30 psi for
16 hours at ambient temperature. The reaction mixture was filtered,
concentratedand the crude product was chromatographed on silica gel
with 7 N-methanolic ammonia in methylene chloride.
EXAMPLE 339G
methyl
2-(3-(3-(dimethylamino)propyl)-1H-indol-4-yloxy)-4-(piperazin-1-yl)-
benzoate
[2866] A solution of EXAMPLE 339F (484 mg) in dichloromethane (22
mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (11
mL) was added. The reaction was stirred for 2 hours,
concentratedand the crude product was chromatographed on silica gel
with 7 N-methanolic ammonia in methylene chloride.
EXAMPLE 339H
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(3-(3-(dimethylamino)propyl)-1H-indol-4-yloxy)benzoate
[2867] To a solution of EXAMPLE 339G (285 mg) and EXAMPLE 60D (171
mg) in dichloromethane (20 mL) was added sodium
triacetoxyborohydride (208 mg) portion wise over a few minutes. The
reaction was stirred 72 hotsrs at ambient temperature, quenched by
the slow addition of saturated aqueous sodium bicarbonate solution
(100 mL) and extracted with methylene chloride (75 mL). The organic
layer was dried over sodium sulfate, filtered and concentrated. The
crude product was purified on silica gel with 7N-methanoic ammonia
in methylene chloride.
EXAMPLE 339I
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(3-(3-(dimethylamino)propyl)-1H-indol-4-yloxy)benzoic acid
[2868] The title compound was prepared by substituting EXAMPLE 399B
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 399J
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({3-nitro-4-[(t-
etrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2869] The title compound was prepared by substituting EXAMPLE 339I
for EXAMPLE 1F EXAMPLE 1H. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 12.00 (s, 1H), 9.24 (s, 1H), 8.49 (m, 1H), 8.43 (d, 1H),
8.37 (d, 1H), 7.45 (m, 2H), 7.25 (m, 2H), 7.11 (d, 2H), 7.00 (t,
1H), 6.81 (m, 3H), 6.63 (d, 1H), 3.96 (d, 2H), 3.30 (t, 2H), 3.06
(m, 10H), 2.82 (m, 7H), 2.49 (m, 2H), 2.24 (m, 5H), 1.99 (m, 1H),
1.76 (m, 1H), 1.55 (m, 2H), 1.41 (m, 2H), 1.25 (m, 4H), 0.96 (m,
6H), 0.84 (m, 2H).
EXAMPLE 340
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-({3-[3-(dimethylamino)propyl]-1H-indol-4-yl}oxy)-N-({4-[(4-methylp-
iperazin-1-yl)amino]-3nitrophenyl}sulfonyl)benzamide
[2870] The title compound was prepared by substituting EXAMPLE 339I
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, pyridine-d.sub.5) .delta. 11.98 (s, 1H), 9.19
(d, 1H), 8.97 (s, 1H), 8.48 (m, 1H), 8.42 (m, 1H), 7.63 (d, 1H),
7.46 (d, 2H), 7.25 (m, 2H), 7.11 (d, 2H), 7.00 (m, 1H), 6.80 (m,
2H), 6.64 (m, 1H), 3.04 (m, 8H), 2.82 (m, 10H), 2.49 (m, 3H), 2.28
(m, 3H), 2.22 (m, 6H), 2.16 (m, 3H), 2.08 (m, 1H), 1.99 (m, 2H),
1.40 (t, 2H), 0.96 (m, 6H), 0.84 (m, 2H).
EXAMPLE 341
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 341A
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
[2871] 1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate
(1.0 g) in tetrahydrofuran (5 mL) was treated with 1.0 N
LiAlH.sub.4 (2.54 mL) at 0.degree. C. The reaction mixture was
stirred at room temperature for 2 hours. Water (0.6 mL) was added
to the reaction mixture drop-wise, followed by 2 N aqueous NaOH
(0.2 mL). The reaction was stirred for another 1 hour. The solid
was removed by filtration via a pack of Celite and washed with
ethyl acetate. The filtrate was washed with brine, dried over
MgSO.sub.4, filtered, and concentrated to give the product.
EXAMPLE 341B
tert-butyl
4-fluoro-4-((2-nitro-4-sulfamoylphenoxy)methyl)piperidine-1-car-
boxylate
[2872] The title compound was prepared by substituting EXAMPLE 341A
for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 264A.
EXAMPLE 341C
4-((4-fluoropiperidin-4-yl)methoxy)-3-ntirobenzenesulfonamide
[2873] The title compound was prepared by substituting EXAMPLE 341B
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 341D
4-((1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamid-
e
[2874] To EXAMPLE 341C (0.24 g) in methanol (3 mL) was added 3
.ANG. molecular sieves (0.1 g), followed sequentially by acetic
acid (0.31 mL), (1-ethoxycyclopropoxyl)trimethylsilane (0.64 mL),
and sodium cyanoborohydride (0.148 g). The reaction was heated
under reflux overnight. After cooling, the reaction mixture was
loaded onto a silica gel column. After drying, the column was
eluted with 100:2:0.2 ethyl acetate/methanol/NH.sub.4OH to give the
title compound.
EXAMPLE 341E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({4-[(1-cyclopropyl-4-fluoropiperidin-4-yl)methoxy]-3-nitrophenyl}-
sulfonyl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2875] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 341l D for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.20 (s,
1H), 8.37 (d, 1H), 8.10 (d, 1H), 7.53 (d, 1H), 7.44 (d, 1H),
7.32-7.37 (m, 4H), 7.24 (d, 1H), 7.04 (d, 2H), 6.63 (dd, 1H), 6.39
(s, 1H), 6.09 (d, 1H), 4.34 (d, 2H), 3.05 (s, 4H), 2.90 (s, 2H),
2.78 (s, 2H), 2.14-2.26 (m, 6H), 1.68-1.82 (m, 4H), 1.38 (d, 2H),
0.92 (s, 6H), 0.40-0.49 (m, 4H).
EXAMPLE 342
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-{[1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro--
4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 342A
4-(tert-Butyl-dimethyl-silanyloxy)-1H-benzotriazole
[2876] To 4-hydroxybenzotriazole (5.000 g) in tetrahydrofuran (250
mL) was added sodium hydride (60% , 0.932 g). The solution was
stirred at room temperature for 20 minutes, cooled to 0.degree. C.,
tert-butyldimethylchlorosilane (5.860 g) was added, the solution
was allowed to warm to room temperature, and stirred for 16 hours.
Additional sodium hydride (60% , 0.500 g) was added, the solution
stirred for 15 minutes, additional tert-butyldimethylchlorosilane
(3.000 g) was added, and the solution stirred for three hours at
room temperature. The solution was then added to saturated aqueous
ammonium chloride and extracted with ethyl acetate. The organic
extract was washed with brine, dried over anhydrous sodium sulfate,
filtered, concentrated and purified by flash column chromatography
on silica gel using 20-30% ethyl acetate in hexanes.
EXAMPLE 342B
4-(tert-Butyl-dimethyl-silanyloxy)-1-(4-methoxy-benzyl)-1H-benzotriazole
[2877] To EXAMPLE 342A (2.00 g) in dimethylformamide (40 mL) was
added sodium hydride (60% , 0.353 g). The solution was mixed for 10
minutes at room temperature and 4-methoxybenzylchloride (1.382 g)
was added. The solution was heated at 80.degree. C. for 16 hours,
cooled, added to water, and extracted with 50% ethyl acetate in
hexanes. The extract was washed with brine, dried over anhydrous
sodium sulfate, filtered, concentrated, and purified by flash
column chromatography on silica gel using 10% ethyl acetate in
hexanes.
EXAMPLE 342C
1-(4-Methoxy-benzyl)-1H-benzotriazol-4-ol
[2878] To a solution of EXAMPLE 342B (2.59 g) in tetrahydrofuran
(40 mL) was added tetraammonium fluoride (1M in tetrahydrofuran
21.03 mL). The solution was mixed at room temperature for two
hours. The solvent was removed under vacuum, the residue was taken
up in ethyl acetate, and the solution was vacuum filtered over a
pad silica gel. The filtrate was concentrated and purified by flash
column chromatography on silica gel using 35% ethyl acetate in
hexanes.
EXAMPLE 342D
4-Fluoro-2-[1-(4-methoxy-benzyl)-1H-benzotriazol-4-yloxy]-benzoic
acid methyl ester
[2879] To a solution of EXAMPLE 342C (990 mg) and methyl
2,4-difluorobenzoate (734 mg) in diglyme (40 mL) was added
potassium tert-butoxide (1M in tetrahydrofuran, 4.07 mL). The
solution was heated to 100.degree. C. for 16 hours, cooled, added
to saturated ammonium chloride, and extracted with 70% ethyl
acetate in hexanes. The extract was washed with brine, dried over
anhydrous sodium sulfate, filtered, concentrated and purified by
flash column chromatography on silica gel using 30% ethyl acetate
in hexanes.
EXAMPLE 342E
2-[1-(4-Methoxy-benzyl)-1H-benzotriazol-4-yloxy]-4-piperzin-1-ylbenzoic
acid methyl ester
[2880] To a solution of EXAMPLE 342D (650 mg) in dimethylsulfoxide
(12 mL) was added piperazine (618 mg). The solution was heated at
100.degree. C. for one hour, cooled, added to dichloromethane,
extracted with water three times, dried over anhydrous sodium
sulfate, filtered, and the solvent was removed under vacuum.
EXAMPLE 342F
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-[1-(4-methoxy-benzyl)-1H-benzotriazol-4-yloxy]-benzoic acid
methyl ester
[2881] The title compound was prepared by susbtituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 342E for
tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 342G
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperszin-1--
yl}-2-[1-(4-methoxy-benzyl)-1H-benzotriazol-4-yloxy]-benzoic
acid
[2882] The title compound was prepared by substituting EXAMPLE 342F
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 342H
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-{[1-(4-methoxybenzyl)-1H-1,2,3-benzotriazol-4-yl]oxy}-N-({3-nitro--
4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2883] The title compound was prepared by substituting EXAMPLE 342G
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.59 (t, 1H), 8.37 (d, 1H), 7.67
(d, 1H), 7.56 (d, 1H), 7.38-7.23 (m, 3H), 7.30 (d, 2H), 7.23 (t,
1H), 7.05 (d, 2H), 7.02 (d, 1H), 6.91 (d, 2H), 6.80 (dd, 1H), 6.51
(d, 1H), 6.37 (d, 1H), 5.87 (s, 2H), 3.85 (dd, 2H), 3.71 (s, 3H),
3.28 (m, 4H), 3.16 (bs,2H), 2.78 (bs, 2H), 2.57 (bs, 2H), 2.29-2.14
(m, 6H), 1.97 (bs, 2H), 1.89 (m, 1H), 1.62 (dd, 2H), 1.40 (t, 2H),
1.26 (m, 2H), 0.93 (s, 6H).
EXAMPLE 343
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl-
)amino]-3-nitrophenyl}sulfonyl)benzamide
[2884] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.04-10.47 (m, 1H), 9.19 (s, 1H), 8.50 (d, 1H), 7.90-7.83 (m, 1H),
7.70 (d, 1H), 7.64 (s, 1H), 7.47 (d, 1H), 7.33 (dd, 3H), 7.06 (d,
2H), 6.63 (d, 1H), 6.20 (d, 1H), 6.07 (s, 2H), 3.08 (s, 4H), 2.95
(s, 4H), 2.75 (s, 3H), 2.42 (s, 4H), 2.19 (m, 8H), 1.97 (s, 2H),
1.41 (d, 2H), 0.94 (s, 6H).
EXAMPLE 344
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-
-3-nitrophenyl]sulfonyl}benzamide
[2885] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 285A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.54-11.15 (m, 1H), 8.35 (t, 2H), 8.05 (dd, 1H), 7.75 (d, 1H),
7.45 (d, 1H), 7.30 (m, 2H), 7.20 (d, 1H), 7.05 (d, 2H), 6.62 (d,
1H), 6.21-6.15 (m, 3H), 3.85-3.75 (m, 3H), 3.51 (m, 6H), 3.12 (m,
4H), 2.79 (s, 2H), 2.21 (m, 6H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94
(s, 6H).
EXAMPLE 345
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycycloh-
exyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 345A
(4-methoxycyclohexyl)methanamine
[2886] (4-Methoxyphenyl)methanamine (1 g) in ethanol (10 mL) was
treated with 5% Rh-Al.sub.2O.sub.3 (99.8 mg) under a H.sub.2
atmosphere (500 psi) at 50.degree. C. for 16 hours. Additional 5%
Rh-Al.sub.2O.sub.3 (0.4 g) was added. The resulting mixture was
stirred under H.sub.2 atmosphere (500 psi 1 at 60.degree. C. for 2
hours. The insoluble material was filtered off and the filtrate was
concentrated to provide a mixture of cis and trans product as an
oil, which was used for next step without further purification.
EXAMPLE 345B
4-((trans-4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[2887] 4-Fluoro-3-nitrobenzenesulfonamide (1.098 g) and EXAMPLE
345A (1 g) in tetrahydrofuran (20 mL) were treated with
diisopropylethylamine (0.871 mL) overnight. The reaction mixtur
ewas concentrated and the residuewas purified by reverse phase
chromatography, and was eluted with 40-55% acetonitrile in 0.1%
trifluoroacetic acid in water over 25 minutes to provide the title
compound.
EXAMPLE 345C
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycycloh-
exyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2888] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 318E and
EXAMPLE 345B, respectively. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.62 (t, 1H), 8.58 (d, 1H), 7.86
(dd, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 7.40 (d, 1H), 7.36 (d, 2H),
7.18 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.18 (s, 3H), 3.26-3.33
(m, 4H), 3.22 (s, 3H), 3.12 (s, 4H), 3.03-3.09 (m, 1H), 2.79 (s,
2H), 2.24 (s, 4H), 2.17 (s, 2H), 1.93-2.03 (m, 4H), 1.80 (d, 2H),
1.62 (dd, 1H), 1.40 (t, 2H), 0.98-1.14 (m, 4H), 0.94 (s, 6H).
EXAMPLE 346
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)-
amino]-3-nitrophenyl}sulfonyl)benzamide
[2889] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 291A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.54-11.15 (m, 1H), 8.59 (t, 2H), 7.87 (dd, 1H), 7.74 (d, 1H),
7.44 (d, 1H), 734 (s, 3), 7.20 (d, 1H), 7.06 (d, 2H), 6.65 (dd,
1H), 6.21-6.15 (m, 3H), 3.84-3.75 (m, 3H), 3.51 (m, 6H), 3.12 (s,
4H), 2.79 (s, 2H), 2.21 (d, 6H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94
(s, 6H).
EXAMPLE 347
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl-
)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
EXAMPLE 347A
4-(3-morpholinopropylamino-3-(trifluoromethylsulfonyl)benzenesulfonamide
[2890] 3-Morpholinopropan-1-amine (376 mg), EXAMPLE 131C (800 mg)
and N-ethyl-N-isopropylpropan-2-amine (1.4 mL) in tetrahydrofuran
(15 mL) were heated at 55.degree. C. for 3 hours. The solvent was
removed and the residue was dissolved in ethyl acetate and washed
with water and brine. The organic layer was dried over
Na.sub.2SO.sub.4, filtered, and concentrated to give the title
compound.
EXAMPLE 347B
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl-
)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
[2891] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 347A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.31-10.55 (m, 1H), 8.14 (s, 1H), 7.96 (d, 1H), 7.73 (d, 1H), 7.44
(d, 1H), 7.36 (d, 4H), 7.12 (d, 1H), 7.06 (d, 2H), 6.64 (d, 1H),
6.17 (d, 3H), 3.61 (s, 4H), 3.42 (d, 2H), 3.10 (s, 4H), 2.77 (s,
2H), 2.48-2.41 (m, 4H), 2.23 (s, 8H), 1.97 (s, 2H), 1.76 (s, 2H),
1.40 (s, 2H), 0.94 (s, 6H).
EXAMPLE 348
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
EXAMPLE 348A
4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-(trifluoromethylsulfonyl)b-
enzenesulfonamide
[2892] To a solution of EXAMPLE 296C (0.500 g) in tetrahydrofuran
(5 mL) was added sodium hydride (0.596 g). Tetrahydrofuran (25 mL)
was added and the mixture was stirred for 30 minutes, and then
EXAMPLE 131C (1.145 g) was added as a solution in tetrataydrofuran
(5 mL). After stirring for 2 hours, the reaction was partitioned
between 1N aqueous HCl (50 mL) and dichloromethane (200 mL). The
dichloromethane layer was dried over magnesium sulfate, filtered,
and concentrated. The resulting solid was chromatographed over
silica gel (Reveleris 80 g) eluting with a gradient of 0.5% to 7.5%
methanol/dichloromethane over 30 minutes (flow=40 ml/min) to give
the title compound.
EXAMPLE 348B
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H--
pyran-4-yl)methoxy]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
[2893] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 348A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.42 (s,
1H), 8.37-8.28 (m, 1H), 7.70 (s, 1H), 7.65-7.55 (m, 1H), 7.46 (d,
J=8.8, 1H), 7.37 (d, J=8.4, 3H), 7.07 (d, J=8.4, 2H), 6.67 (s, 1H),
6.23 (s, 1H), 6.12 (s, 2H), 4.47 (d, J=20.7, 2H), 3.76 (s, 2H),
3.60 (s, 2H), 3.21-3.02 (m, 4H), 2.18 (s, 6H), 2.01-1.79 (m, 8H),
1.42 (s, 2H), 0.95 (s, 6H).
EXAMPLE 349
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro--
2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-
-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
[2894] The title compound was prepared by substituting EXAMPLE 326A
for EXAMPLE 1G and EXAMPLE 318E for EXAMPLE 110E in EXAMPLE 110F,
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.53 (s,
1H), 8.22 (s, 1H), 7.72 (s, 1H), 7.34-7.38 (m, 13H), 7.07 (d, 2H),
6.66 (dd, 1H), 6.23 (s, 1H), 6.12 (s, 2H), 4.55 (d, 2H), 3.756-3.79
(m, 2H), 3.57-3.62 (m, 2H), 3.15 (br s, 4H), 2.18 (m, 2H), 1.99 (s,
2H), 1.82-1.91 (m, 4H), 1.42 (t, 2H), 0.95 (s, 6H).
EXAMPLE 350
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 350A
methyl 2-(6-amino-5-bromopyridin-3-yloxy)-4-fluorobenzoate
[2895] A mixture of example 318B (1.6 g) in N,N-dimethylformamide
(50 mL) was cooled to 0.degree. C., followed by the addition of
n-bromosuccinimide (1.195 g) in N,N-dimethylformamide (10 ml)
solution. The reaction mixture was stirred at 0.degree. C. for 1
hour, and quenched with ice-cold saturated NaHCO.sub.3 aqueous
solution. The reaction mixture was extracted with ethyl acetate.
The combined organic phase was washed with water and brine, dried
over anhydrous sodium sulfate, filtered and concentrated. The crude
material was purified using flash column purification with 30-40%
ethyl acetate/hexane to provide the title compound.
EXAMPLE 350B
[2896] Methyl
2-(6-amino-5-bromopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2897] The title compound was prepared by substituting example 350A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 350C
2-(6-Amino-5-bmmopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2898] The title compound was prepared by substituting EXAMPLE 350B
for EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 350D
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2899] The title compound was prepared by substituting EXAMPLE 350C
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.52 (m, 2H), 7.79 (dd, 1H),
7.73 (d, 1H), 7.49 (d, 1H), 7.40 (s, LH), 736 (d, 2H), 7.13 (d,
1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.23 (d, 1H), 5.98 (s, 2H), 3.85
(dd, 2H), 3.27 (m, 4H), 3.08 (s, 4H), 2.75 (s, 2H), 2.19 (m, 6H),
1.93 (m, 4H), 1.63 (m, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s,
6H).
EXAMPLE 351
2-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)amino]carbonyl}phenoxy)nicotinamide
EXAMPLE 351A
Methyl 2-(6-amino-5-cyanopyridin-3-yloxy)-4-fluorobenzoate
[2900] EXAMPLE 350A 150 mg), zinc cyanide (28 mg) and
tetrakis(triphenylphosphine)palladium(0) (61 mg) were dissolved in
N,N-dimethylformamide (0.5 mL), flushed with N.sub.2three times.
The reaction mixture was heated at 120.degree. C. for 2 hours. The
reaction mixture was cooled to room temperature and diluted with
ethyl acetate. The organic phase was washed with water and brine,
dried over anhydrous sodium sulfate, filtered, and concentrated.
The crude material was purified by column chromatogrpahy on silica
gel with 2.5-5% methanol/dichloromethane to provide the title
compound.
EXAMPLE 351B
Methyl
2-(6-amino-5-cyanopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-di-
methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2901] The title compound was prepared by substituting EXAMPLE 351A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 351C
2-(6-Amino-5-carbamoylpyridin-3-yloxy)-(4-(4-((2-(4-chlorophenyl)-4,4-dime-
thylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2902] The title compound was prepared by substituting EXAMPLE 351B
for EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 351D
2-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piper-
azin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}s-
ulfonyl)amino]carbonyl}phenoxy)nicotinamide
[2903] The title compound was prepared by substituting EXAMPLE 351C
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.50 (m, 2H), 7.91 (m, 1H), 7.79
(m, 3H), 7.50 (d, 1H), 7.36 (d, 2H), 7.31 (m, 1H), 7.07 (m, 5H),
6.59 (dd, 1H), 6.16 (s, 1H), 3.84 (dd, 2H), 3.27 (m, 4H), 3.05 (s,
4H), 2.74 (s, 2H), 2.19 (m, 6H), 1.98 (m, 3H), 1.90 (m, 1H), 1.63
(m, 2H), 1.39 (m, 2H), 1.26 (m, 2H), 0.94 (s, 6H).
EXAMPLE 352
2-amino-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydr-
o-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 352A
2-(6-Amino-5-cyanopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1
[2904] The title compound was prepared by substituting EXAMPLE 351B
for EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 352B
2-amino-[(6-amino-5-cyanopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydr-
o-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2905] The title compound was prepared by substituting EXAMPLE 352A
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.46 (m, 2H), 7.93 (d, 1H), 7.76
(d, 1H), 7.52 (d, 1H), 7.36 (m, 3H), 7.08 (m, 3H), 6.65 (dd, 1H),
6.59 (s, 2H), 6.28 (d, 1H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.09 (s,
4H), 2.76 (s, 2H), 2.20 (m, 6H), 1.93 (m, 5H), 1.64 (m, 2H), 1.40
(t, 2H), 1.27 (m, 2H), 0.94 (s, 6H).
EXAMPLE 353
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroet-
hyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 353A
(R)-tert-butyl 1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate
[2906] (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg) was
combined with 1,1-difluoro-2-iodoethane (618 mg) and
N-ethyl-N-isopropylpropan-2-amine (1.4 mL) in N,N-dimethylformamide
(6 mL) in a 20 mL vial. The reaction was heated to 70.degree. C.
for 48 hours. The reaction mixture was concentrated and the residue
was purified by flash chromatography, eluting with a gradient of
0-5% methanol in dichloromethane to provide the title compound.
EXAMPLE 353B
(R)-1-(2,2-difluoroethyl)pyrrolidin-3-amine
[2907] The title compound was prepared by substituting EXAMPLE 353A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 353C
(R)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamid-
e
[2908] The title compound was prepared by substituting EXAMPLE 353B
for 3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.
EXAMPLE 353D
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroet-
hyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2909] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 353C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.58 (d,
1H), 8.41 (d, 1H), 7.89 (dd, 1H), 7.73 (d, 1H), 7.43 (d, 1H), 7.36
(m, 3H), 7.18 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.27, 6.13,
5.99 (each t, total 1H), 6.18 (d, 1H), 6.17 (br s, 2H), 4.31 (m,
1H), 3.12 (m, 4H), 2.92 (m, 5H), 2.80 (m, 3H), 2.55 (m, 1H), 2.25
(m, 4H), 2.17 (m, 2H), 1.97 (s, 2H), 1.74 (m, 1H), 1.40 (t, 2H),
0.94 (s, 6H).
EXAMPLE 354
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl-
)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide
[2910] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 131D for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.07 (d,
1H), 7.90 (dd, 1H), 7.63 (d, 1H), 7.50 (d, 1H), 7.35 (d, 2H), 7.16
(s, 1H), 7.07 (m, 3H), 7.63 (dd, 1H), 6.54 (br s, 1H), 6.26 (d,
1H), 5.95 (br s, 2H), 3.78 (m, 1H), 3.19 (m, 2H), 3.06 (m, 5H),
2.86 (m, 2H), 2.76 (m, 2H), 2.63 (m, 2H), 2.23 (m, 4H), 2.18 (m,
2H), 2.07 (m, 2H), 1.97 (s, 2H), 1.63 (m, 2H), 1.40 (t, 2H), 0.94
(s, 6H).
EXAMPLE 355
2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 355A
methyl
2-(6-aminopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcy-
clohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2911] The title compound was prepared by substituting EXAMPLE 318B
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 355B
methyl
2-(6-acctamidopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2912] EXAMPLE 355A (200 mg) was dissolved in anhydrous
tetrahydrofuran (15 mL), followed by addition of triethylamine
(0.15 mL) and acetylchloride (0.3 mL). The reaction mixture was
stirred at room temperature overnight. The solvent was removed
under vacuum. The residue was purified by flash column purification
with 20-40% ethyl acetate/hexane to provide the title compound.
EXAMPLE 355C
2-(6-acetamidopyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclo-
hex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2913] The title compound was prepared by susbtituting EXAMPLE 355B
for EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 355D
2-{[6-(acetylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2914] The title compound was prepared by substituting EXAMPLE 355C
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.36 (s, 1H), 8.39 (m, 2H),
7.92 (d, 1H), 7.83 (s, 1H), 7.64 (m, 1H), 7.57 (d, 1H), 7.36 (d,
2H), 7.15 (m, 1H), 7.07 (d, 2H), 6.98 (d, 1H), 6.68 (dd, 1H), 6.34
(d, 1H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.08 (s, 4H), 2.76 (s, 2H),
2.20 (m, 6H), 2.06 (s, 3H), 1.99 (m, 3H), 1.89 (m, 1H), 1.62 (m,
2H), 1.40 (t, 2H), 1.26 (m, 2H), 0.94 (s, 6H)
EXAMPLE 356
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetra-
hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 356A
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(6-(methylsulfonamido)pyridin-3-yloxy)benzoate
[2915] The title compound was prepared by substituting
methanesulfonyl chloride for acetyl chloride in EXAMPLE 355B.
EXAMPLE 356B
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(6-(methylsulfonamido)pyridin-3-yloxy)benzoic acid
[2916] The title compound was prepared by substituting EXAMPLE 356A
for EXAMPLE 38G is EXAMPLE 38H.
EXAMPLE 356C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(tetra-
hydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2917] The title compound was prepared by substituting EXAMPLE 356B
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 10.30 (s, 1H), 8.41 (s, 2H),
7.83 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.16 (d,
1H), 7.05 (m, 3H), 6.88 (d, 1H), 6.69 (dd, 1H), 6.35 (d, 1H), 3.84
(dd, 2H), 3.27 (m, 7H), 3.09 (s, 4H), 2.76 (s, 2H), 2.20 (m, 6H),
1.98 (m, 3H), 1.90 (m, 1H), 1.63 (m, 2H), 1.40 (t, 2H), 1.26 (m,
2H), 0.95 (s, 6H).
EXAMPLE 357
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-
-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
EXAMPLE 357A
(R)-1(1,3-difluoropropan-2-yl)pyrrolidin-3-amine
[2918] To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate
(0.500 g) and 1,3-difluoropropan-2-one (0.278 g) in dichloromethane
(5 mL) was added sodium triacetoxyborohydride (0.853 g). After
stirring for 1 hour, the reaction was quenched with saturated
NaHCO.sub.3solution (5 mL). The product was extracted into
dichloromethane (25 mL), dried over magnesium sulfate, filtered,
and concentrated. The resulting crude material was treated with HCl
(4.0 M in dioxane, 4 mL) and methanol (1 mL) and stirred for 1
hour. The mixture was concentrated to provide the title
compound.
EXAMPLE 357B
(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-nitrobenzenesulf-
onamide
[2919] To 4-fluoro-3-nitrobenzenesulfonamide (0.272 g) and
(R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine (0.195 g) in
tetrahydrofuran (3.0 mL) was added
N-ethyl-N-isopropylpropan-2-amine (0.512 mL) and the reaction was
stirredat room temperature. After stirring for 6 hours, the
reaction was concentrated, loaded onto silica gel (Reverleris 40 g)
and the product was purified by flash chromatography using a
gradient of 25% to 100% ethyl acetate/hexanes over 30 minutes to
provide the title compound.
EXAMPLE 357C
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino-
-3-nitrophenyl]sulfonyl}-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[2920] The title compound was prepared by substituting EXAMPLE 154E
for EXAMPLE 1F and EXAMPLE 357B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.21 (s,
2H), 8.58 (d, 1H), 8.39 (d, 1H), 7.89 (d, 1H), 7.51 (d, 1H),
7.40-7.25 (m, 5H), 7.13 (d, 1H), 7.03 (d, 2H), 6.67 (s, 1H), 6.40
(s, 1H), 6.09 (s, 1H), 4.62 (dd, 4H), 4.31-4.18 (m, 1H), 3.04 (s,
6H), 2.73 (s, 4H), 2.39-2.23 (m, 2H), 2.19 (s, 6H), 1.95 (s, 2H),
1.79-1.60 (m, 1H), 1.38 (s, 2H), 0.92 (s, 6H).
EXAMPLE 358
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-
-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2921] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 65A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.56 (d,
1H), 8.24 (d, 1H), 7.85 (dd, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.35
(m, 3H), 7.22 (d, 1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.19 (d, 1H),
6.12 (br s, 2H), 3.74 (m, 2H), 3.11 (m, 5H), 2.91 (m, 2H), 2.76 (m,
3H), 2.22 (m, 6H), 1.97 (m, 4H), 1.58 (m, 2H), 1.40 (t, 2H), 0.94
(s, 6H), 0.46 (m, 2H), 0.36 (m, 2H).
EXAMPLE 359
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)-
amino]-3-nitrophenyl}sulfonyl)benzamide
[2922] The title compound was prepared by substituting EXAMPLE 350C
for EXAMPLE 110E and EXAMPLE 184A for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.96 (s,
1H), 8.41 (d, 1H), 7.77 (dd, 1H), 7.67 (d, 1H), 7.53 (dd, 2H), 7.36
(d, 2H), 7.29 (d, 1H), 7.07 (d, 2H), 6.62 (dd, 1H), 6.26 (d, 1H),
5.85 (s, 2H), 3.28 (m, 4H), 3.06 (s, 4H), 2.90 (m, 4H), 2.75 (s,
2H), 2.31 (s, 3H), 2.20 (m, 7H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94
(s, 6H).
EXAMPLE 360
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-p-
yran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide
[2923] The title compound was prepared by substituting EXAMPLE 350C
for EXAMPLE 110E and EXAMPLE 296D for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.19 (d,
1H), 7.85 (dd, 1H), 7.62 (d, 1H), 7.57 (d, 1H), 7.36 (d, 2H), 7.31
(d, 1H), 7.22 (d, 1H), 7.08 (d, 2H), 6.63 (dd, 1H), 6.30 (d, 1H),
5.81 (s, 2H), 4.34 (d, 2H), 3.78 (m, 2H), 3.59 (m, 2H), 3.06 (s,
4H), 2.76 (s, 2H), 2.21 (m, 6H), 1.97 (s, 2H), 1.86 (m, 4H), 1.40
(t, 2H), 0.94 (s, 6H).
EXAMPLE 361
2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)a-
mino]-3-nitrophenyl}sulfonyl)benzamide
[2924] The title compound was prepared by substituting EXAMPLE 350C
for EXAMPLE 110E and EXAMPLE 291A for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.48 (m,
2H), 7.78 (m, 1H), 7.68 (m, 1H), 7.50 (m, 1H), 7.35 (m, 3H), 7.06
(m, 3H), 6.62 (m, 1H), 6.25 (m, 1H), 5.92 (m, 2H), 3.79 (m, 3H),
3.63 (m, 2H), 3.49 (m, 2H), 3.40 (m, 3H), 3.08 (s, 4H), 2.76 (s,
2H), 2.19 (m, 6H), 1.97 (s, 2H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 362
2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 362A
methyl 2-(6-amino-5-methylpyridin-3-yloxy)-4-fluorobenzoate
[2925] EXAMPLE 350A (260 mg),
dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphine (25 mg), and
palladium(II) acetate (7 mg) were suspended in anhydrous
tetrahydrofuran (2 mL). The mixture was flushed with N.sub.2 three
times and stirred at room temperature for 5 minutes followed by
addition of methylzinc(II) chloride (0.45 mL). The reaction mixture
was stirred at room temperature for 3 hours. The reaction was
quenched with saturated NH.sub.4Cl aqueous solution and diluted
with ethyl acetate. The organic phase was washed with water and
brine, dried over anhydrous sodium sulfate, filtered ande
concentrated. The residue was purified by flash column purification
with 60-100% ethyl acetate/hexane to provide the title
compound.
EXAMPLE 362B
methyl
2-(6-amino-5-methylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2926] The title compound was prepared by substituting EXAMPLE 362A
for EXAMPLE 3A in EXAMPLE 3G.
EXAMPLE 362C
2-(6-amino-5-methylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2927] The title compound was prepared by substituting EXAMPLE 362B
for EXAMPLE G in EXAMPLE 38 H.
EXAMPLE 362D
2-[(6-amino-5-methylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H--
pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2928] The title compound was prepared by substituting EXAMPLE 362C
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.57 (m, 2H), 7.86 (dd, 1H),
7.58 (d, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.19 (d, 1H), 7.05 (m,
3H), 6.60 (dd, 1H), 6.10 (d, 1H), 5.61 (s, 2H), 3.85 (dd, 2H), 3.25
(m, 4H), 3.05 (s, 4H), 2.74 (s, 2H), 2.18 (m, 6H), 1.97 (m, 7H),
1.63 (m, 2H), 1.39 (t, 2H), 1.25 (m, 2H), 0.94 (s, 6H).
EXAMPLE 363
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-
-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2929] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 337D for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.53-11.08 (m, 1H), 8.66 (t, 1H), 8.59 (d, 1H), 7.87 (dd, 1H),
7.75 (d, 1H), 7.38 (ddd, 5H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.18 (s,
3H), 3.77 (dd, 4H), 3.52 (dd, 2H), 3.12 (s, 4H), 2.81 (s, 2H), 2.22
(d, 6H), 2.03-1.67 (m, 6H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 364
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylp-
iperidin-4-yl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 364A
tert-butyl 1-(oxetan-3-yl)piperidin-4-ylcarbamate
[2930] The title compound was prepared by substituting
tert-butylpiperidin-4-ylcarbamate for tert-butyl
piperazine-1-carboxylate and oxetan-3-one for
4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 364B
1-(oxetan-3-yl)piperidin-4-amine
[2931] The title compound was prepared by substituting EXAMPLE 364A
for EXAMPLE 251A is EXAMPLE 1B.
EXAMPLE 364C
3-nitro-4-(1-(oxetan-3-yl)piperidin-4-ylamino)benzenesulfonamide
[2932] The title compound was prepared by substituting EXAMPLE 364B
for 1-isopropylpiperidinyl-4-amine in EXAMPLE 41A.
EXAMPLE 364D
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-oxetan-3-ylp-
iperidin-4-yl)amino]phenyl}sulfonyl)benzamide
[2933] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 364C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.57 (d,
1H), 8.28 (d, 1H), 7.86 (dd, 1H), 7.73 (d, 1H), 7.43 (d, 1H), 7.36
(m, 3H), 7.23 (d, 1H), 7.06 (d, 2H), 6.64 (dd, 1H), 6.17 (m, 3H),
4.55 (t, 2H), 4.44 (t, 2H), 3.76 (br s, 1H), 3.46 (br s, 1H), 3.11
(m, 5H), 2.77 (m, 2H), 2.67 (m, 2H), 2.20 (m, 6H), 2.08 (m, 1H),
1.97 (m, 4H), 1.65 (m, 2H), 1.40 (t, 2H), 0.94 (s, 6H).
EXAMPLE 365
2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 365A
methyl
2-(6-amino-5-isopropylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2934] The title compound was prepared by substituting EXAMPLE 350B
for EXAMPLE 350A and isopropylzinc(II) chloride for methylzinc(II)
chloride in EXAMPLE 362A.
EXAMPLE 365B
2-(6-amino-5-isopropylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4-dimethy-
lcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2935] The title compound was prepared by substituting EXAMPLE 365A
for EXAMPLE 380 in EXAMPLE 38H.
EXAMPLE 365C
2-[(6-amino-5-isopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2936] The title compound was prepared by substituting EXAMPLE 365B
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.61 (m, 2H), 7.88 (m, 1H), 7.61
(dd, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.22 (dd, 1H), 7.07 (m, 3H),
6.60 (dd, 1H), 6.06 (dd, 1H), 5.71 (d, 2H), 3.85 (dd, 1H), 3.27 (m,
4H), 3.06 (s, 4H), 2.90 (m, 1H), 2.74 (s, 2H), 2.38 (t, 1H), 2.17
(m, 6H), 1.92 (m, 3H), 1.63 (m, 2H), 1.52 (m, 1H), 1.39 (t, 2H),
1.26 (m, 2H), 1.11 (d, 6H), 0.93 (s, 6H).
EXAMPLE 366
2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydr-
o-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 366A
methyl
2-(6-smino-5-cyclopropylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)--
4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2937] The title compound was prepared by substituting EXAMPLE 350B
for EXAMPLE 350A and cyclopropylzinc(II) chloride for
methylzinc(II) chloride in EXAMPLE 362A.
EXAMPLE 366B
2-(6-amino-5-cyclopropylpyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dim-
ethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2938] The title compound was prepared by substituting EXAMPLE 366A
for EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 366C
2-[(6-amino-5-cyclopropylpyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydr-
o-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2939] The title compound was prepared by substituting EXAMPLE 366B
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.64 (t, 1H), 8.59 (d, 1H), 7.88
(dd, 1H), 7.60 (d, 1H), 7.45 (d, 1H), 7.35 (d, 2H), 7.23 (d, 1H),
7.06 (d, 2H), 6.91 (d, 1H), 6.61 (dd, 1H), 6.04 (d, 1H), 5.83 (s,
2H), 3.85 (dd, 2H), 3.27 (m, 4H), 3.06 (s, 4H), 2.73 (s, 2H), 2.18
(m, 6H), 1.97 (m, 3H), 1.65 (m, 3H), 1.40 (t, 2H), 1.26 (m, 2H),
0.94 (s, 6H), 0.87 (m, 2H), 0.49 (m, 2H).
EXAMPLE 367
Trans-2-[(6-amino-5-bromopyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-d-
imethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohe-
xyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2940] The title compound was prepared by substituting EXAMPLE 350C
for EXAMPLE 110E and EXAMPLE 345B for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.50 (m,
2H), 7.78 (d, 1H), 7.73 (d, 1H), 7.48 (d, 1H), 7.40 (s, 1H), 7.36
(d, 2H), 7.07 (m, 3H), 6.64 (dd, 1H), 6.22 (s, 1H), 5.98 (s, 2H),
3.27 (m, 4H), 3.22 (s, 3H), 3.06 (m, 4H), 2.76 (s, 2H), 2.20 (m,
6H), 1.99 (m, 4H), 1.80 (d, 2H), 1.62 (s, 1H), 1.40 (t, 2H), 1.04
(m, 4H), 0.94 (s, 6H).
EXAMPLE 368
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-N-({3-nitro-
-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 368A
methyl 4-fluoro-3-(3-fluoro-2-nitrophenoxy)benzoate
[2941] To a solution of methyl 4-fluoro-2-hydroxybenzoate (1.225 g)
in anhydrous tetrahydrofuran (25 mL) was added potassium t-butoxide
(0.808 g). The mixture was stirred for 20 minutes at room
temperature. A solution of 1,3-difluoro-2-nitrobenzene (0.955 g) in
tetrahydrofuran (6 mL) was then added dropwise. The resulting
mixture was stirred at room temperature for 1 hour, then at
80.degree. C. overnight. The reaction mixture was quenched with
water (40 mL) and extracted with dichlorormethane. The organic
solution was dried (MgSO.sub.4), filtered and concentrated. The
residue was purified on a silica gel column, eluting with 25% ethyl
acetate in hexane to obtain the title compound.
EXAMPLE 368B
methyl
2-(3-(bis-(4-methoxyphenyl)methylamino)-2-nitrophenoxy)-4-fluoroben-
zoate
[2942] A solution of EXAMPLE 368A (1.33 g),
bis(4-methoxyphenyl)methanamine (1.046 g) and
N-ethyl-N-isopropylpropan-2-amine (1.127 ml) in anhydrous
1-methyl-2-pyrrolidinone (20 mL) was stirred at 120.degree. C.
overnight. The mixture was concentrated and the residue was taken
up in water (100 mL) and extracted with dichloromethane. The
residue was absorbed on silica and purified by chromatography on a
silica gel column, duringwith 25% ethyl acetate in hexane to
provide the title compound.
EXAMPLE 368C
methyl
2-(2-amino-3-(bis(4-methoxyphenyl)methylamino)phenoxy)-4-fluorobenz-
oate
[2943] A solution of EXAMPLE 368B (1.1 g) in methanol was
hydrogenated over Raney Ni, at 60 psi of H.sub.2 at room
temperature. the filtered solution was concentrated to give the
title compound.
EXAMPLE 368D
methyl
2-(1-(bis(4-methoxyphenyl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imid-
azol-4-yloxy)-4-fluorobenzoate
[2944] A solution of EXAMPLE 368C (0.58 g) and
N-ethyl-N-isopropylpropan-2-amine (0.804 ml) in dichloromethane (8
mL) was cooled with an ice bath. Then, a 20 wt % solution of
phosgene in toluene (0.850 ml) was added dropwise. The mixture was
stirred at room temperature overnight. The mixture was diluted with
dichloromethane and washed with 5% aq. NaHCO.sub.3. The material
was then absorbed on silica and purified on a silica gel column
eluting with 50% ethyl acetate in hexane to provide the title
compound.
EXAMPLE 368E
methyl
2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-ben-
zo[d]imidazol-4-yloxy)-4-fluorobenzoate
[2945] To a solution of EXAMPLE 368D (250 mg) in anhydrous
N,N-dimethylformamide (6 mL) was added sodium hydride (34.1 mg).
The mixture was stirred at 50.degree. C. for 30 minutes. Then,
iodomethane (35.6 .mu.l) was added and the mixture was stirred at
5.degree. C. overnight. The reaction mixture was quenched with
water (30 mL), then extracted with ethyl acetate. The solution was
dried (MgSO.sub.4), filtered and concentrated to give the title
compound.
EXAMPLE 368F
methyl
2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-ben-
zo[d]imidazol-4-yloxy)-4-(piperazin-1-yl)benzoate
[2946] A flask was charged with EXAMPLE 368E (281 mg), anhydrous
N,N-dimethylformamide (6 mL) and piperazine (268 mg). The mixture
was stirred at 75.degree. C. overnight. The solvent was evaporated
and the residue was re-dissolved in ethyl acetate. The crude
product was purified on a silica gel column eluting with 5%
methanol in dichloromethane to provide the title compound.
EXAMPLE 368G
methyl
2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl)-2-oxo-2,3-dihydro-1H-be-
nzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-e-
nyl)methyl)piperazin-1-yl)benzoate
[2947] To a solution of EXAMPLE 368F (273 mg)and EXAMPLE 60D (169
mg) in anhydrous dichloromethane (5 mL) was added sodium
triacetoxxyborohydride (172 mg) in several portions over 5 minutes.
The resulting mixture was stirred at ambient temperature overnight.
The mixture was quenched with 5% aqueous Na.sub.2CO.sub.3 solution
(10 mL) and extracted with dichloromethane. The crude product was
purified on a silica gel column eluted with 45% ethyl acetate in
hexane to provide the title compound.
EXAMPLE 368H
2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]im-
idazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)meth-
yl)piperazin-1-yl)benzoic acid
[2948] This example was prepared by substituting EXAMPLE 368G for
EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 368I
2-(1-(bis(4-methoxyphenyl)methyl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]im-
idazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)meth-
yl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phe-
nylsulfonyl)benzamide
[2949] This example was prepared by substituting by substituting
EXAMPLE 368H for EXAMPLE 1F in EXAMPLE 1H.
EXAMPLE 368J
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(3-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)oxy]-N-({3-nitro-
-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2950] A solution of EXAMPLE 368I (140 mg) in dichloromethane (10
mL) was cooled with an ice bath. Trifluoroacetic acid (10 mL) was
added. The resulting solution was allowed to warm to room
temperature and stirred for 48 hours. The solution was concentrated
and the residue was triturated with diethyl ether. The resulting
solid was purified by reverse-phase HPLC using a Waters Preparative
LC4000 system wtih Phenomenex Luna C18 column and a
water-acetonitrile mobile phase buffered with ammonium acetate to
proivde the title compound. .sup.1H NMR (500 MHz, pyridine-d.sub.5)
.delta. 12.34 (s, 1H), 9.20 (d, 1H), 8.87 (t, 1H), 8.44 (dd, 1H),
8.01 (d, 1H), 7.44 (d, 2H), 7.08 (d, 2H), 7.01 (d, 1H), 6.86-6.79
(m, 3H), 6.74 (d, 1H), 6.52 (dd, 1H), 3.96 (dd, 2H), 3.65 (s, 3H),
3.30 (d, 2H), 3.24 (m, 2H), 3.19 (m, 4H), 2.81 (s, 2H), 2.30-2.28
(m, 2H), 2.23 (m, 4H), 1.97 (s, 2H), 1.85-1.75 (m, 1H), 1.58 (d,
2H), 1.40 (t, 2H), 1.33 (dq, 2H), 0.94 (s, 6H).
EXAMPLE 369
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholi-
n-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 369A
tert-butyl
2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxyl-
ate
[2951] The title compound was prepared by substituting tert-butyl
2-aminomethyl)morpholine-4-carboxylate for
3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.
EXAMPLE 369B
4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide
[2952] A solution of EXAMPLE 369A (0.8 g) in methylene chloride (10
mL) and trifluoroacetic acid (10 mL) was stirred at room
temperature for 2 hours. The solvents were evaporated and the
residue was triturated with diethyl ether. The resulting solid was
dissolved in 5% aqueous sodium carbonate solution (20 mL). The
mixture was concentrated to dryness and the resulting soid was
triturated with a solution of 10% methanol in methylene chloride
several times. Evaporation of the organic solvent provided the
title compound.
EXAMPLE 369C
4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide
[2953] A solution of EXAMPLE 369B (0.633 g) and
(1-ethyoxycyclopropoxy)trimethylsilane (1.601 mL) in anhydrous
methanol (15 mL) and acetic acid (1.717 mL) was refluxed for 30
minutes and allowed to cool to room temperature. Sodium
cyanoborohydride (0.377 g) was then added and the mixture was
stirred at ambient temperature overnight. The reaction mixture was
concentrated to dryness. The residue was mixed with 5% aqueous
Na.sub.2CO.sub.3 solution (25 mL) and extracted with ethyl acetate.
The crude product was purified on a silica gel column eluting with
5% to 10% methanol in dichloromethane to provide the title
compound.
EXAMPLE 369D
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholi-
n-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2954] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 369C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.34 (br
s, 1H), 8.63 (t, 1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.73 (d, 1H),
7.45 (d, 1H), 7.38 (d, 1H), 7.36 (d, 2H), 7.20 (d, 1H), 7.06 (d,
2H), 6.65 (dd, 1H), 6.19 (d, 1H), 6.17 (br s, 2H), 3.83 (m, 1H),
3.64 (m, 1H), 3.56 (m, 1H), 3.45 (m, 2H), 3.12 (m, 4H), 2.91 (m,
1H), 2.74 (m, 3H), 2.26 (m, 5H), 2.15 (m, 3H), 1.97 (m, 2H), 1.66
(m, 1H), 1.40 (t, 2H), 0.94 (s, 6H), 0.42 (m, 2H), 0.33 (m,
2H).
EXAMPLE 370
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrr-
olidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 370A
(R)-tert-butyl 1-cyclopropylpyrrolidin-3-ylcarbamate
[2955] The title compound was prepared by substituting
(R)-tert-butyl pyrrolidine-3-ylcarbamate for tert-butyl
(trans)-4-aminocyclohexylcarbamate in EXAMPLE 334A.
EXAMPLE 370B
(R)-1-cyclopropylpyrrolidin-3-amine
[2956] The title compound was prepared by substituting EXAMPLE 370A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 370C
(R)-4-(1-cyclopropylpyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide
[2957] The title compound was prepared by substituting EXAMPLE 370B
for 1-isopropylpiperidinyl-4-amine in EXAMPLE 41A.
EXAMPLE 370D
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-cyclopropylpyrr-
olidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2958] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 370C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.52 (d,
1H), 8.33 (d, 1H), 7.84 (dd, 1H), 7.69 (d, 1H), 7.46 (d, 1H), 7.36
(m, 2H), 7.30 (d, 1H), 7.10 (d, 1H), 7.06 (d, 2H), 6.64 (dd, 1H),
6.21 (d, 1H), 6.09 (br s, 2H), 4.27 (m, 1H), 3.09 (m, 4H), 3.01 (m,
1H), 2.91 (m, 1H), 2.76 (m, 3H), 2.62 (m, 1H), 2.22 (m, 6H), 1.97
(m, 2H), 1.76 (m, 1H), 1.68 (m, 1H), 1.40 (t, 2H), 0.94 (s, 6H),
0.43 (m, 2H), 0.37 (m, 2H).
EXAMPLE 371
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro-1-
-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benzam-
ide
EXAMPLE 371A
4-((1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl)methoxy)-3-nitroben-
zenesulfonamide
[2959] To a suspension of EXAMPLE 341C (0.100 g) and
1,3-difluoropropan-2-one (0.025 g) in dichloromethane (2 mL) was
added sodium triacetoxyborohydride (0.071 g). After 15 minutes,
N,N-dimethylformamide added dropwise unitl an organe solution
resulted (.about.15 drops). After stirring overnight additional
1,3-difluoropropan-2-one and sodium triacetoxyborohydride were
added. After 3 hours, the reaction was loaded onto silica gel
(Reverleris 40 g) and eluted with a gradient of 0.5-5%
methanol/dichloromethane over 30 minutes (flow=40 ml/minutes) to
provide the title compound.
EXAMPLE 371B
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({4-fluoro-1-[2-fluoro-1-
-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-3-nitrophenyl]sulfonyl}benzam-
ide
[2960] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 371A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
12.05-10.74 (m, 1H), 8.38 (s, 1H), 8.08 (s, 1H), 7.73 (d, 1H), 7.50
(dd, 2H), 7.37 (d, 3H), 7.07 (d, 2H), 6.65 (d, 1H), 6.18 (d, 3H),
4.62 (dd, 4H), 4.38 (d, 2H), 3.16 (s, 5H), 2.97-2.60 (m, 8H), 2.18
(s, 4H), 2.07-1.60 (m, 6H), 1.42 (s, 2H), 0.94 (s, 6H).
EXAMPLE 372
tert-butyl
6bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-
-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethy-
l)amino]phenyl}sulfonyl)amino]carbonyl}phenyoxy)pyridin-2-ylcarbamate
EXAMPLE 372A
2-(2,6-Dibromo-pyridin-4-yloxy)-4-fluoro-benzoic acid methyl
ester
[2961] A soltuion of methyl 4-fluoro-2-hydroxybenzoate (2.00 g),
2,6-dibromo-4-nitropyridine (3.65 g), and cesium carbonate (4.21 g)
in N,N-dimethylformamide (100 mL) was heated to 55.degree. C. for
16 hours, cooled, added to water, and extracted with 50% ethyl
acetate in hexanes. The organic extract was washed with brine,
dried over anhydrous sodium sulfate, filtered, concentrated and
purified by flash column chromatography on silica gel using 30-50%
ethyl acetate in hexanes.
EXAMPLE 372B
2-(2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-fluoro-benzoic
acid methyl ester
[2962] EXAMPLE 372A (1400 mg), tert-butyl carbamate (405 mg), and
cesium carbonate (1689 mg) were added to 1,4-dioxane (24 mL). The
solution was degassed and flushed with nitrogen three times.
Palladium(II) acetate (39 mg) and
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (200 mg) were
added, and the solution was heated at 80.degree. C. for 2.5 hours,
cooled, added to water, and extracted with 50% ethyl acetate in
hexanes. The extract was washed with brine, dried over anhydrous
sodium sulfate, filtered, concentrated and purified by flash column
chromatography on silica gel using 10-20% ethyl acetate in
hexanes.
EXAMPLE 372C
2-(2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-piperazin-1-yl-be-
nzoic acid methyl ester
[2963] The title compound was prepared by substituting EXAMPLE 372B
for EXAMPLE 342D in EXAMPLE 342E.
EXAMPLE 372D
2-(2-Bromo-6-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-p-
henyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoic
acid methyl ester
[2964] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 372C for
tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 372E
2-(2-Bromo-6-tert-butyoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro--
phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoic
acid
[2965] The title compound was prepared by substituting EXAMPLE 372D
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 372F
tert-butyl
6-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en--
1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmeth-
yl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate
[2966] The title compound was prepared by substituting EXAMPLE 372E
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 9.93 (s, 1H), 8.58 (bs, 1H),
8.47 (d, 1H), 7.70 (d, 1H), 7.57 (d, 1H), 7.37 (d, 2H), 7.18 (d,
1H), 7.08 (d, 1H), 7.07 (d, 2H), 6.83 (dd, 1H), 6.63 (bs, 1H), 6.40
(d, 1H), 3.87 (dd, 2H), 3.35-3.25 (m, 8H), 2.85 (bs, 2H), 2.40-2.15
(m, 6H), 1.97 (bs, 2H), 1.93 (m, 1H), 1.65 (d, 2H), 1.41 (t, 2H),
1.40 (s, 9H), 1.36-1.22 (m, 2H), 0.95 (s, 6H).
EXAMPLE 373
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yl)
oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)benzamide
EXAMPLE 373A
2-(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-fluoro-benzoic
acid methyl ester
[2967] The title compound was prepared during the synthesis of
EXAMPLE 372B.
EXAMPLE 373B
2-(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-piperzin-1-yl-benzo-
ic acid methyl ester
[2968] The title compound was prepared by substituting EXAMPLE 373A
for EXAMPLE 342D in EXAMPLE 342E.
EXAMPLE 373C
2-(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-phe-
nyl)-4,4-dimethyl-cyclohex-1-enylmethyl]piperazin-1-yl}-benzoic
acid methyl ester
[2969] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 373B for
tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 373D
[2970]
2-(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chl-
oro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoic
acid
[2971] The title compound was prepared by substituting EXAMPLE 373C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 373E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(2,6-Bis-tert-butoxycarbonylamino-pyridin-4-yl)oxy]-N-({3-nitro-4-
-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2972] The title compound was prepared by substituting EXAMPLE 373D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 9.12 (bs, 2H), 8.57 (m, 1H),
8.50 (d, 1H), 7.72 (dd, 1H), 7.53 (d, 1H), 7.36 (d, 2H), 7.12 (d,
1H), 7.06 (d, 2H), 6.86 (s, 2H), 6.79 (dd, 1H), 6.56 (bs, 1H), 3.86
(dd, 2H), 3.27-3.18 (m, 8H), 2.79 (bs, 2H), 2.31-2.15 (m, 6H), 1.97
(bs, 2H), 1.93 (m, 1H), 1.64 (d, 2H), 1.42 (t, 2H), 1.41 (s, 18H),
1.33-1.23 (m, 2H), 0.94 (s, 6H).
EXAMPLE 374
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-{[6-(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydro-
-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 374A
methyl 2-(6-(cyclopropylamino)pyridin-3-yloxy)-4-fluorobenzoate
[2973] The title compound was prepared by substituting cyclopropyl
amine for tert-butyl carbamate in EXAMPLE 377B.
EXAMPLE 374B
methyl
2-(6-(cyclopropylamino)pyridin-3-yloxy)-4-(piperazin-1-yl)benzoate
[2974] The title compound was prepared by substituting EXAMPLE 374A
for EXAMPLE 377E in EXAMPLE 377F.
EXAMPLE 374C
methyl
4-(4-((2-(4-chlorophenyl)-4-dimethylcyclohex-1-enyl)methyl)piperazi-
n-1-yl)-2-(6-(cyclopropylamino)pyridin-3-yloxy)benzoate
[2975] The title compound was prepared by substituting EXAMPLE 374B
for tert-butyl piperazine-1-carboxylate and EXAMPLE 60D for
4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 374D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(6-(cyclopropylamino)pyridin-3-yloxy)benzoic acid
[2976] The title compound was prepared by substituting EXAMPLE 374C
for EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 374E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-{[6(cyclopropylamino)pyridin-3-yl]oxy}-N-({3-nitro-4-[(tetrahydro--
2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2977] The title compound was prepared by substituting EXAMPLE 374D
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.54 (m, 2H), 7.85 (m, 1H), 7.77
(d, 1H), 7.48 (d, 1H), 7.36 (d, 2H), 7.17 (m, 2H), 7.06 (d, 2H),
6.60 (m, 3H), 6.13 (d, 1H), 3.85 (dd, 2H), 3.26 (m, 4H), 3.05 (s,
4H), 2.74 (s, 2H), 2.47 (m, 2H), 2.18 (m, 6H), 1.92 (m, 3H), 1.61
(m, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s, 6H), 0.68 (m, 2H),
0.41 (m, 2H).
EXAMPLE 375
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4-(-
methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 375A
methyl
2-(6-(2.2-difluoroethylamino)pyridin-3-yloxy)-4-fluorobenzoate
[2978] The title compound was prepared by substituting
2,2-difluoroethananmine for tert-butyl carbamate in EXAMPLE
377B.
EXAMPLE 375B
methyl
2-(6-(2,2-difluoroethylamino)pyridin-3-yloxy)-4-(piperazin-1-yl)ben-
zoate
[2979] The title compound was prepared by substituting EXAMPLE 375A
for EXAMPLE 377E in EXAMPLE 377F.
EXAMPLE 375C
methyl
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)pipera-
zin-1-yl)-2-(6-(2,2-difluoroethylamino)pyridin-3-yloxy)benzoate
[2980] The title compound was prepared by substituting EXAMPLE 375B
for tert-butyl piperazine-1-carboxylate and EXAMPLE 60D for
4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 375D
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-y-
l)-2-(6-(2,2-difluoroethylamino)pyridin-3-yloxy)benzoic acid
[2981] The title compound was prepared by substituting EXAMPLE 375C
for EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 375E
Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}pipe-
razin-1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-[(4-{[(4-(-
methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[2982] The title compound was prepared by substituting EXAMPLE 375D
for EXAMPLE 110E and EXAMPLE 345B for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.52 (m,
2H), 7.84 (dd, 1H), 7.75 (d, 1H), 7.47 (d, 1H), 7.35 (m, 2H), 7.16
(m, 2H), 7.05 (d, 2H), 6.87 (t, 1H), 6.60 (m, 2H), 6.10 (m, 2H),
3.66 (m, 2H), 3.27 (m, 4H), 3.23 (s, 3H), 3.05 (s, 4H), 2.74 (s,
2H), 2.18 (m, 6H), 1.99 (m, 4H), 1.79 (m, 2H), 1.61 (m, 1H), 1.40
(t, 2H), 1.07 (m, 4H), 0.94 (s, 6H).
EXAMPLE 376
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-({6-[(2,2-difluoroethyl)amino]pyridin-3-yl}oxy)-N-({3-nitro-4-[(te-
trahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2983] The title compound was prepared by substituting EXAMPLE 375D
for EXAMPLE 110E in EXAMPLE 110F. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.55(m, 2H), 7.86 (dd, 1H), 7.76
(d, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.18 (m, 2H), 7.06 (d, 2H),
6.89 (m, 1H), 6.61 (m, 2H), 6.10 (m, 2H), 3.85 (dd, 2H), 3.66 (m,
2H), 3.27 (m, 4H), 3.06 (s, 4H), 2.74 (s, 2H), 2.18 (m, 6H), 1.94
(m, 4H), 1.62 (d, 2H), 1.40 (t, 2H), 1.28 (m, 2H), 0.94 (s,
6H).
EXAMPLE 377
2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 377A
methyl 2-(6-chloropyridin-3-yloxy)-4-fluorobenzoate
[2984] To a solution of 6-chloropyridin-3-ol (2.41 g) in
2-methyltetrahydrofuran (20 mL) and N,N-dimethylformamide (4 mL)
was added potassium tert-butoxide (1.0 M in tetrahydrofuran) (18.60
mL). The reaction was stirred for 15 minutes, then methyl
2,4-difluorobenzoate (3.52 g) was added as a solution in
2-methyltetrahydrofuran (2 mL). The reaction was then heated to
80.degree. C. and stirred under a nitrogen atmosphere for 3 days.
The reaction was cooled, diluted with ethyl acetate (100 mL),
washed with water (50 mL), 1N aqueous HCl (50 mL), and brine (50
mL), dried over magnesium sulfate, filtered, and concentrated.
Silica gel chromatography (Reveleris 80 g), eluting with 10% ethyl
acetate/hexanes provided the title compound.
EXAMPLE 377B
methyl
2-(6-(tert-butoxycarbonylamino)pyridin-3-yloxy)-4-fluorobenzoate
[2985] To EXAMPLE 377A (3.30 g), tert-butylcarbamate (1.51 g) and
cesium carbonate (5.73 g) in dioxane (30 mL) was added
diacetoxypalladium (0.079 g) and
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.41 g)
and the reaction was heated to 85.degree. C. overnight under an
atmosphere of nitrogen. The reaction was cooled, diluted with ethyl
acetate (100 mL) and washed with water (75 mL) and brine (75 mL)
dried over magnesium sulfate, filtered, and concentrated. Silica
gel chromatography (Reveleris 80 g) eluting with 10% ethyl
acetate/hexanes over 20 minutes provided the title compound.
EXAMPLE 377C
methyl
2-(6-tert-butoxycarbonyl(methyl)amino)pyridin-3-yloxy)-4-fluorobenz-
oate
[2986] To a solution of EXAMPLE 377B (0.750 g) in
N,N-dimethylformamide (5 mL) was added sodium hydride (0.091 g).
The reaction was stirred for 30 minutes at room temperature and the
niodomethane(0.142 mL) was added to the reaction and stirring was
continued at room temperature for 2 hours. The reaction was
quenched with water (25 mL) and extracted with ethyl acetate (75
mL). The organic layer was separated, washed with brine (50 mL),
dried over magnesium sulfate, filtered, and concentrated. The
residue was loaded onto silica gel (Reveleris 40 g) and eluted with
a gradient of 5-15% ethyl aeetate/hexanes over 30 minutes (flow=40
ml/min) to provide the title compound.
EXAMPLE 377D
methyl 4-fluoro-2-(6-(methylamino)pyridin-3-yloxy)benzoate
[2987] To EXAMPLE 377C (0.714 g) in dichloromethane (10 mL) was
added trifluoroacetic acid (1.5 mL). After stirring for 3 hours,
the reaction was concentrated, dissolved in dichloromethane (100
mL), washed with saturated aqueous NaHCO.sub.3 (2.times.75 mL) and
brine (75 mL), dried over magnesium sulfate, filtered, and
concentrated to proivde the title compound.
EXAMPLE 377E
methyl
2-(5-chloro-6-methylamino)pyridin-3-yloxy)-4-fluorobenzoate
[2988] A solution of EXAMPLE 377D (0.450 g) and N-chlorosuccinimide
(0.239 g) was stirred together in N,N-dimethylformamide 10 mL) at
room temperature. The reaction was stirred for 48 hours, diluted
with ethyl acetate (100 mL), washed with water (2.times.50 mL) and
brine (50 mL), dried over magnesium sulfate, filtered, and
concentrated. Silica gel chromatography (Reveleris 40 g) eluting
with a gradient of 5-30% ethyl acetate/hexanes over 30 minutes
(flow=40 ml/min) provided the title compound.
EXAMPLE 377F
methyl
2-(5-chloro-6-(methylamino)pyridin-3-yloxy)-4-(piperazin-1-yl)benzo-
ate
[2989] A solution of EXAMPLE 377E (0.230 g) and piperazine (0.255
g) in dimethylsulfoxide (3 mL) was heated to 85.degree. C. for 1
hour. The reaction was cooled and diluted with ethyl acetate (75
mL). The organic layer was washed with water (3.times.50 mL) and
brine (50 mL), dried over magnesium sulfate, filtered, and
concentrated to give the title compound.
EXAMPLE 377G
methyl
2-(5-chloro-6-(methylamino)pyridin-3-yloxy)-4-(4-((2-(4-chloropheny-
l)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate
[2990] To a solution of EXAMPLE 377F (0.230 g) and EXAMPLE 60D
(0.182 g) in dichloromethane (2 mL) was added sodium
triacetoxyborohydride (0.194 g) and the reaction was allowed to
stir at room temperature overnight. The reaction was quenched with
saturated aqueous NaHCO.sub.3 solution (25 mL) and exracted into
dichloromethane (75 mL). The organic layer was washed with brine
(25 mL), dried over magnesium sulfate, filtered, and concentrated.
Silica gel chromatography (Reveleris 40 g) eluting with a gradient
of 5-30% ethyl acetate/hexanes over 30 minutes provided the title
compound.
EXAMPLE 377 H
2-(5-chloro-6-(methylamino)pyridin-3-oxy)-4-(4-((2-(4-chlorophenyl)-4,4-di-
methylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic acid
[2991] To a solution of EXAMPLE 377G (0.295 g) in tetrahydrofuran
(5 mL) and methanol (2 mL) was added 1.0 M aqueous LiOH (1.452 mL)
and the reaction was heated to 55.degree. C. After stirring for 3
hours, the reaction was cooled, diluted with dichloromethane (75
mL) and water (15 mL) and quenched with 1N aqueous HCl (1.45 mL).
The organic layer was separated, washed with brine (15 mL), dried
over magnesium sulfate, filtered, and concentrated to provide the
title compound.
EXAMPLE 377I
2-{[5-chloro-6-(methylamino)pyridin-3-yl]oxy}-4-(4-{[2-(4-chlorophenyl)-4,-
4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2992] The title compound was prepared by substituting EXAMPLE 377
H for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.52-11.16 (m, 1H), 8.63 (s,
1H), 8.57 (d, 1H), 7.87 (dd, 1H), 7.82 (d, 1H), 7.49-7.39 (m, 2H),
7.36 (d, 2H), 7.21 (d, 1H), 7.06 (d, 2H), 6.65 (d, 1H), 6.43 (d,
1H), 6.18 (d, 1H), 3.85 (d, 2H), 3.41-3.19 (m, 4H), 3.12 (s, 4H),
2.84 (d, 3H), 2.79 (s, 2H), 2.20 (d, 6H), 1.97 (s, 3H), 1.62 (d,
2H), 1.41 (d, 2H), 1.29 (dd, 2H), 0.94 (s, 6H).
EXAMPLE 378
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluoro-
methyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide
EXAMPLE 378A
tert-butyl
(4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylcarbamate
[2993] The title compound was prepared by substituting
tert-butylmorpholin-2-ylmethylcarbamate for
tert-butylpiperazine-1-carboxylate and 1,3-difluoropropan-2-one for
4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A
EXAMPLE 378B
(4-(1,3-difluoroprapan-2-yl)morpholin-2-yl)methanamine
[2994] The title compound was prepared by substituting EXAMPLE 378A
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 378C
4-((4-(1,3-difluoropropan-2-yl)morpholin-2-yl)methylamino)-3-nitrobenzenes-
ulfonamide
[2995] The title compound was prepared by substituting EXAMPLE 378B
for 3-(N-morpholinyl)-1-propylamine in EXAMPLE 4A.
EXAMPLE 378D
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({4-[2-fluoro-1-(fluoro-
methyl)ethyl]morpholin-2yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide
[2996] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 378C for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.30 (br
s, 1H), 8.63 (t, 1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.74 (d, 1H),
7.44 (d, 1H), 7.38 (d, 1H), 7.36 (d, 2H), 7.20 (d, 1H), 7.06 (d,
2H), 6.65 (dd, 1H), 6.19 (d, 1H), 6.17 (br s, 2H), 4.68 (t, 2H),
4.56 (t, 2H), 3.83 (d, 1H), 3.71 (m, 1H), 3.51 (m, 4H), 3.12 (m,
4H), 2.90 (d, 1H), 2.80 (m, 2H), 2.73 (m, 1H), 2.57 (t, 1H), 2.42
(t, 1H), 2.25 (m, 4H), 2.17 (m, 2H), 1.97 (m, 2H), 1.40 (t, 2H),
0.94 (s, 6H).
EXAMPLE 379
2-[(2-amino-6-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2997] EXAMPLE 372F (137 mg) was dissolved in dichloromethane (2
mL), and trifluoroacetic acid (0.21 mL) was added. The mixture was
stirred at room temperature for 16 hours, diluted with
dichloromethane, extracted with saturated aqueous sodium
bicarbonate, dried over anhydrous sodium sulfate, and concentrated
under vacuum to provide the title compound. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.57 (bs, 1H), 8.48 (bs, 1H),
7.69 (dd, 1H), 7.54 (d, 1H), 7.37 (d, 2H), 7.08 (d, 1H), 7.07 (d,
2H), 6.80 (dd, 1H), 6.55 (bs, 1H), 6.23 (d, 2H), 6.03 (d, 1H), 5.59
(d, 1H), 3.86 (dd, 2H), 3.24 (m, 8H), 2.81 (bs, 2H), 2.35-2.15 (m,
6H), 1.97 (bs, 2H), 1.93 (m, 1H), 1.65 (d, 2H), 1.42 (t, 2H),
1.35-1.21 (m, 2H), 0.95 (s, 6H).
EXAMPLE 380
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(2,6-diaminopyridin-4-yl)oxy]-N-({3-nitro-4-[(tetrahydro-2H-pyran-
-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[2998] The title compound was prepared by substituting EXAMPLE 373E
for EXAMPLE 372F in EXAMPLE 379. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.36 (d, 1H), 8.34 (t, 1H), 7.70
(dd, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.36 (t, 1H), 7.09 (d, 1H),
7.08 (d, 2H), 6.97 (d, 1H), 6.64 (dd, 1H), 6.28 (d, 1H), 5.21 (bs,
4H), 3.84 (dd, 2H), 3.25 (m, 2H), 3.06 (m, 4H), 2.76 (m, 2H),
2.29-2.15 (m, 8H), 1.98 (bs, 2H), 1.91 (m, 1H), 1.63 (d, 2H), 1.41
(t, 2H), 1.34-1.17 (m, 2H), 0.95 (s, 6H).
EXAMPLE 381
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[3-nitro-4-(tetrahydro-2H-p-
yran-4-ylmethoxy)phenyl]sulfonyl}benzamide
[2999] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 264A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, diraeihylsulfoxide-d.sub.6).delta.
11.78-11.08 (m, 1H), 8.35 (s, 1H), 8.07 (s, 1H), 7.73 (d, 1H),
7.54-7.43 (m, 2H), 7.36 (d, 3H), 7.07 (d, 2H), 6.65 (d, 1H), 6.18
(d, 3H), 4.13 (d, 2H), 3.88 (d, 2H), 3.35 (d, 2H), 3.14 (s, 4H),
2.99-2.78 (m, 2H), 2.08 (t, 9H), 1.66 (d, 2H), 1.45-1.22 (m, 4H),
0.94 (s, 6H).
EXAMPLE 382
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fl-
uoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide
EXAMPLE 382A
(R)-1-(1,3-difluoropropan-2-yl)piperidin-3-amine hydrogen
chloride
[3000] A solution of (R)-tert-butylpiperidin-3-ylcarbamate (0.500
g), 1,3-difluoropropan-2-one (0.258 g) and sodium
triacetoxyhydroborate (0.794 g) were stirred together in
dichloromethane (5 mL) overnight. The reaction was quenched with
saturated aqueous NaHCO.sub.3 (10 mL) and extracted with
dichloromethane (30 mL). The organic layer was washed with brine
(20 mL), dried over magnesium sulfate, filtered, and concentrated.
The crude material was treated with HCl (4.0 M dioxane, 2 mL) in
methanol (2 mL). After stirring for 2 hours, the reaction was
concentrated to provide the title compound.
EXAMPLE 382B
(R)-4-(1-(1,3-difluoropropan-2-yl)piperidin-3-ylamino)-3-nitrobenzenesulfo-
namide
[3001] To EXAMPLE 382A (0.590 g) and
4-chloro-3-nitrobenzenesulfonamide (0.611 g) in dioxane (10 mL) was
added N-ethyl-N-isopropylpropan-2-amine (1.641 mL) and the reaction
heated to 90.degree. C. The reaction was concentrated, loaded onto
silica gel (Reveleris 80 g) and eluted using a gradient of 35% to
100% ethyl acetate/hexanes over 30 minutes to give the title
compound.
EXAMPLE 382C
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fl-
uoromethyl)ethyl]piperidin-3yl}amino)-3-nitrophenyl]sulfonyl}benzamide
[3002] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 382B for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsuifoxide-d.sub.6) .delta.
11.62-11.06 (m, 1H), 8.91 (d, 1H), 8.60 (d, 1H), 7.87 (d, 1H), 7.75
(d, 1H), 7.47-7.32 (m, 4H), 7.19 (d, 1H), 7.06 (d, 2H), 6.65 (d,
1H), 6.18 (s, 3H), 4.64 (dt, 4H), 4.00 (s, 1H), 3.27-3.08 (m, 5H),
2.90-2.58 (m, 6H), 2.20 (d, 6H), 1.97 (s, 2H), 1.60 (s, 4H), 1.40
(s, 2H), 0.94 (s, 6H).
EXAMPLE 383
tert-butyl
5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en--
1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmeth-
yl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate
EXAMPLE 383A
2-(2-Amino-5-bromo-pyridin-4-yloxy)-4-fluoro-benzoic acid methyl
ester
[3003] EXAMPLE 271A (600 mg), potassium bromide (300 mg), and
ammonium molybdate (85 mg) were added to acetic acid (6 mL). Sodium
perborate tetrahydrate (387 mg) was added. The mixture stirred at
room temperature for 16 hours and added to water. The pH was
adjusted to 12 using 1 M aqueous sodium hydroxide, and the solution
was extracted with ethyl acetate. The extract was washed with
brine, dried over anhydrous sodium sulfate, filtered, concentrated
and purified by flash column chromatography on silica gel using
30-70% ethyl acetate in hexanes.
EXAMPLE 383B
2-(5-Bromo-2-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-fluoro-benzoic
acid methyl ester
[3004] EXAMPLE 383A (726 mg), di-tert-butyldicarbonate (557 mg),
and 4-(dimethylamino)pyridine (26 mg) were added to acetonitrile
(15 mL) and stirred at room temperature for 16 hours. The solution
was concentrated and purified by flash column chromatography on
silica gel using 20% ethyl acetate in hexanes to proivde the title
compound.
EXAMPLE 383C
2-(5-Bromo-2-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-piperazin-1-yl-be-
nzoic acid methylester
[3005] The title compound was prepared by substituting EXAMPLE 383B
for EXAMPLE 342D in EXAMPLE 342E.
EXAMPLE 383D
2-(5-Bromo-2-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-p-
henyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoic
acid methyl ester
[3006] The title compound was prepared by substituting EXAMPLE 60D
for 4-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 383C for
tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 383E
2-(5-Bromo-2-tert-butoxycarbonylamino-pyridin-4-yloxy)-4-{4-[2-(4-chloro-p-
henyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-benzoic
acid
[3007] The title compound was prepared by substituting EXAMPLE 383D
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 383F
tert-butyl
5-bromo-4-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en--
1-yl]methyl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmeth-
yl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)pyridin-2-ylcarbamate
[3008] The title compound was prepared by substituting EXAMPLE 383E
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 9.62 (bs, 1H), 8.58 (bs, 1H),
8.48 (bs, 1H), 8.18 (s, 1H), 7.72 (m, 1H), 7.59 (m, 1H), 7.36 (d,
2H), 7.15-6.98 (m, 4H), 6.82 (d, 1H), 6.62 (bs, 1H), 3.87 (d, 2H),
3.35-3.20 (m, 8H), 2.79 (m, 2H), 2.30-2.16 (m, 6H), 1.97 (bs, 2H),
1.92 (m, 1H), 1.64 (d, 2H), 1.41 (t, 2H), 1.32 (s, 9H), 1.30 (m,
2H), 0.95 (s, 6H).
EXAMPLE 384
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tetr-
ahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 384A
2-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-fluoro-benzoic acid
methyl ester
[3009] The title compound was prepared by substituting
4-chloro-1H-pyrrolo[2,3-B]pyridin-5-ol for EXAMPLE 342C in EXAMPLE
342D.
EXAMPLE 384B
2-(4-Chloro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-4-piperazin-1-yl-benzoic
acid methyl ester
[3010] The title compound was prepared by substituting EXAMPLE 384A
for EXAMPLE 342D in EXAMPLE 342E.
EXAMPLE 384C
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzoic acid
methyl ester
[3011] The title compound was prepared by substituting EXAMPLE 60D
for 4'-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 384B for
tert-buty lpiperazine-1-carboxylate in EXAMPLE 1A.
EXAMPLE 384D
4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1--
yl}-2-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzoic acid
[3012] The title compound was prepared by substituting EXAMPLE 384C
for EXAMPLE 1E in EXAMPLE 1F.
EXAMPLE 384E
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-2-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-N-({3-nitro-4-[(tetr-
ahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[3013] The title compound was prepared by substituting EXAMPLE 384D
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 12.07 (s, 1H), 8.60 (t, 1H),
8.58 (d, 1H), 8.07 (s, 1H), 7.88 (dd, 1H), 7.65 (t, 1H), 7.51 (d,
1H), 7.34 (d, 2H), 7.18 (d, 1H), 7.04 (d, 2H), 6.66 (dd, 1H), 6.50
(dd, 1H), 6.03 (d, 1H), 3.84 (dd, 2H), 3.26 (m, 4H), 3.13-2.96 (m,
4H), 2.73 (m, 2H), 2.16 (m, 6H), 1.95 (bs, 2H), 1,91 (m, 1H), 1.61
(d, 2H), 1.38 (t, 2H), 1.36-1.21 (m, 2H), 0.92 (s, 6H).
EXAMPLE 385
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide
EXAMPLE 385A
methyl
2-(6-(tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino)pyridin-3-ylox-
y)-4-fluorobenzoate
[3014] The title compound was prepared by substituting
1,1,1-trifluoro-2-iodoethane for methyliodide in EXAMPLE 377C
EXAMPLE 385B
methyl
2-(6-(tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino)pyridin-3-ylox-
y)-4-(piperazin-1-yl)benzoate
[3015] The title compound was prepared by substituting EXAMPLE 385A
for EXAMPLE 377E in EXAMPLE 377F.
EXAMPLE 385C
methyl
2-(6-(tert-butoxycarbonyl(2,2,2-trifluoroethyL)amino)pyridin-3-ylox-
y)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin--
1-yl)benzoate
[3016] The title compound was prepared by substituting EXAMPLE 385B
for tert-butyl piperazine-1-carboxylate and EXAMPLE 60D for
4'-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
EXAMPLE 385D
2-(6-tert-butoxycarbonyl(2,2,2-trifluoroethyl)amino)pyridin-3-yloxy)-4-(4--
((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)ben-
zoic acid
[3017] The title compound was prepared by substituting EXAMPLE 385C
for EXAMPLE 38G in EXAMPLE 38H.
EXAMPLE 385E
tert-butyl
5-(5-(4-((2-(4-chlorophenyl-4,4-dimethylcyclohex-1-enyl)methyl)-
piperazin-1-yl)-2-(3-nitro-4-((tetrahydro-2H-pyranyl)methylamino)phenylsul-
fonylcarbamoyl)-phenoxy)pyridin-2-yl(2,2,2-trifluoroethyl)carbamate
[3018] The title compound was prepared by substituting EXAMPLE 385D
for EXAMPLE 110E in EXAMPLE 110F.
EXAMPLE 385F
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-({6-[(2,2,2-trifluoro)amino]pyridin-3-yl}oxy)benzamide
[3019] EXAMPLE 385E (20 mg) was dissolved in anhydrous
dichloromethane and trifluoroacetic acid (0.1 mL) was added. The
reaction mixture was stirred at room temperature for 1.5 hours. The
solvent was removed under vacuum. The residue was dissolved in
ethyl acetate, washed with NaHCO.sub.3 aqeuous solution and brine,
dried over an hydrous sodium sulfate, filtered, and concentrated to
provide the title compound. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.56 (m, 2H), 7.86 (dd, 1H),
7.79 (d, 1H), 7.69 (m, 1H), 7.47 (d, 1H), 7.35 (d, 2H), 7.21 (m,
2H), 7.08 (m, 3H), 6.63 (m, 2H), 6.13 (d, 1H), 4.13 (m, 2H), 3.85
(dd, 2H), 3.27 (m, 4H), 3.06 (s, 4H), 2.74 (s, 2H), 2.18 (m, 6H),
1.97 (m, 3H), 1.61 (m, 2H), 1.40 (t, 2H), 1.27 (m, 2H), 0.94 (s,
6H).
EXAMPLE 386
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)m-
ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 386A
trans-4-(aminomethyl)cyclohexanol
[3020] Tert-butyl trans-(4-hydroxycyclohexl)methylcarbamate (1 g)
in dichloromethane (10 ml) was treated with trifluoroacetic acid
(10 ml) at 0.degree. C. for two hours. The reaction mixture was
concentrated and the residue was dried under vacuum to provide the
title compound.
EXAMPLE 386B
4-(trans-(4-hydroxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[3021] The title compound was prepared by substituting EXAMPLE 386A
for 1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 386C
2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethyl-
cyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((4-hydroxycyclohexyl)methylam-
ino)-3-nitrophenylsulfonyl)benzamide
[3022] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 318E and
EXAMPLE 386B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.61 (t, 1H), 8.58 (d, 1H), 7.86 (dd, 1H), 7.75 (d, 1H),
7.44 (d, 1H), 7.40 (d, 1H), 7.36 (d, 2H), 7.18 (d, 1H), 7.06 (d,
2H), 6.65 (dd, 1H), 6.18 (s, 3H), 4.52 (d, 1H), 3.24-3.30 (m, 4H),
3.12 (s, 4H), 2.79 (s, 2H), 2.25 (s, 4H), 2.17 (s, 2H), 1.97 (s,
2H), 1.79-1.89 (m, 2H), 1.75 (d, 2H), 1.50-1.64 (m, 1H), 1.40 (t,
2H), 0.97-1.17 (m, 4H), 0.94 (s, 6H).
EXAMPLE 387
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimeth-
yl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 387A
methyl
2-(6-amino-5-chloropyridin-3-yloxy)-4-(piperazin-1-yl)benozate
[3023] A solution of EXAMPLE 318C (8.90 g) and piperazine (10.34 g)
in dimethylsulfoxide (100 mL) was heated to 85.degree. C. After
stirring for 3 hours, the reaction mixture was cooled, diluted with
ethyl acetate (400 mL), washed with water (2.times.250 mL) and
brine (250 mL), dried over magnesium sulfate, filtered, and
concentrated to provide the title compound.
EXAMPLE 387B
methyl
2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-d-
imethyl-5,6-dihydio-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate
[3024] To a solution of EXAMPLE 387A (0.344 g) and EXAMPLE 38E
(0.238 g) in dichloromethane (5 mL) was added sodium
triacetoxyhydroborate (0.302 g) and the reaction stirred at room
temperature overnight. The reaction was quenched with saturated
aqueous NaHCO.sub.3 (10 mL) and extracted with dichloromethane (50
mL). The organic layers were combined, dried over magnesium
sulfate, filtered, and concentrated. Silica gel chromatography
(Reveleris 40 g) eluting with a gradient of 10-75% ethyl acetate
hexanes over 30 minutes (flow=40 ml/min) provided the title
compound.
EXAMPLE 387C
2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-
-5,6-dihydro-2H-pyran-3yl)methyl)piperazin-1-yl)benzoic acid
[3025] To a solution of EXAMPLE 387B (0.300 g) in tetrahydrofuran
(5 mL) and methanol (1 mL) was added 1.0 M lithium hydroxide (1.506
mL) and the suspension was heated to 55.degree. C. After 3 hours,
the reaction was cooled, diluted with dichloromethane (20 mL) and
water (10 mL), and quenched with 1 N aqueous HCl (1.5 mL). The
organic layer was separated and the aqueous layer was extracted
with 20 ml of dichloromethane. The combined organic extracts were
washed with brine(25 mL), dried over magnesium sulfate, filtered,
and concentrated to give the title compound.
EXAMPLE 387D
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[4-(4-chlorophenyl)-6,6-dimeth-
yl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrah-
ydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[3026] The title compound was prepared by substituting EXAMPLE 387B
for EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 11.40 (s, 1H), 8.64 (t, 1H),
8.59 (d, 1H), 7.87 (dd, 1H), 7.75 (d, 1H), 7.47-7.35 (m, 4H), 7.23
(d, 1H), 7.19-7.11 (m, 2H), 6.65 (dd, 1H), 6.18 (s, 3H), 4.14 (s,
2H), 3.85 (dd, 2H), 3.44-3.21 (m, 4H), 3.11 (s, 4H), 2.87 (s, 2H),
2.24 (s, 4H), 2.16 (s, 2H), 1.91 (s, 1H), 1.63 (d, 2H), 1.38-1.15
(m, 8H).
EXAMPLE 388
N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sul-
fonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]me-
thyl}piperazin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[3027] The title compound was prepared by substituting EXAMPLE 277B
for EXAMPLE 1F and EXAMPLE 326A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.22 (s,
1H), 8.60 (d, 1H), 8.30 (d, 1H), 7.55 (d, 1H), 7.38 (m, 4H), 7.29
(br d, 1H), 7.13 (d, 2H), 6.64 (d, 1H), 6.41 (s, 1H), 6.09 (s, 1H),
4.53 (d, 2H), 4.10 (s, 2H), 3.78 (m, 2H), 3.60 (m, 2H), 3.07 (v br
s, 4H), 2.86 (br s, 2H), 2.25 (v br s, 4H), 2.15 (s, 2H), 1.85 (m,
4H), 1.18 (s, 6H).
EXAMPLE 389
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofura-
n-3-ylmethyl)amino]phenyl}sulfonyl)benzamide
[3028] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 1F and EXAMPLE 332A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.52-11.11 (m, 1H), 8.65 (s, 1H), 8.58 (d, 1H), 7.87 (d, 1H), 7.74
(d, 1H), 7.47-7.32 (m, 4H), 7.22 (d, 1H), 7.06 (d, 2H), 6.65 (d,
1H), 6.17 (s, 3H), 3.86-3.38 (m, 6H), 3.12 (s, 4H), 2.79 (s, 2H),
2.61 (s, 1H), 2.21 (d, 6H), 1.97 (s, 3H), 1.65 (d, 1H), 1.40 (s,
2H), 0.94 (s, 6H).
EXAMPLE 390
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4-fluorotetrahydro--
2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-
-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)benzamide
[3029] The title compound was prepared by substituting EXAMPLE 387C
for EXAMPLE 1F and EXAMPLE 326A for EXAMPLE 1G in EXAMPLE 1H.
.sup.1H NMR (300 MHz, dimethylsulfoxide-d.sub.6) .delta.
11.94-11.04 (m, 1H), 8.58 (d, 1H), 8.26 (d, 1H), 7.75 (d, 1H), 7.48
(d, 1H), 7.40 (d, 3H), 7.16 (d, 2H), 6.66 (d, 1H), 6.18 (d, 3H),
4.56 (d, 2H), 4.15 (s, 2H), 3.77 (dd, 2H), 3.67-3.51 (m, 2H), 3.14
(s, 4H), 2.95 (s, 2H), 2.33 (s, 4H), 2.17 (s, 2H), 1.87 (td, 4H),
1.20 (s, 6H).
EXAMPLE 391
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluor-
o-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)piperazin-1-
-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-
benzamide
EXAMPLE 391A
benzyl 4-(piperidin-1-ylmethylene)piperidine-1-carboxylate
[3030] To a solution of benzyl 4-formylpiperidine-1-carboxylate
(22.35 g) in toluene (300 mL) was added piperidine (11.55 g). The
mixture was stirred at reflux under a Dean-Stark trap overnight.
The mixture was then concentrated under vacuum and the residue was
used directly in the next step.
EXAMPLE 391B
benzyl 9-oxa-3-azaspiro[5.5]undec-7-enc-3-carboxylate
[3031] To a solution of crude EXAMPLE 391A (35.5 g) in ethanol (300
mL) was added but-3-enone (8.71 g). The mixture was stirred at
reflux overnight . Acetic acid (30 mL) was added to the mixture
which was stirred at reflux again overnight. The mixture was then
concentrated under vacuum and the residue was diluted with ethyl
acetate (600 mL) and washed with water, brine and dried over
Na.sub.2SO.sub.4. After filtration and evaporation of the solvent,
silica gel chromatography using 5-20% ethyl acetate in hexanes
provided the title compound.
EXAMPLE 391C
benzyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate
[3032] EXAMPLE 391B (21 g) and tetrahydrofuran (160 mL) were added
to wet 5% Pt-C (3.15 g) in a 250 mL SS pressure bottle and the
mixture was stirred for 24 hours at 30 psi H.sub.2. The mixture was
filtered through a nylon membrane and concentrated to afford the
product.
EXAMPLE 391D
benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate
[3033] To a solution of EXAMPLE 391C (23.66 g) in dichloromethane
(350 mL) was added Dess-Martin Periodinane (33.1 g). The mixture
was stirred overnight. The mixture was diluted with ethyl acetate
(600 mL) and washed with 2 N aqueous NaOH, water, and brine. After
drying over Na.sub.2SO.sub.4, the mixture was filtered and
concentrated to proivde the title compound.
EXAMPLE 391E
benzyl
9-chloro-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylate
[3034] Phosphorus oxychloride (5.68 mL) was added dropwise to a
cooled (0.degree. C.) solution of EXAMPLE 391D (18.37 g) in
N,N-dimethylformaraide (20 mL) and dichloromethane (80 mL). The
mixture was then stirred overnight before it was diluted with ethyl
acetate (600 mL) and washed with aqueous sodium acetate, water
(3.times.), and brine and dried over Na.sub.2SO.sub.4. After
filtration and concentration, the crude product was used directly
in the next reaction without further purification.
EXAMPLE 391F
benzyl
9-(4-chlorophenyl)-8-formyl-3-azaspiro[5.5]undec-8-ene-3-carboxylat-
e
[3035] To a mixture of 4-chlorophenylboronic acid (11.34 g, 72.5
mmol), EXAMPLE 391E (21.01 g), palladium(II) acetate(271 mg),
K.sub.2CO.sub.3 (25.05 g) and tetrabutylammonium bromide (19.5 g)
was added water (120 mL). The mixture was stirred at 50.degree. C.
overnight. The mixture was diluted with ethyl acetate (400 mL) and
washed with water (3.times.) and brine and dried over
Na.sub.2SO.sub.4. After filtration and concentration, the residue
was loaded on a column and eluted with 5-20% ethyl acetate in
hexane to provide the title compound.
EXAMPLE 391G
benzyl
8-((4-(3-(6-amino-5-Chloropyridin-3-yloxy)-4-(methoxycarbonyl)pheny-
l)piperazin-1-yl)methyl)-9-(4-chlorophenyl-3-azaspiro[5.5]undec-8-ene-3-ca-
rboxylate
[3036] To a solution of EXAMPLE 387A (498 mg) in dichloromethane
(10 mL) was added EXAMPLE 391F (582 mg) and sodium
triacetoxyborohydride (436 mg). The mixture was stirred overnight.
The reaction mixture was diluted with ethyl acetate (300 mL) and
washed with 2 N aqueous NaOH and brine, and dried over
Na.sub.2SO.sub.4. Filtration, evaporation of the solvent, and flash
chromatography (2% methanol in dichloromethane) provided the title
compound.
EXAMPLE 391H
methyl
2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((9-(4-chlorophenyl)-3-aza-
spiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoate
[3037] To a solution of EXAMPLE 391G (1.02 g) in ethanol (20 mL)
was added Pd/C (10% , 150 mg). The mixture was stirred for 5 hours.
The mixture was filtered and the filtrate was concentrated to
provide the title compound.
EXAMPLE 391I
2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((9-(4-chlorophenyl)-3-(1,3-diflu-
oropropan-2-yl)-3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzo-
ic acid
[3038] To a solution of EXAMPLE 391H (318 mg) in dichloromethane (4
mL) was added 1,3-difluoropropan-2-one (282 mg) and sodium
acetoxyborohydride (318 mg). The mixture was stirred overnight. The
reaction mixture was diluted with ethyl acetate (300 mL) and washed
with 2 N aqueous NaOH and brine, and dried over Na.sub.2SO.sub.4.
Filtration and concentration gave the crude product which was
dissolved in tetrahydrofuran (10 mL), methanol (5 mL) and water (5
mL). LiOH.H.sub.2O (450 mg) was added and the mixture was stirred
overnight. The mixture was neutralized with 2N aqueous HCl and
extracted with ethyl acetate (300 mL) and dichloromethane (300 mL)
respectively. The organic extracts were combinedand dried over
Na.sub.2SO.sub.4. Filtration and concentration provided the title
compound.
EXAMPLE 391J
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({9-(4-chlorophenyl)-3-[2-fluor-
o-1-(fluoromethyl)ethyl]-3-azaspiro[5.5]undec-8-en-8-yl}methyl)piperazin-1-
-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-
benzamide
[3039] The title compound was prepared as described in EXAMPLE 1H,
replacing EXAMPLE 1F with EXAMPLE 391I. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.62 (t, 1H), 8.57 (d, 1H), 7.86
(dd, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 7.36 (m, 4H), 7.21 (d, 1H),
7.08 (m, 3H), 6.65 (dd, 1H), 6.17 (m, 3H), 4.69 (d, 2H), 4.53 (d,
2H), 3.85 (dd, 2H), 3.10 (m, 6H), 2.71 (m, 9H), 2.25 (m, 8H), 2.06
(m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.48 (m, 4H), 1.25 (m,
2H).
EXAMPLE 392
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isopropy-
l-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(te-
trahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 392A
2-(6-amino-5-chloropyridin-3-yloxy)-4-(4-((9-(4-chlorophenyl)-3-isopropyl--
3-azaspiro[5.5]undec-8-en-8-yl)methyl)piperazin-1-yl)benzoic
acid
[3040] The title compound was prepared as in EXAMPLE 391I by
replacing difluoropropan-2-one with acetone.
EXAMPLE 392B
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[9-(4-chlorophenyl)-3-isopropy-
l-3-azaspiro[5.5]undec-8-en-8-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(te-
trahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[3041] The title compound was prepared as in EXAMPLE 1H by
replacing EXAMPLE 1F with EXAMPLE 392A. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.40 (m, 2H), 7.71 (dd, 1H),
7.60 (d, 1H), 7.54 (d, 1H), 7.38 (d, 3H), 7.11 (d, 4H), 7.00 (d,
1H), 6.62 (dd, 1H), 6.28 (d, 1H), 5.88 (s, 2H), 3.84 (dd, 3H), 3.04
(m, 7H), 2.73 (m, 4H), 2.23 (m, 9H), 1.90 (m, 2H), 1.63 (m, 10H),
1.27 (m, 6H)
EXAMPLE 393
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylglyc-
yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
EXAMPLE 393A
tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate
[3042] 1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate
(1.0 g) in tetrahydrofuran (10 mL) at 0.degree. C. was treated with
a 1N solution of LiAlH.sub.4 (2.54 mL), stirred 2 hours at room
temperature, treated sequentially dropwise with water (0.2 mL) and
a 2 N aqueous solution of NaOH (0.6 mL) and stirred for 1 hour. The
solid was removed by filtration through a pad of diatomaceous
earth, rinsing with ethyl acetate. The filtrate was washed with
water and brine, dried (MgSO.sub.4), filtered and concentrated to
proivde the title compound.
EXAMPLE 393B
tert-butyl
4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperid-
ine-1-carboxylate
[3043] The title compound was prepared by substituting EXAMPLE 393A
for (tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 303A for
4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 264A.
EXAMPLE 393C
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide,
2-trifluoroacetic acid salt
[3044] The title compound was prepared by substituting EXAMPLE 393B
for EXAMPLE 1A in EXAMPLE 1B.
EXAMPLE 393D
5-chloro-6-((1-(2-(dimethylamino)acetyl)-4-fluoropiperidin-4-yl)methoxy)py-
ridine-3-sulfonamide
[3045]
5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide,
2-trifluoroacetic acid (0.131 g), 2-(dimethylamino)acetyl chloride,
hydrochloric acid (0.139 g), and sodium carbonate (0.048 g) were
combined in a 5-mL vial with N,N-dimethylformamide (3 mL) and
stirred overnight at room temperature. Additional sodium carbonate
(0.048 g) was added followed by 2-(dimethylamino)acetyl chloride,
hydrochloric acid (0.139 g) and stirring was continued over a
second night. The reaction mixture was concentrated under high
vacuum, slurried in CH.sub.2CL.sub.2, filtered, concentrated,
chromatographed on amine functionalized silica gel with 0 to 4%
methanol in CH.sub.2CL.sub.2 as the eluent and dried in a vacuum
oven at 80.degree. C.
EXAMPLE 393E
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(N,N-dimethylglyc-
yl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlo-
rophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
[3046] The title compound was prepared by substituting EXAMPLE 318E
for EXAMPLE 110E and EXAMPLE 393D for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (500 MHz, PYRIDINE-d.sub.5) .delta. 9.14 (d, 1H), 8.75
(d, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.45 (m, 2H), 7.40 (d, 1H),
7.09 (m, 2H), 6.73 (dd, 1H), 6.53 (d, 1H), 4.66 (d, 1H), 4.57 (d,
1H), 4.53 (d, 1H), 4.08 (d, 1H), 3.40 (m, 2H), 3.27 (m, 1H), 3.11
(m, 5H), 2.80 (s, 2H), 2.33 (s, 6H), 2.29 (t, 2H), 2.19 (m, 4H),
2.06 (m, 2H), 1.99 (s, 2H), 1.84 (m, 2H), 1.41 (t, 2H), 0.95 (s,
6H).
EXAMPLE 394
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fl-
uoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide
[3047] This example was prepared by substituting EXAMPLE 318E for
EXAMPLE 1E and EXAMPLE 357B for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.58 (d, 1H), 8.41
(d, 1H), 7.89 (d, 1H), 7.73 (d, 1H), 7.44 (d, 1H), 7.37 (m, 3H),
7.19 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.18 (m, 3H), 4.67 (d,
2H), 4.58 (d, 2H), 4.30 (m, 1H), 3.11 (m, 5H), 2.95 (m, 2H), 2.78
(m, 4H), 2.23 (m, 7H), 1.97 (m, 2H), 1.72 (m, 1H), 1.40 (t, 2H),
0.94 (s, 6H).
EXAMPLE 395
2-[(2-amino-5-bromopyridin-4-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethy-
lcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-p-
yran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[3048] This example was prepared by substituting EXAMPLE 383F for
EXAMPLE 372F in EXAMPLE 379. .sup.1H NMR (300 MHz,
dimethylsulfoxide-d.sub.6) .delta. 8.61 (t, 1H), 8.49 (d, 1H), 7.81
(s, 1H), 7.74 (dd, 1H), 7.54 (d, 1H), 7.37 (d, 2H), 7.12 (d, 1H),
7.08 (d, 2H), 6.82 (dd, 1H), 5.65 (bs, 1H), 5.93 (bs, 2H), 5.49 (s,
1H), 3.87 (dd, 2H), 3.31-3.19 (m, 8H), 2.84 (m, 2H), 2.40-2.15 (m,
6H), 1.99 (bs, 2H), 1.94 (m, 1H), 1.64 (d, 2H), 1.42 (t, 2H),
1.35-1.21 (m, 2H), 0.95 (s, 6H).
EXAMPLE 396
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexy-
l)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 396A
tert-butyl(4,4-difluorocyclohexyl)methylcarbamate
[3049] Tert-butyl (4-oxocyclohexyl)methylcarbamate (5 g) and
diethylaminosulphurtrifluoride (7.45 g) were stirred in
dichloromethane (100 mL) for 24 hours. The mixture was quenched
with pH 7 buffer (100 mL), and poured into ether (400 mL). The
resulting solution was separated, and the organic layer was washed
twice with water and brine, and concentrated to give the crude
product and fluoroolefin 3:2 ratio. The crude product was taken up
in tetrahydrofuran (70 mL) and water (30 mL), and
N-methylmorpholine-N-oxide (1.75 g) and OsO.sub.4 (2.5 wt %
solution in t-butanol) were added, and the mixture was stirred for
24 hours. Na.sub.2S.sub.2O.sub.3 (10 g) was then added, and the
mixture was stirred for 30 minutes. The mixture was then diluted
with ether (300 mL), and the resulting solution was separated, and
rinsed twice with water and brine, and concentrated. The crude
product was chromatographed on silica gel using 5-10% ethyl acetate
in hexanes to give the title compound.
EXAMPLE 396B
(4,4-difluorocyclohexyl)methanamine
[3050] A solution of EXAMPLE 396A (3 g) in dichloromethane (35 mL),
trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred
for 2 hours. The solution was concentrated, then condensed from
toluene, and left under high vacuum for 24 hours. The semi-solid
was taken up in ether/hexane and filtered to give the title
compound as its TFA salt.
EXAMPLE 396C
4-((4,4-difluorocyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[3051] This example was prepared by substituting EXAMPLE 396B for
1-isopropylpiperidin-4-amine in EXAMPLE 41A.
EXAMPLE 396D
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexy-
l)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[3052] This example was prepared by substituting EXAMPLE 318E for
EXAMPLE 1F and EXAMPLE 396C for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.67 (t, 1H), 8.58
(d, 1H), 7.86 (dd, 1H), 7.75 (d, 1H), 7.45 (d, 1H), 7.40 (d, 1H),
7.35 (d, 2H), 7.22 (d, 1H), 7.06 (d, 2H), 6.65 (dd, 1H), 6.17 (m,
3H), 3.35 (m, 2H), 3.12 (v br m, 4H), 2.80 (br s, 2H), 2.25 (v br
m, 4H), 2.17 (br t, 2H), 2.01 (br m, 2H), 1.98 (s, 2H), 1,80 (br m,
5H), 1.40 (t, 2H), 1.28 (br m, 2H), 0.93 (s, 6H).
EXAMPLE 397
[3-chloro-5-(5-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]meth-
yl}piperazin-1-yl)-2-{[({3-nitro-4-[(tetrahydro-2H-pyran-4-
ylmethyl)amino]phenyl}sulfonyl)amino]carbonyl}phenoxy)-2-iminopyridin-1(2-
H)-yl]methyl dihydrogen phosphate
[3053] A mixture of EXAMPLE 318F (93 mg),
di-tert-butylchloromethylphosphate (82 mg) and
N,N-diisopropylethylamine (0.12 mL) in 3 mL of acetonitrile was
heated at 90.degree. C. in a Bitage microwave synthesizer 3 hours,
cooled and concentrated. The residue was dissolved in
dichloromethane (3 mL) and trifluoroacetic acid (2 mL) was added.
The resulting solution was stirred at room temperature and
concentrated. The residue was dissolved in a mixture of
dimethylsulfoxide and methanol, purified by HPLC, eluting with
40-55% acetonitrile in 0.1% trifluoroacetic acid in water over 40
minutes. The title compound was obtained as a TFA salt. .sup.1H NMR
(500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.67 (t, 1H), 8.59 (d,
1H), 8.21 (d, 1H), 8.12 (d, 1H), 7.89 (dd, 1H), 7.50 (d, 1H), 7.41
(d, 2H), 7.28 (d, 1H), 7.11 (d, 2H), 6.74 (dd, 1H), 6.39 (d, 1H),
5.77 (d, 2H), 3.86 (dd, 4H), 3.32-3.42 (m, 4H), 3.27 (dd, 4H), 2.99
(s, 4H), 2.23 (s, 2H), 2.04 (s, 2H), 1.91 (dd, 1H), 1.63 (d, 2H),
1.47 (t, 2H), 1.20-1.33 (m, 2H), 0.96 (s, 6H).
EXAMPLE 398
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4'-chloro-3-[2-(dimethylamino-
)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahy-
dro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
EXAMPLE 398A
4'-chloro-3-hydroxybiphenyl-2-carbaldehyde
[3054] 2-Bromo-6-hydroxybenzaldehyde (2.0 g), 4-chlorophenylboronic
acid (1.86 g) and tetrakis(triphenylphosphine)palladium(0) (0.575
g) were suspended in a mixed solvent of dimethoxyethane (7 mL),
ethanol (2 mL) and 2 N Na.sub.2CO.sub.3 aqueous soltuion (5 mL).
The reaction mixture was heated at 90.degree. C. for 2 hours. The
reaction mixture was diluted with ethyl acetate and poured into
water. The organic layer was washed with water and with brine,
dried over anhydrous sodium sulfate, filtered, and concentrated.
The resulting solid was triturated with methanol anjd filtered to
afford the title compound.
EXAMPLE 398D
4'-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-carbaldehyde
[3055] EXAMPLE 398A (250 mg) and 2-chloro-N,N-dimethylethanamine
hydrochloride salt (310 mg) was dissolved in mixed solvent of
dichloromethane (5 mL) and 50% sodium hydroxide aqueous soltuion
(0.5 mL), followed by addition of tetrabutylammonium iodide (79
mg). The reaction mixture was stirred at room temperature
overnight. The reaction mixture was diluted with ethyl acetate and
washed with water and brine. The organic phase was dried over
anhydrous sodium sulfate, filtered, and concentrated. Flash column
purification was performed 0-5% methanol/dichloromethane to afford
the title compound.
EXAMPLE 398C
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-[4-({4'-chloro-3-[2-(dimethylamino-
)ethoxy]-1,1'-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahy-
dro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[3056] This example was prepared by substituting EXAMPLE 398B for
EXAMPLE 1F in EXAMPLE 1H. .sup.1H NMR (300 MHz, DMSO) .delta.
11.67-11.61 (m, 1H), 9.91-9.71 (m, 1H), 9.13-8.93 (m, 1H),
8.68-8.65 (m, 1H), 8.59 (d, 1H), 7.85 (s, 1H), 7.75 (d, 1H), 7.54
(d, 3H), 7.47 (d, 1H), 7.41 (d, 1H), 7.38 (s, 2H), 7.24 (d, 2H),
6.98 (s, 1H), 6.71-6.64 (m, 1H), 6.21 (s, 2H), 4.45 (s, 8H), 3.83
(s, 3H), 3.60 (s, 3H), 3.31 (d, 6H), 2.92 (s, 4H), 1,99-1.82 (m,
1H), 1.60 (s, 2H), 1.36-1.18 (m, 2H).
EXAMPLE 399
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1--
(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[-
2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)be-
nzamide
EXAMPLE 399A
(R)-5-chloro-6-((1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)methoxy)pyridi-
ne-3-sulfonamide
[3057] EXAMPLE 400B (278 mg) and 1,3-difluoropropan-2-one (94 mg)
were suspended in 1,2-dichloroethane (10 mL). N,N-Dimethylformamide
(1.5 mL) was added drop wise until a milky suspension formed. The
reaction mixture was stirred at room temperature for 15 minutes
followed by the addition of sodium triacetoxyborohydride (424 mg).
The reaction mixture was stirred at room temperature overnight. The
solvent was removed under vacuum. Flash column purificationwith
2.5-5% methanol/dichloromethane provided the title compound.
EXAMPLE 399B
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-{[5-chloro-6-({(3R)-1-[2-fluoro-1--
(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[-
2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)be-
nzamide
[3058] This example was prepared by substituting EXAMPLE 318E for
EXAMPLE 110E and EXAMPLE 399A for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.37 (d,
1H), 8.06 (d, 1H), 7.62 (d, 1H), 7.54 (d, 1H), 7.36 (m, 2H), 7.17
(d, 1H), 7.07 (m, 2H), 6.63 (dd, 1H), 6.27 (d, 1H), 5.92 (bs, 2H),
4.65 (m, 2H), 4.53 (m, 2H), 4.28 (m, 2H), 3.07 (s, 4H), 2.90 (m,
2H), 2.76 (m, 4H), 2.58 (m, 2H), 2.20 (m, 6H), 1.99 (m, 3H), 1.54
(m, 1H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 400
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluor-
oethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chloroph-
enyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
EXAMPLE 400A
(R)-tert-butyl
3-((3-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)pyrrolidine-1-carboxyl-
ate
[3059] This example was prepared by substituting (R)-tert-butyl
3-(hydroxymethyl)pyrrolidine-1-carboxylate for
(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 303B.
EXAMPLE 400B
(R)-5-chloro-6-(pyrrolidin-3-ylmethoxy)pyridine-3-sulfonamide
[3060] EXAMPLE 400A (480 mg) was dissolved in anhydrous
tetrahydrofuran (10 mL) followed by addition of hydrogen chloride
in dioxane solution (4 M, 2.5 mL). The reaction mixture was stirred
at room temperature overnight. The solvent was removed under vacuum
to provide the title compound.
EXAMPLE 400C
(R)-5-chloro-6-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methoxy)pyridine-3-s-
ulfonamide
[3061] A reaction mixture of EXAMPLE 400B (353 mg),
1,1-difluoro-2-iodoethane (268 mg) and Na.sub.2CO.sub.3 (283 mg) in
N,N-dimethylformamide (10 mL) was heated at 80.degree. C.
overnight. The reaction mixture was cooled to room temperature and
diluted with ethyl acetate. The organic phase was washed with water
and brine, dried over anhydrous sodium sulfate, filtered, and
concentrated. Flash column purification with 2.5-3%
methanol/dichloromethane provided the title compound.
EXAMPLE 400D
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[(3R)-1-(2,2-difluor-
oethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chloroph-
enyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
[3062] This example was prepared by substituting EXAMPLE 318E for
EXAMPLE 110E and EXAMPLE 400C for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.37 (d,
1H), 8.05 (d, 1H), 7.62 (d, 1H), 7.54 (d, 1H), 7.36 (m, 2H), 7.17
(d, 1H), 7.07 (d, 2H), 6.62 (dd, 1H), 6.27 (d, 1H), 6.07 (m, 3H),
4.27 (m, 2H), 3.07 (s, 4H), 2.83 (m, 5H), 2.64 (m, 3H), 2.20 (m,
6H), 1.99 (m, 4H), 1.54 (m, 1H), 1.41 (t, 2H), 0.94 (s, 6H).
EXAMPLE 401
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohex-
yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
EXAMPLE 401A
2-(trans-4-(aminomethyl)cyclohexyl)acetonitrile
[3063] To a solution of
tert-butyl(trans-4-(cyanomethyl)cyclohexyl)methylcarbamate (500 mg)
in dichloromethane (5 mL) was slowly added trifluoroacetic acid (3
mL) at 0.degree. C. The mixture was warmed to room temperature,
stirred for 1 hour and concentrated. The residue was dried under
vacuum to provide the title compound.
EXAMPLE 401B
4-((trans-4-cyanocyclohexyl)methylamino)-3-nitrobenzenesulfonamide
[3064] The title compound was prepared by substituting EXAMPLE 401A
for 1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1G.
EXAMPLE 401C
Trans-2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4--
dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohex-
yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide
[3065] The title compound was prepared as described in EXAMPLE 110F
by replacing EXAMPLE 110E and EXAMPLE 1G with EXAMPLE 318E and
EXAMPLE 401B. .sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6)
.delta. 8.63 (t, 1H), 8.58 (d, 1H), 7.85 (dd, 1H), 7.75 (d, 1H),
7.44 (d, 1H), 7.40 (d, 1H), 7.36 (d, 2H), 7.19 (d, 1H), 7.06 (d,
2H), 6.65 (dd, 1H), 6.19 (s, 3H), 3.24-3.31 (m, 4H), 3.12 (s, 4H),
2.79 (s, 2H), 2.58-2.69 (m, 1H), 2.25 (s, 4H), 2.17 (s, 2H),
1.92-2.07 (m, 4H), 1.79 (d, 2H), 1.60-1.73 (m, 1H), 1.34-1.55 (m,
4H), 0.97-1.12 (m, 2H), 0.94 (s, 6H).
EXAMPLE 402
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide-N-({5-fluoro-6-[(4-fl-
uorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide
EXAMPLE 402A
5-bromo-3-fluoro-2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine
[3066] This example was prepared by substituting EXAMPLE 296C for
(tetrahydro-2H-pyran-4-yl)methanol and 5-bromo-2,3-difluoropyridine
for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 264A.
EXAMPLE 402B
tert-butyl
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-
-ylcarbamate
[3067] EXAMPLE 402A (0.658 g), tert-butylcarbamate (0.300 g),
palladium(II) acetate (0.024 g),
4.5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.093 g) and
cesium carbonate (1.044 g) were combined in a 20 mL vial with
dioxane (10.7 ml). The vial was flushed with nitrogen, capped and
stirred at 100.degree. C. overnight. The reaction mixture was
diluted with ethyl acetate, washed with water and brine, dried
(MgSO.sub.4), filtered, concentrated and chromatographed on silica
gel with 20% ethyl acetate in hexanes as eluent.
EXAMPLE 402C
5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonyl
chloride
[3068] Under ice-cooling, thionyl chloride (1.563 mL) was added
dropwise over 20 minutes to water (9 mL). The mixture was stirred
for 12 hours to give a SO.sub.2-containing solution. Separately,
EXAMPLE 402B (0.295 g) was added to a mixture of dixane (3.2 mL)
and concentrated HCl (8 ml) at 0.degree. C. The solution was
stirred for 15 minutes, treated with a solution of sodium nitrite
(0.065 g) in water (2 mL) dropwise at 0.degree. C. and stirred at
0.degree. C. for 3 hours. The SO.sub.2-containing solution was
cooled to 0.degree. C., treated sequentially with copper(I)
chloride (0.042 g) and the diazotized mixture, and stirred for 30
minutes. The reaction mixture was then extracted with ethyl acetate
and the orgnaic layer was dried (MgSO.sub.4), filtered and
concentrated. The residue was chromatographed on silica gel with
5-10% ethyl acetate in hexanes as the eluent.
EXAMPLE 402D
5fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamid-
e
[3069] EXAMPLE 402C (0.08 g, ) in isopropanol (2 mL) at 0.degree.
C. was treated with ammonium hydroxide (1.70 mL) and stirred
overnight. The reaciton mixture was concentrated, slurried in
water, filtered, rinsed with water and dried under vacuum.
EXAMPLE 402E
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetra-
hydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl) benzamide
[3070] This example was prepared by substituting EXAMPLE 402D for
EXAMPLE 1G and EXAMPLE 318E for EXAMPLE 110E in EXAMPLE 110F.
.sup.1H NMR (400 MHz, pyridine-d.sub.5) .delta. 9.05 (d, 1H), 8.49
(dd, 1H), 8.03 (d, 1H), 8.00 (d, 1H), 7.45 (m, 2H), 7.39 (d, 1H),
7.09 (m, 2H), 6.73 (dd, 1H), 6.52 (d, 1H), 4.59 (d, 2H), 3.81 (m,
4H), 3.12 (m, 4H), 2.80 (s, 2H), 2.29 (t, 2H), 2.18 (m, 4H), 1.99
(s, 2H), 1.88 (m, 4H), 1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 403
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroethy-
l)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
EXAMPLE 403A
[3071] EXAMPLE 393C (0.263 g), 1,1-difluoro-2-iodoethane (0.23 g),
and sodium carbonate (0.254 g) were combined in a 20 mL vial with
N,N-dimethylformamide (6 mL) and the mixture stirred at 70.degree.
C. overnight. The reaction mixture was concentrated under high
vacuum, chromatographed on silica gel with 0-5% methanol in
dichloromethane as the eluent, and dried overnight in a vacuum oven
80.degree. C.
EXAMPLE 403B
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-[(5-chloro-6-{[1-(2,2-difluoroethy-
l)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlor-
ophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
[3072] This example was prepared by substituting EXAMPLE 403A for
EXAMPLE 1G and EXAMPLE 318E for EXAMPLE 110E in EXAMPLE 110F.
.sup.1H NMR (400 MHz, pyridine-d.sub.5) .delta. 9.15 (d, 1H), 8.75
(d, 1H), 8.02 (d, 1H), 8.00 (d, 1H), 7.45 (m, 2H), 7.38 (d, 1H),
7.09 (m, 2H), 6.72 (dd, 1H), 6.50 (d, 1H), 6.18 (tt, 1H), 4.55 (d,
2H), 3.12 (m, 4H), 2.80 (m, 6H), 2.60 (td, 2H), 2.28 (t, 2H), 2.17
(m, 4H), 1.93 (m, 6H), 1.41 (t, 2H), 0.95 (s, 6H).
EXAMPLE 404
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro--
2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
EXAMPLE 404A
3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide
[3073] To a solution of EXAMPLE 296C (0.175 g) in tetrahydrofuran
(5 ml) was added sodium hydride (0.209 g) and the reaction stirred
at room temperature for 15 minutes,
3-Chloro-4-fluorobenzenesulfonamide(0.273 g) was added and the
reaction stirred for 3 hours. to the thick suspension was added
tetrahydrofuran (2 ml) and N,N-dimethylformamide (3 ml). The
reaction was stirred for 3 hours at 60.degree. C. then poured into
dichloromethane (50 ml) and 1N aqueous HCl (50 ml). The organic
layer was washed with brine (35 ml) dried over magnesium sulfate,
filtered, and concentrated. Silica gel chromatography (Reveleris 40
g) eluting with a gradient of 10-100% ethyl acetate/hexanes over 30
minutes (flow=40 ml/minute) gave the title compound.
EXAMPLE 404B
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({3-chloro-4-[(4-fluorotetrahydro--
2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimet-
hylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
[3074] This example was prepared by substituting EXAMPLE 318E for
EXAMPLE 1F and EXAMPLE 404A for EXAMPLE 1G in EXAMPLE 1H. .sup.1H
NMR (300 MHz, DMSO) .delta. 11.44-11.17 (m, 1H), 7.91 (d, 1H), 7.83
(dd, 1H), 7.77 (d, 1H), 7.44 (d, 2H), 7.35 (dd, 3H), 7.06 (d, 2H),
6.66 (d, 1H), 6.19 (d, 3H), 4.31 (d, 2H), 3.84-3.73 (m, 2H),
3.66-3.55 (m, 2H), 3.13 (s, 4H), 2.81 (s, 2H), 2.26 (s, 4H), 2.17
(s, 2H), 2.02-1.74 (m, 6H), 1,41 (s, 2H), 0.94 (s, 6H).
EXAMPLE 405
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-
-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3--
yl]sulfonyl}benzamide
EXAMPLE 405A
5-nitro-3-(trifluoromethyl)pyridin-2-ol
[3075] 3-(Trifluoromethyl)pyridin-2-ol (2.3 g) was added to
concentrated sulfuric acid (15 mL) at 0.degree. C. The mixture was
stirred at 0.degree. C. for 5 minutes. To this solution was added
nitric acid (fuming, 6 mL) dropwise over 5 minutes. The reaction
mixture was stirred at room temperature for 2 hours, and then
heated at 50.degree. C. for 3 hours. After cooling, the reaction
mixture was poured into ice (200 g), and the mixture was extracted
with ethyl acetate three times. The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure to give the title compound.
EXAMPLE 405B
2-chloro-5-nitro-3-(trifluoromethyl)pyridine
[3076] A mixture of EXAMPLE 405A (1.69 g), phosphorus pentachloride
(2.03 g), and phosphoryl trichloride (0.97 mL) was heated at
90.degree. C. for 3 hours. After cooling, the reaction mixture was
poured into ice, and extracted with ethyl acetate three times. The
extract was washed with brine, dried over MgSQ.sub.4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel eluting with 1:9 ethyl
acetate\hexanes to give the title compound.
EXAMPLE 405C
[3077] A mixture of iron (1.5 g) and ammonium chloride (2.38 g) in
water (40 mL) was stirred at room temperature for 5 minutes. To
this suspension was added EXAMPLE 405B in methanol (40 mL). The
reaction mixture was stirred at room temperature for 1 hour. More
iron (1.8 g) was added to the reaction mixture, and it was stirred
for another 3 hours. The solid from the reaction mixture was
filtered off, and the filtrate was partitioned between water and
ethyl acetate. The combined organic layers were washed with brine,
dried over MgSO.sub.4, filtered, and concentrated under reduced
pressure. The residue was purified by flash column chromatography
on silica gel eluting with 1:4 ethyl acetate\hexanes to give the
title compound.
EXAMPLE 405D
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride
[3078] Under ice-cooling, thionyl chloride (4 mL) was added
dropwise over 20 minutes to water (27 mL). The mixture was stirred
overnight for 12 hours to give a SO.sub.2 containing solution.
Separately, EXAMPLE 405C (1.14 g) in dioxane (5 mL) was added to
concentrated HCl (20 mL) at 0.degree. C. The solution was stirred
for 5 minutes. To this suspension/solution was added sodium nitrite
(0.44 g) in water (6 mL) dropwise at 0.degree. C. The solution
stirred at 0.degree. C. for 3 hours. to the SO.sub.2 containing
solution was added copper(I) chloride (0.115 g). Then, to this
solution was added the diazotized EXAMPLE 405C at 0.degree. C. The
solution was stirred for 30 minutes. The reaction mixture was
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel eluting with 1:20 ethyl
acetate hexanes to give the title compound.
EXAMPLE 405E
6-chloro-5-(trifluoromethyl)pyridine-3-sulfonamide
[3079] This example was prepared by substituting EXAMPLE 405D for
5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 305A.
EXAMPLE 403F
tert-butyl
4-fluoro-4-((5-sulfamoyl-3-(trifluoromethyl)pyridin-2-yloxy)met-
hyl)piperidine-1-carboxylate
[3080] This example was prepared by substituting EXAMPLE 405E for
EXAMPLE 305A and EXAMPLE 341A for (1,4-dioxan-2-yl)methanol in
EXAMPLE 305B.
EXAMPLE 405G
6-((4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonam-
ide
[3081] This example was prepared by substituting EXAMPLE 405F for
EXAMPLE 400A in EXAMPLE 400B.
EXAMPLE 405H
6-((1-(1,3-difluoropropan-2-yl)-4-fluooropiperidin-4-yl)methoxy)-5-(triflu-
oromethyl)pyridine-3-sulfonamide
[3082] This example was prepared by substituting EXAMPLE 405G for
EXAMPLE 400B in EXAMPLE 399A.
EXAMPLE 405I
2-[(6-amino-5-chloropyridin-3-yl)oxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimeth-
ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-
-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3--
yl]sulfonyl}benzamide
[3083] This example was prepared by substituting EXAMPLE 318E for
EXAMPLE 110E and EXAMPLE 405 H for EXAMPLE 1G in EXAMPLE 110F.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.62 (d,
1H), 8.29 (d, 1H), 7.57 (m, 2H), 7.36 (d, 2H), 7.09 (m, 3H), 6.62
(dd, 1H), 6.29 (d, 1H), 5.86 (bs, 2H), 4.67 (d, 2H), 4.53 (m, 4H),
3.08 (m, 5H), 2.74 (m, 6H), 2.19(m, 6H), 1.89 (m, 6H), 1.41 (t,
2H), 0.94 (s, 6H).
EXAMPLE 406
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide
EXAMPLE 406A
2-(2-bromophenoxy)-4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)meth-
yl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phe-
nylsulfonyl)benzamide
[3084] The title compound was prepared as described is EXAMPLE 110F
by replacing EXAMPLE 110E with EXAMPLE 42C.
EXAMPLE 406B
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-[2-(1H-pyrazol-4-yl)phenoxy]benzamide
[3085] A mixture of EXAMPLE 406A (57 mg), tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
(27.7 mg), dichlorobis(triphenylphosphine)palladium(II) (6.61 mg),
K.sub.2CO.sub.3 (0.2 ml) in a dimethoxyethane/ethanol/water (7:2:3)
was heated at 160.degree. C. for 10 minutes in a Biotage microwave
synthesizer and concentrated. The residue was dissolved in
dimethylsulfoxide:methanol (1:1) and purified by HPLC, eluting with
40-65% acetonitrile in 0.1% TFA water over 40 minutes to provide
the title compound as a TFAsalt. The TFA salt was dissolved in
dichloromethane and washed with saturated NaHCO.sub.3 aqueous
solution. The organic layer was dried over Na.sub.2SO.sub.4,
filtered, and concentrated to proivde the title compound. .sup.1H
NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 12.87 (s, 1H),
11.55 (s, 1H), 8.58 (t, 1H), 8.47 (d, 1H), 8.11 (s, 1H), 7.85 (s,
1H), 7.76 (dd, 1H), 7.59-7.67 (m, 1H), 7.48 (d, 1H), 7.34 (d, 2H),
7.00-7.11 (m, 5H), 6.73 (dd, 1H), 6.67 (dd, 1H), 6.08 (d, 1H), 3.85
(dd, 2H), 3.20-3.29 (m, 4H), 3.04 (s, 4H), 2.77 (s, 2H), 2.17 (d,
6H), 1.96 (s, 2H), 1.80-1.92 (m, 1H), 1.55-1.70 (m, 2H), 1.39 (t,
2H), 1.19-1.32 (m, 2H), 0.93 (s, 6H).
EXAMPLE 407
2-[2-(2-aminopyridin-3-yl)phenoxy]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyr-
an-4-ylmethyl)amino]phenyl}sulfonyl)benzamide
[3086] The title compound was prepared as described in EXAMPLE 406B
by replacing tert-butyl
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate
with tert-butyl
3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-ylcarbamate.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.57 (t,
1H), 8.41 (d, 1H), 7.92 (dd, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 7.41
(d, 1H), 7.36 (d, 2H), 7.18 (dd, 1H), 7.02-7.13 (m, 5H), 6.97 (t,
1H), 6.70 (dd, 1H), 6.61-6.67 (m, 1H), 6.55 (d, 1H), 6.31 (d, 1H),
3.84 (dd, 2H), 3.21-3.30 (m, 4H), 3.15 (s, 4H), 2.83 (s, 2H),
2.23-2.34 (m, 4H), 2.17 (s, 2H), 1.84-2.02 (m, 3H), 1.63 (dd, 2H),
1.40 (t, 2H), 1.20-1.33 (m, 2H), 0.94 (s, 6H).
EXAMPLE 408
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin--
1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl-
)-2-[2-(1H-pyrazol-5-yl)phenoxy]benzamide
[3087] The title compound was prepared as described in EXAMPLE 406B
by replacing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2
-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate with
1H-pyrazol-5-ylboronic acid. .sup.1H NMR (400 MHz,
dimethylsulfoxide-d.sub.6) .delta. 12.95 (s, 1H), 8.60 (s, 1H),
8.52 (s, 1H), 7.85 (s, 2H), 7.57-7.73 (m, 1H), 7.48 (d, 1H),
7.22-7.37 (m, 4H), 7.00 -7.15 (m, 4H), 6.56-6.70 (m, 2H), 5.96 (s,
2H), 3.85 (dd, 2H), 3.21-3.28 (m, 4H), 3.02 (s, 4H), 2.70-2.85 (m,
2H), 2.10-2.30 (m, 5H), 1.83-1.99 (m, 3H), 1.62 (d, 2H), 1.39 (t,
2H), 1.19-1.31 (m, 2H), 0.92 (s, 6H),
EXAMPLE 409
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4-difluorocyclohe-
xyl)methoxy]pyridin-3-yl}suflonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
EXAMPLE 409A
(4,4-difluorocyclohexyl)methanol
[3088] Lithium aluminum hydride (0.24 g) was added to diethylether
(15 mL), to which was then added dropwise ethyl
4,4-difluorocyclohexanecarboxylate (1.0 g) in diethyl ether (2 mL),
and the reaction was stirred at reflux under nitrogen for 4 hours.
The reaction was cooled to 0.degree. C., followed by the careful
addition of water (0.24 mL), 4N aqueous NaOH (0.24 mL), and
additional water (0.72 mL). Then Na.sub.2SO.sub.4 (40 mL) were
added and the mixture was stirred for 30 minutes. After filtration
through diatomaceous earth and concentration, the title compound
was used in the next step without further purification.
EXAMPLE 409B
5-chloro-6-((4,4-difluorocyclohexyl)methoxy)pyridine-3-sulfonamide
[3089] This example was prepared by substituting EXAMPLE 409A for
(1,4-dioxan-2-yl)methanol and EXAMPLE 303A for EXAMPLE 305A in
EXAMPLE 305B.
EXAMPLE 409C
2-[(6-amino-5-chloropyridin-3-yl)oxy]-N-({5-chloro-6-[(4,4-difluorocyclohe-
xyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylc-
yclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide
[3090] This example was prepared by substituting EXAMPLE 318E for
EXAMPLE 122C and EXAMPLE 409B for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 8.54 (s,
1H), 8.20 (2, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.37 (m, 3H), 7.07
(d, 2H), 6.66 (dd, 1H), 6.22 (s, 1H), 6.13 (br s, 2H), 4.30 (d,
2H), 3.17 (v br m, 4H), 2.98 (v br s, 2H), 2.43 (v br m, 4H), 2.18
(br t, 2H), 2.05 (br m, 3H), 1.98 (s, 2H), 1.8 (br m, 4H), 1.43 (t,
2H), 1.35 (br m, 2H), 0.94 (s, 6H).
EXAMPLE 410
N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(-
4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piper-
azin-1-yl)-2-[(6-fluoro-1H-indol-5-yl)oxy]benzamide
[3091] This example was prepared by substituting EXAMPLE 277B for
EXAMPLE 122C and EXAMPLE 409B for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.22 (s,
1H), 8.60 (d, 1H), 8.26 (d, 1H), 7.54 (d, 1H), 7.38 (m, 4H), 7.29
(br d, 1H), 7.13 (d, 2H), 6.64 (d, 1H), 6.41 (s, 1H), 6.09 (s, 1H),
4.30 (d, 2H), 4.10 (s, 2H), 3.05 (v br s, 4H), 2.86 (v br s, 2H),
2.25 (v br s, 4H), 2.15 (s, 2H), 2.03 (br m, 2H), 1.96 (br m, 1H),
1.85 (br m, 4H), 1.36 (m, 2H), 1.18 (s, 6H).
EXAMPLE 411
4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-yl]methyl}piperazin-1--
yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]--
2-[(6-fluoro-1H-indol-5-yl)oxyl]benzamide
[3092] This example was prepared by substituting EXAMPLE 154E for
EXAMPLE 122C and EXAMPLE 396C for EXAMPLE 11A in EXAMPLE 137.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. 11.22 (s,
1H), 8.65 (t, 1H), 8.60 (d, 1H), 7.88 (dd, 1H), 7.52 (d, 1H), 7.39
(dd, 1H), 7.35 (m, 4H), 7.18 (d, 1H), 7.03 (d, 2H), 6.65 (dd, 1H),
6.21 (s, 1H), 6.08 (s, 1H), 3.04 (v br m, 4H), 2.76 (br s, 2H),
2.20 (v br m, 4H), 2.13 (br t, 2H), 2.00 (br m, 3H), 1.95 (s, 2H),
1.81 (br m, 6H), 1.39 (t, 2H), 1.24 (br m, 2H), 0.91 (s, 6H).
Sequence CWU 1
1
1116PRTArtificial SequenceF-Bak Probe PeptideMOD_RES1Gly is
modified with acetylMOD_RES13Lys is modified with 6-FAMMOD_RES16Arg
is modified with NH2 1Gly Gln Val Gly Arg Gln Leu Ala Ile Ile Gly
Asp Lys Ile Asn Arg1 5 10 15
* * * * *