U.S. patent application number 17/558227 was filed with the patent office on 2022-09-29 for compounds useful for treating gastrointestinal tract disorders.
This patent application is currently assigned to Ardelyx, Inc.. The applicant listed for this patent is Ardelyx, Inc.. Invention is credited to Irina DOTSENKO, Dean DRAGOLI, Jason LEWIS.
Application Number | 20220306610 17/558227 |
Document ID | / |
Family ID | 1000006366248 |
Filed Date | 2022-09-29 |
United States Patent
Application |
20220306610 |
Kind Code |
A1 |
DRAGOLI; Dean ; et
al. |
September 29, 2022 |
COMPOUNDS USEFUL FOR TREATING GASTROINTESTINAL TRACT DISORDERS
Abstract
The present disclosure is directed to compounds and methods for
the treatment of disorders associated with fluid retention or salt
overload, such as heart failure (in particular, congestive heart
failure), chronic kidney disease, end-stage renal disease, liver
disease, and peroxisome proliferator-activated receptor (PPAR)
gamma agonist-induced fluid retention. The present disclosure is
also directed to compounds and methods for the treatment of
hypertension. The present disclosure is also directed to compounds
and methods for the treatment of gastrointestinal tract disorders,
including the treatment or reduction of pain associated with
gastrointestinal tract disorders.
Inventors: |
DRAGOLI; Dean; (Fremont,
CA) ; DOTSENKO; Irina; (Fremont, CA) ; LEWIS;
Jason; (Fremont, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ardelyx, Inc. |
Fremont |
CA |
US |
|
|
Assignee: |
Ardelyx, Inc.
Fremont
CA
|
Family ID: |
1000006366248 |
Appl. No.: |
17/558227 |
Filed: |
December 21, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16476836 |
Jul 9, 2019 |
11242337 |
|
|
PCT/US2018/013020 |
Jan 9, 2018 |
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17558227 |
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62541097 |
Aug 4, 2017 |
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62444335 |
Jan 9, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 241/04 20130101;
A61P 1/10 20180101; A61P 3/12 20180101; A61P 9/04 20180101; C07D
401/14 20130101; C07D 487/08 20130101; C07D 401/12 20130101; C07D
403/12 20130101; A61K 47/55 20170801; C07D 403/14 20130101; A61P
1/00 20180101; A61P 9/12 20180101; A61P 29/00 20180101 |
International
Class: |
C07D 403/14 20060101
C07D403/14; A61K 47/55 20060101 A61K047/55; A61P 1/10 20060101
A61P001/10; A61P 9/12 20060101 A61P009/12; A61P 1/00 20060101
A61P001/00; A61P 9/04 20060101 A61P009/04; A61P 29/00 20060101
A61P029/00; A61P 3/12 20060101 A61P003/12; C07D 241/04 20060101
C07D241/04; C07D 401/12 20060101 C07D401/12; C07D 401/14 20060101
C07D401/14; C07D 403/12 20060101 C07D403/12; C07D 487/08 20060101
C07D487/08 |
Claims
1. A compound of formula I: ##STR00296## or a pharmaceutically
acceptable salt thereof, wherein: Linker is
--R.sup.13--(CHR.sup.13).sub.p--[Y--(CH.sub.2).sub.r].sub.s--Z--R.sup.13--
-(CH.sub.2).sub.t--Z--; X is a bond, H, N, O, CR.sup.11R.sup.12,
CR.sup.11, C, --NHC(O)NH--, --(CHR.sup.13).sub.p-- or
C.sub.3-C.sub.6cyclolakyl; W is independently, at each occurrence,
S(O).sub.2, C(O), or --(CH.sub.2).sub.m--; Z is independently, at
each occurrence, a bond, C(O), or --C(O)NH--; Y is independently,
at each occurrence, O, S, NH, N(C.sub.1-C.sub.3alkyl), or
--C(O)NH--; Q is a bond, NH, --C(O)NH--, --NHC(O)NH--,
--NHC(O)N(CH.sub.3)--, or --NHC(O)NH--(CHR.sup.13); m is an integer
from 1 to 2; n is an integer from 1 to 4; r and p are
independently, at each occurrence, integers from 0 to 8; s is an
integer from 0 to 4; t is an integer from 0 to 4; u is an integer
from 0 to 2; R.sup.1 and R.sup.2 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more halogen, OH, CN, --NO.sub.2, oxo,
--SR.sup.9, --OR.sup.9, --NHR.sup.9, --NR.sup.9R.sup.10,
--S(O).sub.2N(R.sup.9).sub.2--, --S(O).sub.2R.sup.9, --C(O)R.sup.9,
--C(O)OR.sup.9, --C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.8S(O)R.sup.9,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl; or R.sup.1 and R.sup.2 together with the nitrogen to
which they are attached can form a heterocyclyl or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, wherein the heterocyclyl or heteroaryl group is
optionally substituted with one or more halogen, OH, CN,
--NO.sub.2, oxo, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10; S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--C(O)NR.sup.9R.sup.10; NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.10,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl; R.sup.3 and R.sup.4 are independently halogen, OH, CN,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, or
--C(O)NR.sup.9R.sup.10; R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently H, halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10NR.sup.8S(O)R.sup.9; R.sup.9 and R.sup.10 are
independently H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O R.sup.11 and R.sup.12 are independently H,
C.sub.1-C.sub.6alkyl, OH, NH.sub.2, CN, or NO.sub.2; R.sup.13 is
independently, at each occurrence, a bond, H, C.sub.1-C.sub.6alkyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, or heteroaryl, wherein each cycloalkenyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more R.sup.19; R.sup.14 is independently,
at each occurrence, H, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6haloalkyl; or R.sup.6 and R.sup.14 together with the
atoms to which they are attached may combine to form,
independently, at each occurrence, 5- to-6 membered heterocyclyl,
wherein each C.sub.3-C.sub.8 cycloalkyl, or heterocyclyl is
optionally substituted with one or more R.sup.19; or R.sup.13 and
R.sup.14 together with the atoms to which they are attached may
combine to form independently, at each occurrence, C.sub.3-C.sub.8
cycloalkyl, heterocyclyl, aryl, or heteroaryl containing 1-5
heteroatoms selected from the group consisting of N, S, P and O,
wherein each heterocyclyl or heteroaryl is optionally substituted
with one or more R.sup.19; R.sup.15, R.sup.16, R.sup.17, and
R.sup.18 are independently, at each occurrence, H, OH, NH.sub.2, or
C.sub.1-C.sub.3 alkyl, wherein the alkyl is optionally substituted
with one or more R.sup.19; and R.sup.19 are independently, at each
occurrence, H, OH, NH.sub.2, oxo, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6Hhaloalkyl, C.sub.1-C.sub.6alkoxy; provided that:
(1) when X is H, n is 1; (2) when X is a bond, O, or
CR.sup.11R.sup.12, n is 2; (3) when n is 3, X is CR.sup.11 or N;
(4) when n is 4 X is C; (5) only one of Q or X is --NHC(O)NH-- at
the time, (6) R.sup.1 and R.sup.2 together with the nitrogen to
which they are attached, cannot form a pyrrolidinyl; (7) when
R.sup.1 and R.sup.2 are methyl, R.sup.3 and R.sup.4 are halogen,
and R.sup.5 and R.sup.8 are H, Linker is not ##STR00297## (8) when
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached form a piperidinyl, R.sup.3 and R.sup.4 are halogen, and
R.sup.5 and R.sup.8 are H, Linker is not and ##STR00298## (9) when
R.sup.1 and R.sup.2, together with the nitrogen to which they are
attached, form 3-aminopiperidin-1-yl, R.sup.3 and R.sup.4 are
halogen, and R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are H, Linker
is not ##STR00299##
2. The compound of claim 1, wherein Linker is selected the group
consisting of ##STR00300## ##STR00301##
3. The compound of claim 1, wherein Linker is selected from the
group consisting of ##STR00302##
4. (canceled)
5. The compound of claim 1, wherein R.sup.1 and R.sup.2 are
methyl.
6. (canceled)
7. The compound of claim 1, wherein R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached can form a
heterocyclyl, wherein the heterocyclyl is optionally substituted
with one or more oxo.
8-32. (canceled)
33. The compound of claim 1 having the formula Ia: ##STR00303##
wherein the ring Het represents R.sup.1 and R.sup.2 together with
the nitrogen to which they are attached can form a heterocyclyl or
heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl
group is optionally substituted with one or more halogen, OH, CN,
--NO.sub.2, oxo, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
NR.sup.9R.sup.10, S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--C(O)NR.sup.9R.sup.10, NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sub.10, NR.sup.9S(O)R.sup.10, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
heterocycle, aryl, or heteroaryl.
34. The compound of claim 1 having the formula Ib: ##STR00304##
wherein the ring Het represents R.sup.1 and R.sup.2 together with
the nitrogen to which they are attached can form a heterocyclyl or
heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl
group is optionally substituted with one or more halogen, OH, CN,
--NO.sub.2, oxo, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--C(O)NR.sup.9R.sup.10, NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O) NR.sup.9R.sup.10, NR.sup.9S(O)R.sup.10,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl.
35. The compound of claim 1 having the formula Ic: ##STR00305##
wherein Het B represents a C.sub.3-C.sub.8 cycloalkyl,
heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms
selected from the group consisting of N, S, P and O, wherein each
heterocyclyl or heteroaryl is optionally substituted with one or
more R.sup.19.
36. The compound of claim 1 having the formula Id: ##STR00306##
wherein Het is R.sup.n which represents
C.sub.4-C.sub.8cycloalkenyl, C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, or heteroaryl, wherein each cycloalkenyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more R.sup.19.
37. The compound of claim 1 having the formula Ie: ##STR00307##
wherein the ring Het A represents R.sup.1 and R.sup.2 together with
the nitrogen to which they are attached can form a heterocyclyl or
heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl
group is optionally substituted with one or more halogen, OH, CN,
--NO.sub.2, oxo, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--C(O)NR.sup.9R.sup.10, NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O) NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.10,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl; and Het is R.sup.13 which represents
C.sub.4-C.sub.8cycloalkenyl, C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, or heteroaryl, wherein each cycloalkenyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more R.sup.19.
38. The compound of claim 1 having the formula If: ##STR00308##
39. The compound of claim 1 having the formula If: ##STR00309##
40. The compound of claim 1 having the formula Ig: ##STR00310##
41. The compound of claim 1 having the formula Ih: wherein:
##STR00311## Het represents R.sup.6 and R.sup.14 together with the
atoms to which they are attached forming, independently, at each
occurrence, a 5- to-6 membered heterocyclyl.
42. The compound of claim 1 having the formula Ii: ##STR00312##
43. The compound of claim 1 selected from the group consisting of:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]
ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]-
ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]
ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]etho-
xy] ethoxy)ethyl] carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[-
4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methox-
y-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-
-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-met-
hoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl-
]carbamoyl]amino)butyl]urea;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-fluoro-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)-
ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlo-
ro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]eth-
oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]
ethoxy]
ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfona-
mido] ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl] urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano--
2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlor-
o-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methox-
y-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]
ethoxy]
ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfon-
amido]ethoxy]ethoxy)ethyl]carbamoyl]amino) butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2--
[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]-
urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dih-
ydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2--
(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-ind-
en-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]-
urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-
-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]
amino)butyl]urea; 3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dim ethyl
amino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonam-
ido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethy-
lamino)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonam-
ido]ethoxy] ethoxy)ethyl]carbamoyl]amino)butyl]urea;
1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[-
4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]
ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethyl
amino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy-
]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4--
methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)et-
hyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethyl
amino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamid-
o]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethyla-
mino)-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-
ethoxy]ethoxy)ethyl]carbamoyl]amino) butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethyl
amino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methyl
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6--
chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylb-
enzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethyl
amino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]-
ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethyl
amino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]-
ethoxy) ethyl] carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2-
,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)et-
hyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoro-
methyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]-
ethoxy)ethyl]carbamoyl]amino)butyl]urea;
1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)--
2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluor-
omethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethox-
y]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]
ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylam-
ino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-
ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-y-
l]oxy]-3-methyl
benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea
dihydrochloride;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-y-
l]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)but-
yl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3--
dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl-
]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-di-
hydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin--
1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethy-
l]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)pip-
eridin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]etho-
xy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin--
1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]et-
hoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethyl-
amino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfo-
namido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin--
1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]et-
hoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethyl-
amino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfo-
namido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy-
)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)pi-
peridin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]e-
thoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]etho-
xy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethy-
lamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylben-
zene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]etho-
xy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethy-
lamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoroben-
zene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-
-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]b-
enzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2--
(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)b-
utyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-di-
hydro-/H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]--
1-[4-([[2-(2-[2-(4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoy-
l]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[-
2-(4-([(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea-
;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydr-
o-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbam-
oyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4--
([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamo-
yl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-i-
nden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]a-
mino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)-
ethyl]-1-[4-[[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlor-
o-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]etho-
xy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperi-
din-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]
ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3-
R)-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methy-
lbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperi-
din-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethox-
y]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenze-
ne)sulfon amido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-
-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1--
yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea;
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethox-
y)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino-
)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]-
methoxy]ethoxy)ethyl]carbamoyl]amino) butyl]urea;
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]
pyrrolidin-3-yl]methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-
-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylben-
zene) sulfonyl] pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]
amino)butyl]urea;
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]e-
thoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimet-
hylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolid-
in-3-yl]methoxy] ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]
methoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyan-
o-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfony-
l]
pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-
-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylam-
ino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3--
yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;
3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-
-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylam-
ino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3--
yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;
3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihyd-
ro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyr-
idin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(di-
methylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrro-
lidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;
3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihyd-
ro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyr-
idin-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(di-
methylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrro-
lidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,-
2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methyl-
benzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)
carbamoyl]amino]butyl)urea;
3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethy-
l)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-d-
ihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]etho-
xy]ethyl)carbamoyl]amino]butyl)urea;
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamin-
o)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-
-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;
3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamin-
o)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-
-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;
1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[([1-
-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)
ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea;
(2R,3S,4R,5S)--N.sup.1,N.sup.6-Bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-am-
inopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulf-
onamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahy-
droxyhexanediamide;
3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)m-
ethyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dich-
loro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-tri-
azol-4-yl)methyl]carbamoyl]amino)butyl]urea;
3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)m-
ethyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dich-
loro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-tri-
azol-4-yl)methyl]carbamoyl]amino)butyl]urea;
(4R,4aS,8S,8aR)--N.sup.4,N.sup.8-Bis([1-(4-[4-((1S,2S)-2-[(3R)-3-aminopip-
eridin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenyl
sulfonamide]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetr-
ahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide; (4R,4aS,8
S,8aR)--N.sup.4,N.sup.8-Bis([1-(6-[4-((1S,2S)-2-[(3R)-3-amino
piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenyl
sulfonamido]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetr-
ahydro-[1,3]dioxino[5,4-d][1,3]di oxine-4,8-dicarboxamide;
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydr-
o-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[-
(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]ben-
zene) sulfonamido]octyl]carbamoyl)amino]butyl]urea;
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydr-
o-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-
-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]o-
ctyl]carbamoyl)amino]butyl]urea;
3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1--
yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(-
dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]octyl]carbamoyl)amino]butyl]urea;
3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1--
yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dic-
hloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]octyl]carbamoyl)amino]butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]
carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]
ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]-
heptan-2-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamid-
o]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carba-
moyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carba-
moyl]amino)butyl]urea;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-Azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]
ethoxy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]-
nonan-9-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido-
]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihy-
dro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H--
inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)but-
yl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)--
2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl-
)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy-
)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihy-
dro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H--
inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)but-
yl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy-
)ethyl]carbamoyl]amino)butyl]urea;
4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6--
dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl-
]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)eth-
oxy]ethoxy]ethyl)
sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-ca-
rboxamide;
4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1-
S,2S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H--
inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]-
amino)butyl]carbamoyl]amino)eth
oxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N-
,N-dimethylpiperazine-1-carboxamide;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino-
]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichlo-
ro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inde-
n-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]u-
rea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy]-3,5-dimethyl
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2--
[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-
,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]u-
rea; hydrochloride;
1-[2-(2-[2-[(3-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)
ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-d-
ihydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)et-
hyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3--
aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimet-
hylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]
carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-
-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]a-
mino)butyl]urea;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]
ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sul-
fonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
hydrochloride;
1-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethyl
amino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamid-
o]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3--
aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-diflu-
orobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]
amino)butyl]urea;
4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-
-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-
-yl]oxy)-3,5-difluorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,-
11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]eth-
oxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,-
6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethyl
amino)-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamid-
o]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]eth-
oxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,-
6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethyl
amino)-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamid-
o]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethox-
y]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolid-
in-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]e-
thoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimeth-
ylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxo-
pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethox-
y)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-
-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethox-
y)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-
-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethy-
l]-1-[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichl-
oro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)etho-
xy]ethyl]carbamoyl)amino]butyl]urea;
1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-
-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichl-
oro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl-
)carbamoyl]amino]butyl)urea; hydrochloride;
3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-
-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichl-
oro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl-
)carbamoyl]amino]butyl)urea;
3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4-
,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea
dihydrochloride;
3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4-
,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbut-
oxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethy-
l]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]etho-
xy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethy-
l]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]etho-
xy)ethyl]carbamoyl]amino)butyl]urea;
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl-
]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy-
)ethyl]carbamoyl] amino)butyl]urea;
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl-
]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy-
)ethyl]carbamoyl]amino)butyl]urea;
4-(1S,2S)-2-[(R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-
-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamido)-10,17-di
oxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfo-
namide;
4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)--
2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-
-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorob-
enzenesulfonamide; tetra(trifluoroacetate);
4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy-
)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2
S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluor-
ophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetra-
azaicosyl)pyrrolidin-3-yl]-3-fluorobenzenesulfonamide;
tetra(trifluoroacetate);
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14--
dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonami-
de; tetra(trifluoroacetate);
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14--
dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonami-
de; tetra(trifluoroacetate);
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1--
yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluo-
robenzenesulfonamide; tetra(trifluoroacetate);
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1--
yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluo-
robenzenesulfonamide; tetra(trifluoroacetate);
4-(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-
--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihyd-
ro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dio-
xo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesul-
fonamide; tetra(trifluoroacetate);
4-(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-N-
--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihyd-
ro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dio-
xo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesul-
fonamide; tetra(trifluoroacetate);
4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-
-dihydro-1H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2--
[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,-
13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;
tetra(trifluoroacetate);
4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-
-dihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2--
[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,-
13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;
tetra(trifluoroacetate);
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo--
5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-4,11,-
14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonami-
de;
4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-y-
l]oxy)-N--[(S)-1-[(2S,13S)-14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(pip-
erazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-
-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolid-
in-3-yl]benzenesulfonamide;
N.sup.1,N.sup.14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-
-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;
N.sup.1,N.sup.14-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-
-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;
N.sup.1,N.sup.18-Bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)--
2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5-
,7,12,14-tetraazaoctadecanediamide;
4-(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3-di-
hydro-1H-inden-1-yl]oxy)-N-[26-([4-(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(dime-
thylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido-
)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesulfo-
namide;
-(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]--
2,3-dihydro-1H-inden-1-yl]oxy)-N-[26-([4-(1S,2S)-6-chloro-4-cyano-2-[(S)-3-
-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfo-
namido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzen-
esulfonamide;
4-(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]o-
xy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihy-
dro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidin-1-yl)-7,14-dioxo-3,18-d-
ioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide;
N.sup.1,N.sup.18-Bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-
-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazao-
ctadecanediamide;
N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden--
1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(pipe-
razin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperi-
din-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide;
4-(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-y-
l]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-'-
7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulf-
onamide;
4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,-
4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolid-
in-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]be-
nzenesulfonamide;
4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-
-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
in-3-yl]benzenesulfonamide;
4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4--
methyl-1,4-di
azepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin--
1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benze-
nesulfonamide;
4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cya-
no-2,3-dihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-[(1-
S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H--
inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6-
,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;
4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cya-
no-2,3-dihydro-1H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1-
S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H--
inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6-
,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;
4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[(5)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R-
)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido-
)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidi-
n-3-yl]benzenesulfonamide;
4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(-
R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
in-3-yl]benzenesulfonamide;
4-(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H--
inden-1-yl]oxy)-N-[(5)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)--
3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)p-
yrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin--
3-yl]benzenesulfonamide;
4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-(1S,2S)-6-chloro-4-cyano-2-[(S)-
-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-
pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-
-3-yl]benzenesulfonamide;
4-(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dih-
ydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyan-
o-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phe-
nyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazai-
cosyl)pyrrolidin-3-yl]benzenesulfonamide;
4-(1S,2S)-6-chloro-4-cyano-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dih-
ydro-1H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyan-
o-2-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phe-
nyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazai-
cosyl)pyrrolidin-3-yl]benzenesulfonamide;
4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-[(5)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxopiperidin-1-yl]--
7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzen-
esulfonamide;
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano--
2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy-
]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonam-
ide;
4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1--
yl]oxy)-N--[(R)-1-(18-(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1--
yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13-
,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonami-
de;
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy)benzenesulfonamide;
N-(2-[2-(2-Aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(pipe-
razin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;
N-[1-(4-Aminobutanoyl)piperidin-4-yl]-4-(1S,2S)-6-chloro-4-cyano-2-(piper-
azin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)benzenesulfonamide;
4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]o-
xy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfonamide;
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide-
;
4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-
-1-yl]oxy)phenyl]sulfonamido)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-
-2-yl]piperidine-1-carboxamide;
4-(3-[4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H--
inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-(1S,2S)-6-chlo-
ro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfony-
l)butanamide;
4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]o-
xy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-
-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl)u-
reido]butanoyl)piperidin-4-yl]benzenesulfonamide;
4-(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]o-
xy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazano-
nadecyl]benzenesulfonamide;
4-([(1S,2S)-6-Chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,-
16,18-tetraazahexacosyl]benzenesulfonamide;
4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,-
16,18-tetraazahexacosyl]benzenesulfonamide;
1,1'-(Butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-o-
xobutyl)urea];
1,1'-(Butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-o-
xobutyl)urea];
N,N-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-(1S,2-
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4--
dihydroisoquinoline-2(1H)-carboxamide];
N,N-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-(1S,2-
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4--
dihydroisoquinoline-2(1H)-carboxamide];
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R-
)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido-
)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-
-3-yl]benzenesulfonamide;
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R-
)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido-
)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-
-3-yl]benzenesulfonamide;
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[1-(18-[4-([4-(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methyl-
piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-
-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzen-
esulfonamide;
N.sup.1,N.sup.14-Bis(2-[(S)-3-[(S)-(1S,2S)-6-chloro-4-cyano-2-[(R)-3-meth-
ylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrroli-
din-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-meth-
ylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperid-
in-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]ben-
zenesulfonamide;
4-([(1S,2S)-4,6-Dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-in-
den-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-met-
hylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrol-
idin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-
benzenesulfonamide;
N.sup.1,N.sup.14-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylp-
iperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-
-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;
1,1'-(Butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(pipera-
zin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl-
]urea); and
1,1'-(Butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(pipera-
zin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl-
]urea).
(1S,2S)-1-(4-{(3S)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4-car-
boxy-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]ox-
y}benzenesulfonamido)-1-hydroxy-1.lamda..sup.4-pyrrolidin-1-yl]ethoxy}ethy-
l)carbamoyl]amino}butyl)carbamoyl]amino}
ethoxy)ethyl]-1-hydroxy-1.lamda..sup.4-pyrrolidin-3-yl]sulfamoyl}phenoxy)-
-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-4-carboxyl-
ic acid; 3-(2-{2-[(3S)-3-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}(2,3,5,6-.sup.2H.sub.4)benzenesulfonamido)pyrrolidin-1-yl]ethoxy}-
ethyl)-1-(4-{[(2-{2-[3S)-3-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}
(2,3,5,6-.sup.2H.sub.4)benzenesulfonamido)pyrrolidin-1-yl]ethoxy-
}ethyl)carbamoyl]amino} (1, 1,2,2,3,3,4,4-.sup.2H.sub.8)butyl)urea;
3-(2-{2-[2-(4-{[(1 S,2
S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[(1S,-
2
S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-
-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)ure-
a; 3-(2-{2-[(3 S)-3-(4-{[(1 S,2
S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl-
]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3
S)-3-(4-[(1 S,2
S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl-
]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy
ethyl)carbamoyl]amino}butyl)urea; N-{2-[(3 S)-3-(4-{[(1 S,2
S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl-
]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4-({[({2-[(3
S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydr-
o-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamo-
yl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide;
3-(2-{2-[2-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)ethoxy]ethoxy}ethyl)-1-[(1 s,4
s)-4-{[(2-{2-[2-(4-{[(1S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)ethoxy]ethoxy ethyl)carbamoyl]amino}cyclohexyl]urea;
1,3-bis(2-{2-[2-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)ethoxy]ethoxy}ethyl)urea;
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diaza-
nonadecyl]benzenesulfonamide; 3-(2-{2-[2-(4-{[(1S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)ethoxy]ethoxy}ethyl)-1-[(1r,4r)-4-[(2-{2-[2-(4-{[(1
S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}cyclohexyl]urea;
3-(2-{2-[(3 S)-3-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy
ethyl)-1-(4-{[(2-{2-[(3 S)-3-(4-[(1 S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}
(1,1,2,2,3,3,4,4-.sup.2H.sub.8)butyl)urea; 3-{4-[(3 S)-3-(4-{[(1
S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}-1-{4-[({4-[(3
S)-3-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}carbamoyl)amino]bu-
tyl}urea; 3-{4-[4-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)piperidin-1-yl]-4-oxobutyl}-1-{4-[({4-[4-(4-{[-
(1S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-i-
nden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]-4-oxobutyl}carbamoyl)amin-
o]butyl}urea; N-{2-[(3R)-3-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)pyrrolidin-1-yl]-2-oxoethyl-2-([Lk{R
{2-[(3R)-3-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)methyl]carbamoyl}amin-
o)butyl]carbamoyl}amino)acetamide; 3-(2-{2-[4-(4-{[(1S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)piperidin-1-yl]ethoxy
ethyl)-1-(4-{[(2-{2-[4-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)piperidin-1-yl]ethoxy}ethyl)carbamoyl]amino}bu-
tyl)urea; 3-{2-[(3 S)-3-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-1-{4-R {2-[(3
S)-3-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)amino]butyl}urea;
and (3 S)--N-(4-{[(1 S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonyl)-1-[2-(2-{[(4-{[(2-{2-[(3 S)-3-[(4-{[(1 S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonyl)carbamoyl]pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)c-
arbamoyl]amino}ethoxy)ethyl]pyrrolidine-3-carboxamide.
44. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier.
45. A method for inhibiting NHE-mediated antiport of sodium and
hydrogen ions, the method comprising administering to a mammal in
need thereof a pharmaceutically effective amount of a compound or
pharmaceutical composition of claim 1.
46. A method for treating a disorder associated with fluid
retention or salt overload, the method comprising administering to
a mammal in need thereof a pharmaceutically effective amount of a
compound or pharmaceutical composition of claim 1.
47. The method of claim 46, wherein the disorder is selected from
the group consisting of gastrointestinal motility disorder,
irritable bowel syndrome, chronic constipation, chronic idiopathic
constipation, chronic constipation occurring in cystic fibrosis,
opioid-induced constipation, chronic intestinal pseudo-obstruction,
colonic pseudo-obstruction, ulcerative colitis, inflammatory bowel
disease, gastrointestinal tract disorder is associated with chronic
kidney disease (stage 4 or 5), constipation induced by calcium
supplement, constipation associated with the use of a therapeutic
agent, constipation associated with a neuropathic disorder
(Parkinson's disease, multiple sclerosis), post-surgical
constipation (postoperative ileus), idiopathic constipation
(functional constipation or slow transit constipation),
constipation associated with neuropathic, metabolic or an endocrine
disorder, constipation due the use of drugs selected from
analgesics (e.g., opioids), antihypertensive, anticonvulsants,
antidepressants, antispasmodics and antipsychotics, gastric ulcers,
infectious diarrhea, leaky gut syndrome, cystic fibrosis
gastrointestinal disease, microscopic colitis, necrotizing
enterocolitis, atopy, food allergy, acute inflammation, chronic
inflammation, obesity-induced metabolic diseases, kidney disease,
chronic kidney disease, diabetic kidney disease, heart disease,
heart failure, congestive heart failure, hypertension, essential
hypertension, primary hypertension, salt-sensitive hypertension,
liver disease, cirrhosis, nonalcoholic steatohepatitis,
nonalcoholic fatty liver disease, steatosis, primary sclerosing
cholangitis, primary biliary cholangitis, portal hypertension, Type
1 diabetes, celiac disease, multiple sclerosis, ankylosing
spondylitis, rheumatoid arthritis, lupus, alopecia areata,
polymyalgia rheumatica, multiple sclerosis, fibromyalgia, chronic
fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis,
vasculitis, Crohn's disease, ulcerative colitis, urticaria (hives),
Raynaud's syndrome, schizophrenia, autism spectrum disorders,
multiple sclerosis, hepatic encephalopathy, small intestinal
bacterial overgrowth, secondary hyperparathyroidism (PTH), celiac
disease, hyperphosphatemia and chronic alcoholism.
48-57. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 16/476,836 that was filed on Jul. 9, 2019, which is a 35 U.S.C.
.sctn. 371 application of International Application Serial No.
PCT/US2018/013020 that was filed filed on Jan. 9, 2018, which
claims priority to U.S. provisional patent application No.
62/444,335 that was filed on 9 Jan. 2017, and U.S. provisional
patent application No. 62/541,097 that was filed on Aug. 4, 2017.
The entire content of the applications referenced above is hereby
incorporated by reference herein.
FIELD OF INVENTION
[0002] The present disclosure is directed to indanes derivatives
that are substantially active in the gastrointestinal tract to
inhibit NHE-mediated antiport of sodium ions and hydrogen ions, and
the use of such compounds in the treatment of disorders associated
with fluid retention or salt overload and in the treatment of
gastrointestinal tract disorders, including the treatment or
reduction of pain associated with a gastrointestinal tract
disorder.
BACKGROUND OF THE INVENTION
[0003] Disorders Associated with Fluid Retention and Salt
Overload
[0004] According to the American Heart Association, more than 5
million Americans have suffered from heart failure, and an
estimated 550,000 cases of congestive heart failure (CHF) occur
each year (Schocken, D. D. et al., Prevention of heart failure: a
scientific statement from the American Heart Association Councils
on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular
Nursing, and High Blood Pressure Research; Quality of Care and
Outcomes Research Interdisciplinary Working Group; and Functional
Genomics and Translational Biology Interdisciplinary Working Group:
Circulation, v. 117, no. 19, p. 2544-2565 (2008)). The clinical
syndrome of congestive heart failure occurs when cardiac
dysfunction prevents adequate perfusion of peripheral tissues. The
most common form of heart failure leading to CHF is systolic heart
failure, caused by contractile failure of the myocardium. A main
cause of CHF is due to ischemic coronary artery disease, with or
without infarction. Long standing hypertension, particularly when
it is poorly controlled, may lead to CHF.
[0005] In patients with CHF, neurohumoral compensatory mechanisms
(i.e., the sympathetic nervous system and the renin-angiotensin
system) are activated in an effort to maintain normal circulation.
The renin-angiotensin system is activated in response to decreased
cardiac output, causing increased levels of plasma renin,
angiotensin II, and aldosterone. As blood volume increases in the
heart, cardiac output increases proportionally, to a point where
the heart is unable to dilate further. In the failing heart,
contractility is reduced, so the heart operates at higher volumes
and higher filling pressures to maintain output. Filling pressures
may eventually increase to a level that causes transudation of
fluid into the lungs and congestive symptoms (e.g., edema,
shortness of breath). All of these symptoms are related to fluid
volume and salt retention, and this chronic fluid and salt overload
further contribute to disease progression.
[0006] Compliance with the medication regimen and with dietary
sodium restrictions is a critical component of self-management for
patients with heart failure and may lengthen life, reduce
hospitalizations and improve quality of life. Physicians often
recommend keeping salt intake below 2.3 g per day and no more than
2 g per day for people with heart failure. Most people eat
considerably more than this, so it is likely that a person with
congestive heart failure will need to find ways to reduce dietary
salt.
[0007] A number of drug therapies currently exist for patients
suffering from CHF. For example, diuretics may be used or
administered to relieve congestion by decreasing volume and,
consequently, filling pressures to below those that cause pulmonary
edema. By counteracting the volume increase, diuretics reduce
cardiac output; however, fatigue and dizziness may replace CHF
symptoms. Among the classes or types of diuretics currently being
used is thiazides. Thiazides inhibit NaCl transport in the kidney,
thereby preventing reabsorption of Na in the cortical diluting
segment at the ending portion of the loop of Henle and the proximal
portion of the distal convoluted tubule. However, these drugs are
not effective when the glomerular filtration rate (GFR) is less
than 30 ml/min. Additionally, thiazides, as well as other
diuretics, may cause hypokalemia. Also among the classes or types
of diuretics currently being used is loop diuretics (e.g.,
furosemide). These are the most potent diuretics and are
particularly effective in treating pulmonary edema. Loop diuretics
inhibit the NaKCl transport system, thus preventing reabsorption of
Na in the loop of Henle.
[0008] Patients that have persistent edema despite receiving high
doses of diuretics may be or become diuretic-resistant. Diuretic
resistance may be caused by poor availability of the drug. In
patients with renal failure, which has a high occurrence in the CHF
population, endogenous acids compete with loop diuretics such as
furosemide for the organic acid secretory pathway in the tubular
lumen of the nephron. Higher doses, or continuous infusion, are
therefore needed to achieve entrance of an adequate amount of drug
into the nephron. However, recent meta-analysis has raised
awareness about the long-term risk of chronic use of diuretics in
the treatment of CHF. For instance, in a recent study (Ahmed et
al., Int J Cardiol. 2008 Apr. 10; 125(2): 246-253) it was shown
that chronic diuretic use was associated with significantly
increased mortality and hospitalization in ambulatory older adults
with heart failure receiving angiotensin converting enzyme
inhibitor and diuretics.
[0009] Angiotensin-converting enzyme ("ACE") inhibitors are an
example of another drug therapy that may be used to treat
congestive heart failure. ACE inhibitors cause vasodilatation by
blocking the renin-angiotensin-aldosterone system. Abnormally low
cardiac output may cause the renal system to respond by releasing
renin, which then converts angiotensinogen into angiotensin I. ACE
converts angiotensin I into angiotensin II. Angiotensin II
stimulates the thirst centers in the hypothalamus and causes
vasoconstriction, thus increasing blood pressure and venous return.
Angiotensin II also causes aldosterone to be released, causing
reabsorption of Na and concomitant passive reabsorption of fluid,
which in turn causes the blood volume to increase. ACE inhibitors
block this compensatory system and improve cardiac performance by
decreasing systemic and pulmonary vascular resistance. ACE
inhibitors have shown survival benefit and conventionally have been
a treatment of choice for CHF. However, since ACE inhibitors lower
aldosterone, the K-secreting hormone, one of the side-effects of
their use is hyperkalemia. In addition, ACE inhibitors have been
show to lead to acute renal failure in certain categories of CHF
patients. (See, e.g., C. S. Cruz et al., "Incidence and Predictors
of Development of Acute Renal Failure Related to the Treatment of
Congestive Heart Failure with ACE Inhibitors, Nephron Clin. Pract.,
v. 105, no. 2, pp c77-c83 (2007)).
[0010] Patients with end stage renal disease ("ESRD"), i.e., stage
5 chronic kidney failure, must undergo hemodialysis three times per
week. The quasi-absence of renal function and ability to eliminate
salt and fluid results in large fluctuations in body weight as
fluid and salt build up in the body (sodium/volume overload). The
fluid overload is characterized as interdialytic weight gain. High
fluid overload is also worsened by heart dysfunction, specifically
CHF. Dialysis is used to remove uremic toxins and also adjust salt
and fluid homeostasis. However, symptomatic intradialytic
hypotension (SIH) may occur when patients are over-dialyzed. SIH is
exhibited in about 15% to 25% of the ESRD population (Davenport,
A., C. Cox, and R. Thuraisingham, Blood pressure control and
symptomatic intradialytic hypotension in diabetic haemodialysis
patients: a cross-sectional survey; Nephron Clin. Pract., v. 109,
no. 2, p. c65-c71 (2008)). Like in hypertensive and CHF patients,
dietary restrictions of salt and fluid are highly recommended but
poorly followed because of the poor palatability of low-salt
food
[0011] The cause of primary or "essential" hypertension is elusive.
However, several observations point to the kidney as a primary
factor. The strongest data for excess salt intake and elevated
blood pressure come from INTERSALT, a cross-sectional study of
greater than 10,000 participants. For individuals, a significant,
positive, independent linear relation between 24-hour sodium
excretion and systolic blood pressure was found. Higher individual
24-hour urinary sodium excretions were found to be associated with
higher systolic/diastolic blood pressure on average, by 6-3/3-0 mm
Hg. Primary hypertension is a typical example of a complex,
multifactorial, and polygenic trait. All these monogenic
hypertensive syndromes are virtually confined to mutated genes
involving gain of function of various components of the
renin-angiotensin-aldosterone system, resulting in excessive renal
sodium retention. In a broad sense, these syndromes are
characterized by increased renal sodium reabsorption arising
through either primary defects in sodium transport systems or
stimulation of mineralocorticoid receptor activity (Altun, B., and
M. Arici, 2006, Salt and blood pressure: time to challenge;
Cardiology, v. 105, no. 1, p. 9-16 (2006)). A much larger number of
controlled studies have been performed on hypertensive subjects
during the last three decades to determine whether sodium reduction
will reduce established high blood pressure. Meta-analyses of these
studies have clearly shown a large decrease in blood pressure in
hypertensive patients.
[0012] In end stage liver disease (ESLD), accumulation of fluid as
ascites, edema or pleural effusion due to cirrhosis is common and
results from a derangement in the extracellular fluid volume
regulatory mechanisms. Fluid retention is the most frequent
complication of ESLD and occurs in about 50% of patients within 10
years of the diagnosis of cirrhosis. This complication
significantly impairs the quality of life of cirrhotic patients and
is also associated with poor prognosis. The one-year and five-year
survival rate is 85% and 56%, respectively (Kashani et al., Fluid
retention in cirrhosis: pathophysiology and management; QJM, v.
101, no. 2, p. 71-85 (2008)). The most acceptable theories
postulate that the initial event in ascites formation in the
cirrhotic patient is sinusoidal hypertension. Portal hypertension
due to an increase in sinusoidal pressure activates vasodilatory
mechanisms. In advanced stages of cirrhosis, arteriolar
vasodilation causes underfilling of systemic arterial vascular
space. This event, through a decrease in effective blood volume,
leads to a drop in arterial pressure. Consequently,
baroreceptor-mediated activation of renin-angiotensin aldosterone
system, sympathetic nervous system and nonosmotic release of
amidiuretic hormone occur to restore the normal blood homeostasis.
These events cause further retention of renal sodium and fluid.
Splanchnic vasodilation increases splanchnic lymph production,
exceeding the lymph transportation system capacity, and leads to
lymph leakage into the peritoneal cavity. Persistent renal sodium
and fluid retention, alongside increased splanchnic vascular
permeability in addition to lymph leakage into the peritoneal
cavity, play a major role in a sustained ascites formation.
[0013] Thiazolidinediones (TZD's), such as rosiglitazone, are
peroxisome proliferator-activated receptor (PPAR) gamma agonist
agents used for the treatment of type-2 diabetes and are widely
prescribed. Unfortunately, fluid retention has emerged as the most
common and serious side-effect of TZD's and has become the most
frequent cause of discontinuation of therapy. The incidence of
TZD-induced fluid retention ranges from 7% in monotherapy and to as
high as 15% when combined with insulin (Yan, T., Soodvilai, S.,
PPAR Research volume 2008, article ID 943614). The mechanisms for
such side-effects are not fully understood but may be related in Na
and fluid re-absorption in the kidney. However TZD-induced fluid
retention is resistant to loop diuretics or thiazide diuretics, and
combination of peroxisome proliferator-activated receptor (PPAR)
alpha with PPAR gamma agonists, which were proposed to reduce such
fluid overload, are associated with major adverse cardiovascular
events.
[0014] In view of the foregoing, it is recognized that salt and
fluid accumulation contribute to the morbidity and mortality of
many diseases, including heart failure (in particular, congestive
heart failure), chronic kidney disease, end-stage renal disease,
liver disease and the like. It is also accepted that salt and fluid
accumulation are risk factors for hypertension. Accordingly, there
is a clear need for a medicament that, when administered to a
patient in need, would result in a reduction in sodium retention,
fluid retention, or both. Such a medicament would also not involve
or otherwise impair renal mechanisms of fluid/Na homeostasis.
[0015] One option to consider for treating excessive fluid overload
is to induce diarrhea. Diarrhea may be triggered by several agents
including, for example, laxatives such as sorbitol,
polyethyleneglycol, bisacodyl and phenolphthaleine. Sorbitol and
polyethyleneglycol triggers osmotic diarrhea with low levels of
secreted electrolytes; thus, their utility in removing sodium salt
from the GI tract is limited. The mechanism of action of
phenolphthalein is not clearly established, but is thought to be
caused by inhibition of the Na/K ATPase and the C/HCO.sub.3 anion
exchanger and stimulation of electrogenic anion secretion (see,
e.g., Eherer, A. J., C. A. Santa Ana, J. Porter, and J. S.
Fordtran, 1993, Gastroenterology, v. 104, no. 4, p. 1007-1012).
However, some laxatives, such as phenolphthalein, are not viable
options for the chronic treatment of fluid overload, due to the
potential risk of carcinogenicity in humans. Furthermore, laxatives
may not be used chronically, as they have been shown to be an
irritant and cause mucosal damage. Accordingly, it should also be
recognized that the induction of chronic diarrhea as part of an
effort to control salt and fluid overload would be an undesired
treatment modality for most patients. Any medicament utilizing the
GI tract for this purpose would therefore need to control diarrhea
in order to be of practical benefit.
[0016] One approach for the treatment of mild diarrhea is the
administration of a fluid-absorbing polymer, such as the natural
plant fiber psyllium. Polymeric materials, and more specifically
hydrogel polymers, may also be used for the removal of fluid from
the gastrointestinal (GI) tract. The use of such polymers is
described in, for example, U.S. Pat. Nos. 4,470,975 and 6,908,609,
the entire contents of which are incorporated herein by reference
for all relevant and consistent purposes. However, for such
polymers to effectively remove significant quantities of fluid,
they must desirably resist the static and osmotic pressure range
existing in the GI tract. Many mammals, including humans, make a
soft feces with a water content of about 70%, and do so by
transporting fluid against the high hydraulic resistance imposed by
the fecal mass. Several studies show that the pressure required to
dehydrate feces from about 80% to about 60% is between about 500
kPa and about 1000 kPa (i.e., about 5 to about 10 atm). (See, e.g.,
McKie, A. T., W. Powrie, and R. J. Naftalin, 1990, Am J Physiol, v.
258, no. 3 Pt 1, p. G391-G394; Bleakman, D., and R. J. Naftalin,
1990, Am J Physiol, v. 258, no. 3 Pt 1, p. G377-G390; Zammit, P.
S., M. Mendizabal, and R. J. Naftalin, 1994, J Physiol, v. 477 (Pt
3), p. 539-548.) However, the static pressure measured
intraluminally is usually between about 6 kPa and about 15 kPa. The
rather high pressure needed to dehydrate feces is essentially due
to an osmotic process and not a mechanical process produced by
muscular forces. The osmotic pressure arises from the active
transport of salt across the colonic mucosa that ultimately
produces a hypertonic fluid absorption. The osmotic gradient
produced drives fluid from the lumen to the serosal side of the
mucosa. Fluid-absorbing polymers, such as those described in for
example U.S. Pat. Nos. 4,470,975 and 6,908,609, may not be able to
sustain such pressure. Such polymers may collapse in a normal colon
where the salt absorption process is intact, hence removing a
modest quantity of fluid and thereby salt.
[0017] Synthetic polymers that bind sodium have also been
described. For example, ion-exchange polymeric resins, such as
Dowex-type cation exchange resins, have been known since about the
1950's. However, with the exception of Kayexalate.TM. (or
Kionex.TM.), which is a polystyrene sulfonate salt approved for the
treatment of hyperkalemia, cation exchange resins have very limited
use as drugs, due at least in part to their limited capacity and
poor cation binding selectivity. Additionally, during the
ion-exchange process, the resins may release a stoichiometric
amount of exogenous cations (e.g., H, K, Ca), which may in turn
potentially cause acidosis (H), hyperkalemia (K) or contribute to
vascular calcification (Ca). Such resins may also cause
constipation.
Gastrointestinal Tract Disorders
[0018] Constipation is characterized by infrequent and difficult
passage of stool and becomes chronic when a patient suffers
specified symptoms for over 12 non-consecutive weeks within a
12-month period. Chronic constipation is idiopathic if it is not
caused by other diseases or by use of medications. An
evidence-based approach to the management of chronic constipation
in North America (Brandt et al., 2005, Am. J. Gastroenterol.
100(Suppl.1):S5-S21) revealed that prevalence is approximately 15%
of the general population. Constipation is reported more commonly
in women, the elderly, non-whites, and individuals from lower
socioecyanomic groups.
[0019] Irritable bowel syndrome (IBS) is a common GI disorder
associated with alterations in motility, secretion and visceral
sensation. A range of clinical symptoms characterizes this
disorder, including stool frequency and form, abdominal pain and
bloating. The recognition of clinical symptoms of IBS are yet to be
defined, but it is now common to refer to diarrhea-predominant IBS
(D-IBS) and constipation-predominant IBS (C-IBS), wherein D-IBS is
defined as continuous passage of loose or watery stools and C-IBS
as a group of functional disorders which present as difficult,
infrequent or seemingly incomplete defecation. The pathophysiology
of IBS is not fully understood, and a number of mechanisms have
been suggested. Visceral hypersensitivity is often considered to
play a major etiologic role and has been proposed to be a
biological marker even useful to discriminate IBS from other causes
of abdominal pain. In a recent clinical study (Posserud, 1. et al,
Gastroenterology, 2007:133:1113-1123) IBS patients were submitted
to a visceral sensitivity test (Balloon distention) and compared
with healthy subjects. It revealed that 61% of the IBS patients had
an altered visceral perception as measured by pain and discomfort
threshold. Other reviews have documented the role of visceral
hypersensitivity in abdominal pain symptomatic of various
gastrointestinal tract disorders (Akbar, A, et al, Aliment.
Pharmaco. Ther., 2009, 30, 423-435; Bueno et al.,
Neurogastroenterol Motility (2007) 19 (suppl.1), 89-119). Colonic
and rectal distention have been widely used as a tool to assess
visceral sensitivity in animal and human studies. The type of
stress used to induce visceral sensitivity varies upon the models
(see for instance Eutamen, H Neurogastroenterol Motil. 2009 Aug.
25. [Epub ahead of print]), however stress such as Partial
restraint stress (PRS) is a relatively mild, non-ulcerogenic model
that is considered more representative of the IBS setting.
[0020] Constipation is commonly found in the geriatric population,
particularly patients with osteoporosis who have to take calcium
supplements. Calcium supplements have shown to be beneficial in
ostoporotic patients to restore bone density but compliance is poor
because of calcium-induced constipation effects.
[0021] Opioid-induced constipation (OIC) (also referred to as
opioid-induced bowel dysfunction or opioid bowel dysfuntion (OBD))
is a common adverse effect associated with opioid therapy. OIC is
commonly described as constipation; however, it is a constellation
of adverse gastrointestinal (GI) effects, which also includes
abdominal cramping, bloating, and gastroesophageal reflux. Patients
with cancer may have disease-related constipation, which is usually
worsened by opioid therapy. However, OIC is not limited to cancer
patients. A recent survey of patients taking opioid therapy for
pain of non-cancer origin found that approximately 40% of patients
experienced constipation related to opioid therapy (<3 complete
bowel movements per week) compared with 7.6% in a control group. Of
subjects who required laxative therapy, only 46% of opioid-treated
patients (control subjects, 84%) reported achieving the desired
treatment results >50% of the time (Pappagallo, 2001, Am. J.
Surg. 182(5A Suppl.):11S-18S).
[0022] Some patients suffering from chronic idiopathic constipation
can be successfully treated with lifestyle modification, dietary
changes and increased fluid and fiber intake, and these treatments
are generally tried first. For patients who fail to respond to
these approaches, physicians typically recommend laxatives, most of
which are available over-the-counter. Use of laxatives provided
over-the-counter is judged inefficient by about half of the
patients (Johanson and Kralstein, 2007, Aliment. Pharmacol. Ther.
25(5):599-608). Other therapeutic options currently prescribed or
in clinical development for the treatment of IBS and chronic
constipation including OIC are described in, for example: Chang et
al., 2006, Curr. Teat. Options Gastroenterol. 9(4):314-323; Gershon
and Tack, 2007, Gastroenterology 132(1):397-414; and, Hammerle and
Surawicz, 2008, World J. Gastroenterol. 14(17):2639-2649. Such
treatments include but are not limited to serotonin receptor
ligands, chloride channel activators, opioid receptor antagonists,
guanylate-cyclase receptor agonists and nucleotide P2Y(2) receptor
agonists. Many of these treatment options are inadequate, as they
may be habit forming, ineffective in some patients, may cause long
term adverse effects, or otherwise are less than optimal.
[0023] Na.sup.+/H.sup.+ Exchanger (NHE) Inhibitors
[0024] A major function of the GI tract is to maintain water/Na
homeostasis by absorbing virtually all water and Na to which the GI
tract is exposed. The epithelial layer covering the apical surface
of the mammalian colon is a typical electrolyte-transporting
epithelium, which is able to move large quantities of salt and
water in both directions across the mucosa. For example, each day
the GI tract processes about 9 liters of fluid and about 800 meq of
Na. (See, e.g., Zachos et al., Molecular physiology of intestinal
Na.sup.+/H.sup.+ exchange; Annu. Rev. Physiol., v. 67, p. 411-443
(2005).) Only about 1.5 liters of this fluid and about 150 meq of
this sodium originates from ingestion; rather, the majority of the
fluid (e.g., about 7.5 liters) and sodium (about 650 meq) is
secreted via the GI organs as part of digestion. The GI tract
therefore represents a viable target for modulating systemic sodium
and fluid levels.
[0025] Many reviews have been published on the physiology and
secretory and/or absorption mechanisms of the GI tract (see, e.g.,
Kunzelmann et al., Electrolyte transport in the mammalian colon:
mechanisms and implications for disease; Physiol. Rev., v. 82, no.
1, p. 245-289 (2002); Geibel, J. P.; Secretion and absorption by
colonic crypts; Annu. Rev. Physiol, v. 67, p. 471-490 (2005);
Zachos et al., supra; Kiela, P. R. et al., Apical NA.sup.+/H.sup.+
exchangers in the mammalian gastrointestinal tract; J. Physiol.
Pharmacol., v. 57 Suppl. 7, p. 51-79 (2006)). The two main
mechanisms of Na absorption are electroneutral and electrogenic
transport. Electroneutral transport is essentially due to the
Na.sup.+/H.sup.+ antiport NHE (e.g., NHE-3) and is responsible for
the bulk of Na absorption. Electrogenic transport is provided by
the epithelium sodium channel ("ENaC"). Electroneutral transport is
located primarily in the ileal segment and proximal colon and
electrogenic transport is located in the distal colon.
[0026] Plasma membrane NHEs contribute to maintenance of
intracellular pH and volume, transcellular absorption of NaCl and
NaHCO.sub.3, and fluid balance carried out by epithelial cells,
especially in the kidney, intestine, gallbladder, and salivary
glands, as well as regulation of systemic pH. There exists a body
of literature devoted to the role and clinical intervention on
systemic NHEs to treat disorders related to ischemia and
reperfusion for cardioprotection or renal protection. Nine isoforms
of NHEs have been identified (Kiela, P. R., et al.; Apical
NA.sup.+/H.sup.+ exchangers in the mammalian gastrointestinal
tract; J. Physiol. Pharmacol., v. 57 Suppl 7, p. 51-79 (2006)), of
which NHE-2, NHE-3 and NHE-8 are expressed on the apical side of
the GI tract, with NHE-3 providing a larger contribution to
transport. Another, yet to be identified, Cl-dependant NHE has been
identified in the crypt of rat cells. In addition, much research
has been devoted to identifying inhibitors of NHEs. The primary
targets of such research have been NHE-1 and NHE-3. Small molecule
NHE inhibitors are, for example, described in: U.S. Pat. Nos.
5,866,610; 6,399,824; 6,911,453; 6,703,405; 6,005,010; 6,736,705;
6,887,870; 6,737,423; 7,326,705; 5,824,691 (WO 94/026709);
6,399,824 (WO 02/024637); U.S. Pat. Pub. Nos. 2004/0039001 (WO
02/020496); 2005/0020612 (WO 03/055490); 2004/0113396 (WO
03/051866); 2005/0020612; 2005/0054705; 2008/0194621; 2007/0225323;
2004/0039001; 2004/0224965; 2005/0113396; 2007/0135383;
2007/0135385; 2005/0244367; 2007/0270414; International Publication
Nos. WO 01/072742; WO 01/021582 (CA2387529); WO 97/024113
(CA02241531) and European Pat. No. EP0744397 (CA2177007); all of
which are incorporated herein by reference in their entirety for
all relevant and consistent purposes.
[0027] However, such research failed to develop or recognize the
value or importance of NHE inhibitors that are not absorbed (i.e.,
not systemic) and target the gastrointestinal tract, as disclosed
recently in WO 2010/078449. Such inhibitors can be utilized in the
treatment of disorders associated with fluid retention and salt
overload and in the treatment of GI tract disorders, including the
treatment or reduction of pain associated with a gastrointestinal
tract disorder. Such inhibitors are particular advantageous because
they can be delivered with reduced fear of systemic on-target or
off-target effects (e.g., little or no risk of renal involvement or
other systemic effects.
[0028] Accordingly, while progress has been made in the foregoing
fields, there remains a need in the art for novel compounds for use
in the disorders associated with fluid retention and salt overload
and in the treatment of gastrointestinal tract disorders, including
the treatment or reduction of pain associated with a
gastrointestinal tract disorder. The present invention fulfills
this need and provides further related advantages.
SUMMARY OF THE INVENTION
[0029] In brief, the present invention is directed to compounds
that are substantially active in the gastrointestinal tract to
inhibit NHE-mediated antiport of sodium ions and hydrogen ions, and
the use of such compounds in the treatment of disorders associated
with fluid retention and salt overload and in the treatment of
gastrointestinal tract disorders, including the treatment or
reduction of pain associated with a gastrointestinal tract
disorder.
[0030] A compound of formula I:
##STR00001##
or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,
isomer, or tautomer thereof, wherein:
[0031] Linker is
--R.sup.13--(CHR.sup.13).sub.p--[Y--(CH.sub.2).sub.r].sub.s--Z--R.sup.13--
-(CH.sub.2).sub.t--Z--;
[0032] X is a bond, H, N, O, CR.sup.11R.sup.12, CR.sup.11, C,
--NHC(O)NH--, --(CHR.sup.13).sub.p-- or
C.sub.3-C.sub.6cyclolakyl;
[0033] W is independently, at each occurrence, S(O).sub.2, C(O), or
--(CH.sub.2).sub.m--;
[0034] Z is independently, at each occurrence, a bond, C(O), or
--C(O)NH--;
[0035] Y is independently, at each occurrence, O, S, NH,
N(C.sub.1-C.sub.3alkyl), or --C(O)NH--;
[0036] Q is a bond, NH, --C(O)NH--, --NHC(O)NH--,
--NHC(O)N(CH.sub.3)--, or --NHC(O)NH--(CHR.sup.13);
[0037] m is an integer from 1 to 2;
[0038] n is an integer from 1 to 4;
[0039] r and p are independently, at each occurrence, integers from
0 to 8;
[0040] s is an integer from 0 to 4;
[0041] t is an integer from 0 to 4;
[0042] u is an integer from 0 to 2;
[0043] R.sup.1 and R.sup.2 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more halogen, OH, CN, --NO.sub.2, oxo,
--SR.sup.9, --OR.sup.9, --NHR.sup.9, --NR.sup.9R.sup.10,
--S(O).sub.2N(R.sup.9).sub.2--, --S(O).sub.2R.sup.9, --C(O)R.sup.9,
--C(O)OR.sup.9, --C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.9,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl; or
[0044] R.sup.1 and R.sup.2 together with the nitrogen to which they
are attached can form a heterocyclyl or heteroaryl containing 1-5
heteroatoms selected from the group consisting of N, S, P and O,
wherein the heterocyclyl or heteroaryl group is optionally
substituted with one or more halogen, OH, CN, --NO.sub.2, oxo,
--SR.sup.9, --OR.sup.9, --NHR.sup.9, --NR.sup.9R.sup.10,
--S(O).sub.2N(R.sup.9).sub.2--, --S(O).sub.2R.sup.9, --C(O)R.sup.9,
--C(O)OR.sup.9, --C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.10,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl;
[0045] R.sup.3 and R.sup.4 are independently halogen, OH, CN,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, or
--C(O)NR.sup.9R.sup.10;
[0046] R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently H,
halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.8S(O)R.sup.9;
[0047] R.sup.9 and R.sup.10 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O
[0048] R.sup.11 and R.sup.12 are independently H,
C.sub.1-C.sub.6alkyl, OH, NH.sub.2, CN, or NO.sub.2;
[0049] R.sup.13 is independently, at each occurrence, a bond, H,
C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl,
wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted with one or more R.sup.9;
[0050] R.sup.14 is independently, at each occurrence, H,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6haloalkyl; or
[0051] R.sup.6 and R.sup.14 together with the atoms to which they
are attached may combine to form, independently, at each
occurrence, 5-to-6 membered heterocyclyl, wherein each
C.sub.3-C.sub.8 cycloalkyl, or heterocyclyl is optionally
substituted with one or more R.sup.19; or
[0052] R.sup.13 and R.sup.14 together with the atoms to which they
are attached may combine to form independently, at each occurrence,
C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, wherein each heterocyclyl or heteroaryl is optionally
substituted with one or more R.sup.19;
[0053] R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are
independently, at each occurrence, H, OH, NH.sub.2, or
C.sub.1-C.sub.3 alkyl, wherein the alkyl is optionally substituted
with one or more R.sup.19; and
[0054] R.sup.19 are independently, at each occurrence, H, OH,
NH.sub.2, oxo, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6Hhaloalkyl,
C.sub.1-C.sub.6alkoxy;
provided that: (1) when X is H, n is 1; (2) when X is a bond, O, or
CR.sup.11R.sup.12, n is 2; (3) when n is 3, X is CR.sup.11 or N;
(4) when n is 4 X is C; (5) only one of Q or X is --NHC(O)NH-- at
the time, (6) R.sup.1 and R.sup.2 together with the nitrogen to
which they are attached, cannot form a pyrrolidinyl; (7) when
R.sup.1 and R.sup.2 are methyl, R.sup.3 and R.sup.4 are halogen,
and R.sup.5 and R.sup.8 are H, Linker is not
##STR00002##
(8) when R.sup.1 and R.sup.2 together with the nitrogen to which
they are attached form a piperidinyl, R.sup.3 and R.sup.4 are
halogen, and R.sup.5 and R.sup.8 are H, Linker is not
##STR00003##
and (9) when R.sup.1 and R.sup.2, together with the nitrogen to
which they are attached, form 3-aminopiperidin-1-yl, R.sup.3 and
R.sup.4 are halogen, and R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
H, Linker is not
##STR00004##
[0055] In another aspect pharmaceutical compositions are provided
comprising a compound as set forth above, or a stereoisomer,
pharmaceutically acceptable salt or prodrug thereof, and a
pharmaceutically acceptable carrier, diluent or excipient. The
pharmaceutical composition can be effective for treating a disease
or disorder associated with fluid retention or salt overload. The
pharmaceutical compositions can comprise the compounds of the
present invention for use in treating diseases described herein.
The compositions can contain at least one compound of the invention
and a pharmaceutically acceptable carrier.
[0056] Another aspect of the invention relates a method for
inhibiting NHE-mediated antiport of sodium and hydrogen ions. The
method comprises administering to a mammal in need thereof a
pharmaceutically effective amount of a compound or pharmaceutical
composition described herein.
[0057] In another aspect, a method for treating a disorder
associated with fluid retention or salt overload is provided. The
method comprises administering to a mammal in need thereof a
pharmaceutically effective amount of a compound or pharmaceutical
composition as set forth above.
[0058] The present invention further provides compounds that can
inhibit NHE-mediated antiport of sodium and hydrogen ions. The
efficacy-safety profile of the compounds of the current invention
can be improved relative to other known NHE-3 inhibitors.
Additionally, the present technology also has the advantage of
being able to be used for a number of different types of diseases,
including, but not limited to, heart failure (such as congestive
heart failure), chronic kidney disease, end-stage renal disease,
hypertension, essential hypertension, primary hypertension,
salt-sensitive hypertension, liver disease, and peroxisome
proliferator-activated receptor (PPAR) gamma agonist-induced fluid
retention is provided, gastrointestinal motility disorder,
irritable bowel syndrome, chronic constipation, chronic idiopathic
constipation, chronic constipation occurring in cystic fibrosis
patients, chronic constipation occurring in chronic kidney disease
patients, calcium-induced constipation in osteoporotic patients,
opioid-induced constipation, a functional gastrointestinal tract
disorder, Parkinson's disease, multiple sclerosis, gastroesophageal
reflux disease, functional heartburn, dyspepsia, functional
dyspepsia, non-ulcer dyspepsia, gastroparesis, chronic intestinal
pseudo-obstruction, Crohn's disease, ulcerative colitis and related
diseases referred to as inflammatory bowel syndrome, colonic
pseudo-obstruction, gastric ulcers, infectious diarrhea, cancer
(colorectal), "leaky gut syndrome", cystic fibrosis
gastrointestinal disease, multi-organ failure, microscopic colitis,
necrotizing enterocolitis, allergy--atopy, food allergy, infections
(respiratory), acute inflammation (e.g., sepsis, systemic
inflammatory response syndrome), chronic inflammation (arthritis),
obesity-induced metabolic diseases (e.g., nonalcoholic
steatohepatitis, Type I diabetes, Type II diabetes, cardiovascular
disease), kidney disease, diabetic kidney disease, cirrhosis,
nonalcoholic steatohepatitis, nonalcoholic fatty acid liver
disease, Steatosis, primary sclerosing cholangitis, primary biliary
cholangitis, portal hypertension, autoimmune disease (e.g., Type I
diabetes, Celiac's Secondary PTH, ankylosing spondylitis, lupus,
alopecia areata, rheumatoid arthritis, polymyalgia rheumatica,
fibromyalgia, chronic fatigue syndrome, Sjogren's syndrome,
vitiligo, thyroiditis, vasculitis, urticarial (hives), Raynaud's
syndrome), Schizophrenia, autism spectrum disorders, hepatic
encephlopathy, small intestitinal bacterial overgrowth, and chronic
alcoholism, secondary hyperparathyroidism (PTH), celiac disease,
hyperphosphatemia and the like. Additional features and advantages
of the present technology will be apparent to one of skill in the
art upon reading the Detailed Description of the Invention,
below.
BRIEF DESCRIPTION OF THE DRAWINGS
[0059] FIGS. 1A-1D: Depicts NHE3-independent changes in
intracellular pH (pHi) modulate trans-epithelial electrical
resistance in intestinal ileum monolayer cultures. Changes in pHi
and trans-epithelial electrical resistance (TEER) with (FIG. 1A,
FIG. 1B) nigericin and (FIG. 1C, FIG. 1D) BAM 15 (3 .mu.M) and FCCP
(3 .mu.M) compared with the known NHE3 inhibitor tenapanor and
vehicle (DMSO) control in monolayer cultures. *P<0.05,
**P<0.01, ***P<0.001, ****P<0.0001 vs DMSO.
[0060] FIG. 2: Depicts dose-dependent reduction in urinary albumin
excretion.
DETAILED DESCRIPTION OF THE INVENTION
[0061] A first aspect of the present invention relates to compounds
of Formula
##STR00005##
pharmaceutically acceptable salt, prodrug, solvate, hydrate,
isomer, or tautomer thereof, wherein: R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.15, R.sup.16,
R.sup.17, R.sup.18, n, u, X, and Linker are described as
herein.
[0062] The details of the invention are set forth in the
accompanying description below. Although methods and materials
similar or equivalent to those described herein can be used in the
practice or testing of the present invention, illustrative methods
and materials are now described. Other features, objects, and
advantages of the invention will be apparent from the description
and from the claims. In the specification and the appended claims,
the singular forms also include the plural unless the context
clearly dictates otherwise. Unless defined otherwise, all technical
and scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which this
invention belongs. All patents and publications cited in this
specification are incorporated herein by reference in their
entireties.
Definitions
[0063] Unless the context requires otherwise, throughout the
present specification and claims, the word "comprise" and
variations thereof, such as, "comprises" and "comprising" are to be
construed in an open, inclusive sense, that is as "including, but
not limited to".
[0064] The articles "a" and "an" are used in this disclosure to
refer to one or more than one (i.e., to at least one) of the
grammatical object of the article. By way of example, "an element"
means one element or more than one element.
[0065] The term "and/or" is used in this disclosure to mean either
"and" or "or" unless indicated otherwise.
[0066] Reference throughout this specification to "one embodiment"
or "an embodiment" means that a particular feature, structure or
characteristic described in connection with the embodiment is
included in at least one embodiment of the present invention. Thus,
the appearances of the phrases "in one embodiment" or "in an
embodiment" in various places throughout this specification are not
necessarily all referring to the same embodiment. Furthermore, the
particular features, structures, or characteristics may be combined
in any suitable manner in one or more embodiments.
[0067] "Amino" refers to the --NH.sub.2 radical.
[0068] "Cyano" refers to the --CN radical.
[0069] "Hydroxy" or "hydroxyl" refers to the --OH radical.
[0070] "Imino" refers to the .dbd.NH substituent.
[0071] "Nitro" refers to the --NO.sub.2 radical.
[0072] "Oxo" refers to the .dbd.O substituent.
[0073] "Thioxo" refers to the .dbd.S substituent.
[0074] The term "substituted" used herein means any of the above
groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl,
aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,
N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/or
heteroarylalkyl) wherein at least one hydrogen atom is replaced by
a bond to a non-hydrogen atoms such as, but not limited to: a
halogen atom such as F, Cl, Br, and I; an oxygen atom in groups
such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur
atom in groups such as thiol groups, thioalkyl groups, sulfone
groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in
groups such as amines, amides, alkylamines, dialkylamines,
arylamines, alkylarylamines, diarylamines, N-oxides, imides, and
enamines; a silicon atom in groups such as trialkylsilyl groups,
dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl
groups; and other heteroatoms in various other groups.
"Substituted" also means any of the above groups in which one or
more hydrogen atoms are replaced by a higher-order bond (e.g., a
double- or triple-bond) to a heteroatom such as oxygen in oxo,
carbonyl, carboxyl, and ester groups; and nitrogen in groups such
as imines, oximes, hydrazones, and nitriles. For example,
"substituted" includes any of the above groups in which one or more
hydrogen atoms are replaced with --NR.sub.gR.sub.h,
--NR.sub.gC(.dbd.O)R.sub.h, --NR.sub.gC(.dbd.O)NR.sub.gR.sub.h,
--NR.sub.gC(.dbd.O)OR.sub.h, --NR.sub.gSO.sub.2R.sub.h,
--OC(.dbd.O)NR.sub.gR.sub.h, --OR.sub.g, --SR.sub.g, --SOR.sub.g,
--SO.sub.2R.sub.g, --OSO.sub.2R.sub.g, --SO.sub.2OR.sub.g,
.dbd.NSO2R.sub.g, and --SO.sub.2NR.sub.gR.sub.h. "Substituted" also
means any of the above groups in which one or more hydrogen atoms
are replaced with --C(.dbd.O)R.sub.g, --C(.dbd.O)OR.sub.g,
--C(.dbd.O)NR.sub.gR.sub.h, --CH.sub.2SO.sub.2R.sub.g,
--CH.sub.2SO.sub.2NR.sub.gR.sub.h,
--(CH.sub.2CH.sub.2O).sub.2-10R.sub.g. In the foregoing, R.sub.g
and R.sub.h are the same or different and independently hydrogen,
alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl,
cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,
heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.
"Substituted" further means any of the above groups in which one or
more hydrogen atoms are replaced by a bond to an amino, cyano,
hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy,
alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl,
haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,
heteroaryl, N-heteroaryl and/or heteroarylalkyl group. In addition,
each of the foregoing substituents may also be optionally
substituted with one or more of the above substituents.
[0075] The term "optionally substituted" is understood to mean that
a given chemical moiety (e.g. an alkyl group) can (but is not
required to) be bonded other substituents (e.g. heteroatoms). For
instance, an alkyl group that is optionally substituted can be a
fully saturated alkyl chain (i.e. a pure hydrocarbon).
Alternatively, the same optionally substituted alkyl group can have
substituents different from hydrogen. For instance, it can, at any
point along the chain be bonded to a halogen atom, a hydroxyl
group, or any other substituent described herein. Thus the term
"optionally substituted" means that a given chemical moiety has the
potential to contain other functional groups, but does not
necessarily have any further functional groups.
[0076] "Alkyl" refers to a straight or branched hydrocarbon chain
radical consisting solely of carbon and hydrogen atoms, which is
saturated or unsaturated (i.e., contains one or more double and/or
triple bonds), having from one to twelve carbon atoms
(C.sub.1-C.sub.12 alkyl), one to eight carbon atoms
(C.sub.1-C.sub.8 alkyl) or one to six carbon atoms (C.sub.1-C.sub.6
alkyl), and which is attached to the rest of the molecule by a
single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl
(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),
3-methylhexyl, 2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl,
pent-1-enyl, penta-1,4-dienyl, ethynyl, propynyl, butynyl,
pentynyl, hexynyl, and the like. Unless stated otherwise
specifically in the specification, an alkyl group may be optionally
substituted.
[0077] "Alkoxy" refers to a radical of the formula --OR.sub.a where
R.sub.a is an alkyl radical as defined above containing one to
twelve carbon atoms. Unless stated otherwise specifically in the
specification, an alkoxy group may be optionally substituted.
[0078] "Alkenyl" refers to a straight or branched chain unsaturated
hydrocarbon containing 2-12 carbon atoms. The "alkenyl" group
contains at least one double bond in the chain. The double bond of
an alkenyl group can be unconjugated or conjugated to another
unsaturated group. Examples of alkenyl groups include ethenyl,
propenyl, n-butenyl, iso-butenyl, pentenyl, or hexenyl. An alkenyl
group can be unsubstituted or substituted. Alkenyl, as herein
defined, may be straight or branched.
[0079] "Alkynyl" refers to a straight or branched chain unsaturated
hydrocarbon containing 2-12 carbon atoms. The "alkynyl" group
contains at least one triple bond in the chain. Examples of alkenyl
groups include ethynyl, propanyl, n-butynyl, iso-butynyl, pentynyl,
or hexynyl. An alkynyl group can be unsubstituted or
substituted.
[0080] The term "cycloalkyl" means monocyclic or polycyclic
saturated carbon rings containing 3-18 carbon atoms. Examples of
cycloalkyl groups include, without limitations, cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl,
norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or
bicyclo[2.2.2]octenyl. A C.sub.3-C.sub.8 cycloalkyl is a cycloalkyl
group containing between 3 and 8 carbon atoms. A cycloalkyl group
can be fused (e.g., decalin) or bridged (e.g., norbornane).
[0081] The term "cycloalkenyl" means monocyclic, non-aromatic
unsaturated carbon rings containing 4-18 carbon atoms. Examples of
cycloalkenyl groups include, without limitation, cyclopentenyl,
cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. A
C.sub.4-C.sub.8 cycloalkenyl is a cycloalkenyl group containing
between 4 and 8 carbon atoms.
[0082] The terms "heterocyclyl" or "heterocycloalkyl" or
"heterocycle" refer to monocyclic or polycyclic 3 to 24-membered
rings containing carbon and heteroatoms taken from oxygen,
phosphorous, nitrogen, or sulfur and wherein there is not
delocalized n electrons (aromaticity) shared among the ring carbon
or heteroatoms. Heterocyclyl rings include, but are not limited to,
oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,
oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,
tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,
thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl
S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl,
and homotropanyl. A heteroycyclyl or heterocycloalkyl ring can also
be fused or bridged, e.g., can be a bicyclic ring.
[0083] As used herein, the term "halo" or "halogen" means a fluoro,
chloro, bromo, or iodo group.
[0084] The term "carbonyl" refers to a functional group composing a
carbon atom double-bonded to an oxygen atom. It can be abbreviated
herein as "oxo", as C(O), or as C.dbd.O.
[0085] The term "aryl" refers to cyclic, aromatic hydrocarbon
groups that have 1 to 2 aromatic rings, including monocyclic or
bicyclic groups such as phenyl, biphenyl or naphthyl. Where
containing two aromatic rings (bicyclic, etc.), the aromatic rings
of the aryl group may be joined at a single point (e.g., biphenyl),
or fused (e.g., naphthyl). The aryl group may be optionally
substituted by one or more substituents, e.g., 1 to 5 substituents,
at any point of attachment. Exemplary substituents include, but are
not limited to, --H, -halogen, --O--C.sub.1-C.sub.6alkyl,
--C.sub.1-C.sub.6alkyl, --OC.sub.2-C.sub.6alkenyl,
--OC.sub.2-C.sub.6alkynyl, --C.sub.2-C.sub.6alkenyl,
--C.sub.2-C.sub.6alkynyl, --OH, --OP(O)(OH).sub.2,
--OC(O)C.sub.1-C.sub.6alkyl, --C(O)C.sub.1-C.sub.6alkyl,
--OC(O)OC.sub.1-C.sub.6alkyl, --NH.sub.2,
--NH(C.sub.1-C.sub.6alkyl), --N(C.sub.1-C.sub.6alkyl).sub.2,
--S(O).sub.2--C.sub.1-C.sub.6alkyl, --S(O)NHC.sub.1-C.sub.6alkyl,
and --S(O)N(C.sub.1-C.sub.6alkyl).sub.2. The substituents can
themselves be optionally substituted. Furthermore when containing
two fused rings the aryl groups herein defined may have an
unsaturated or partially saturated ring fused with a fully
saturated ring. Exemplary ring systems of these aryl groups include
indanyl, indenyl, tetrahydronaphthalenyl, and
tetrahydrobenzoannulenyl.
[0086] Unless otherwise specifically defined, "heteroaryl" means a
monovalent monocyclic aromatic radical or a polycyclic aromatic
radical of 5 to 24 ring atoms, containing one or more ring
heteroatoms selected from N, S, P, and O, the remaining ring atoms
being C. Heteroaryl as herein defined also means a bicyclic
heteroaromatic group wherein the heteroatom is selected from N, S,
P, and O. The aromatic radical is optionally substituted
independently with one or more substituents described herein.
Examples include, but are not limited to, furyl, thienyl, pyrrolyl,
pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl,
oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl,
benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,
benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,
imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl,
imidazo[1,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl,
pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl,
thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl,
thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl,
indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,
benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,
dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,
1,6-naphthyridinyl, benzo[de]isoquinolinyl,
pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl,
quinazolinyl, tetrazolo[1,5-a]pyridinyl,
[1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,
pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,
pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,
pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,
3,4-dihydro-2H-.sup.2-pyrrolo[2,1-b]pyrimidine,
dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2-c]pyridinyl,
furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4]thiazinyl,
benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl,
benzothiophenyl, 1,5-naphthyridinyl, furo[3,2-b]pyridine,
[1,2,4]triazolo[1,5-a]pyridinyl, benzo [1,2,3]triazolyl,
imidazol[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,
benzo[c][1,2,5]thiadiazolyl, benzo[cl][1,2,5]oxadiazole,
1,3-dihydro-2H-benzo[d]imidazol-2-one,
3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,
4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,
thiazolo[5,4-d]thiazolyl, imidazo[2,1-b][1,3,4]thiadiazolyl,
thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof.
Furthermore when containing two fused rings the heteroaryl groups
herein defined may have an unsaturated or partially saturated ring
fused with a fully saturated ring. Exemplary ring systems of these
heteroaryl groups include indolinyl, indolinonyl,
dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl,
thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine,
3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl,
indolyl, and dihydrobenzoxanyl.
[0087] "Prodrug" is meant to indicate a compound that may be
converted under physiological conditions or by solvolysis to a
biologically active compound of the invention. Thus, the term
"prodrug" refers to a metabolic precursor of a compound of the
invention that is pharmaceutically acceptable. A prodrug may be
inactive when administered to a subject in need thereof, but is
converted in vivo to an active compound of the invention. Prodrugs
are typically rapidly transformed in vivo to yield the parent
compound of the invention, for example, by hydrolysis in blood. The
prodrug compound often offers advantages of solubility, tissue
compatibility or delayed release in a mammalian organism (see,
Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier,
Amsterdam)). A discussion of prodrugs is provided in Higuchi, T.,
et al., A.C.S. Symposium Series, Vol. 14, and in Bioreversible
Carriers in Drug Design, Ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987.
[0088] The term "prodrug" is also meant to include any covalently
bonded carriers, which release the active compound of the invention
in vivo when such prodrug is administered to a mammalian subject.
Prodrugs of a compound of the invention may be prepared by
modifying functional groups present in the compound of the
invention in such a way that the modifications are cleaved, either
in routine manipulation or in vivo, to the parent compound of the
invention. Prodrugs include compounds of the invention wherein a
hydroxy, amino or mercapto group is bonded to any group that, when
the prodrug of the compound of the invention is administered to a
mammalian subject, cleaves to form a free hydroxy, free amino or
free mercapto group, respectively. Examples of prodrugs include,
but are not limited to, acetate, formate and benzoate derivatives
of alcohol or amide derivatives of amine functional groups in the
compounds of the invention and the like.
[0089] The invention disclosed herein is also meant to encompass
the in vivo metabolic products of the disclosed compounds. Such
products may result from, for example, the oxidation, reduction,
hydrolysis, amidation, esterification, and the like of the
administered compound, primarily due to enzymatic processes.
Accordingly, the invention includes compounds produced by a process
comprising administering a compound of this invention to a mammal
for a period of time sufficient to yield a metabolic product
thereof. Such products are typically identified by administering a
radiolabelled compound of the invention in a detectable dose to an
animal, such as rat, mouse, guinea pig, monkey, or to human,
allowing sufficient time for metabolism to occur, and isolating its
conversion products from the urine, blood or other biological
samples.
[0090] "Stable compound" and "stable structure" are meant to
indicate a compound that is sufficiently robust to survive
isolation to a useful degree of purity from a reaction mixture, and
formulation into an efficacious therapeutic agent.
[0091] "Pharmaceutically acceptable carrier, diluent or excipient"
includes without limitation any adjuvant, carrier, excipient,
glidant, sweetening agent, diluent, preservative, dye/colorant,
flavor enhancer, surfactant, wetting agent, dispersing agent,
suspending agent, stabilizer, isotonic agent, solvent, or
emulsifier which has been approved by the United States Food and
Drug Administration as being acceptable for use in humans or
domestic animals.
[0092] "Pharmaceutically acceptable salt" includes both acid and
base addition salts.
[0093] "Pharmaceutically acceptable acid addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free bases, which are not biologically or
otherwise undesirable, and which are formed with inorganic acids
such as, but are not limited to, hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, and
organic acids such as, but not limited to, acetic acid,
2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid,
aspartic acid, benzenesulfonic acid, benzoic acid,
4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,
capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic
acid, citric acid, cyclamic acid, dodecylsulfuric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid,
2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric
acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic
acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric
acid, lactic acid, lactobionic acid, lauric acid, maleic acid,
malic acid, malonic acid, mandelic acid, methanesulfonic acid,
mucic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic
acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid,
orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic
acid, pyroglutamic acid, pyruvic acid, salicylic acid,
4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,
tartaric acid, thiocyanic acid, p-toluenesulfonic acid,
trifluoroacetic acid, undecylenic acid, and the like.
[0094] "Pharmaceutically acceptable base addition salt" refers to
those salts which retain the biological effectiveness and
properties of the free acids, which are not biologically or
otherwise undesirable. These salts are prepared from addition of an
inorganic base or an organic base to the free acid. Salts derived
from inorganic bases include, but are not limited to, the sodium,
potassium, lithium, ammonium, calcium, magnesium, iron, zinc,
copper, manganese, aluminum salts and the like. Preferred inorganic
salts are the ammonium, sodium, potassium, calcium, and magnesium
salts. Salts derived from organic bases include, but are not
limited to, salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines and basic ion exchange resins, such as
ammonia, isopropylamine, trimethylamine, diethylamine,
triethylamine, tripropylamine, diethanolamine, ethanolamine,
deanol, 2 dimethylaminoethanol, 2 diethylaminoethanol,
dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,
hydrabamine, choline, betaine, benethamine, benzathine,
ethylenediamine, glucosamine, methylglucamine, theobromine,
triethanolamine, tromethamine, purines, piperazine, piperidine, N
ethylpiperidine, polyamine resins and the like. Particularly
preferred organic bases are isopropylamine, diethylamine,
ethanolamine, trimethylamine, dicyclohexylamine, choline and
caffeine.
[0095] Often crystallizations produce a solvate of the compound of
the invention. As used herein, the term "solvate" refers to an
aggregate that comprises one or more molecules of a compound of the
invention with one or more molecules of solvent. The solvent may be
water, in which case the solvate may be a hydrate. Alternatively,
the solvent may be an organic solvent. Thus, the compounds of the
present invention may exist as a hydrate, including a monohydrate,
dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and
the like, as well as the corresponding solvated forms. The compound
of the invention may be true solvates, while in other cases, the
compound of the invention may merely retain adventitious water or
be a mixture of water plus some adventitious solvent.
[0096] A "pharmaceutical composition" refers to a formulation of a
compound of the invention and a medium generally accepted in the
art for the delivery of the biologically active compound to
mammals, e.g., humans. Such a medium includes all pharmaceutically
acceptable carriers, diluents or excipients therefor.
[0097] The compounds of the invention, or their pharmaceutically
acceptable salts may contain one or more asymmetric centers and may
thus give rise to enantiomers, diastereomers, and other
stereoisomeric forms that may be defined, in terms of absolute
stereochemistry, as (R) or (S) or, as (D) or (L) for amino acids.
The present invention is meant to include all such possible
isomers, as well as their racemic and optically pure forms.
Optically active (+) and (-), (R) and (S), or (D) and (L) isomers
may be prepared using chiral synthons or chiral reagents, or
resolved using conventional techniques, for example, chromatography
and fractional crystallization. Conventional techniques for the
preparation/isolation of individual enantiomers include chiral
synthesis from a suitable optically pure precursor or resolution of
the racemate (or the racemate of a salt or derivative) using, for
example, chiral high pressure liquid chromatography (HPLC). When
the compounds described herein contain olefinic double bonds or
other centres of geometric asymmetry, and unless specified
otherwise, it is intended that the compounds include both E and Z
geometric isomers. Likewise, all tautomeric forms are also intended
to be included.
[0098] A "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable. The
present invention contemplates various stereoisomers and mixtures
thereof and includes "enantiomers", which refers to two
stereoisomers whose molecules are nonsuperimposeable mirror images
of one another.
[0099] A "tautomer" refers to a proton shift from one atom of a
molecule to another atom of the same molecule. The present
invention includes tautomers of any said compounds.
[0100] In accordance with the present disclosure, the compounds
described herein are designed to be substantially active or
localized in the gastrointestinal lumen of a human or animal
subject. The term "gastrointestinal lumen" is used interchangeably
herein with the term "lumen," to refer to the space or cavity
within a gastrointestinal tract (GI tract, which can also be
referred to as the gut), delimited by the apical membrane of GI
epithelial cells of the subject. In some embodiments, the compounds
are not absorbed through the layer of epithelial cells of the GI
tract (also known as the GI epithelium). "Gastrointestinal mucosa"
refers to the layer(s) of cells separating the gastrointestinal
lumen from the rest of the body and includes gastric and intestinal
mucosa, such as the mucosa of the small intestine. A
"gastrointestinal epithelial cell" or a "gut epithelial cell" as
used herein refers to any epithelial cell on the surface of the
gastrointestinal mucosa that faces the lumen of the
gastrointestinal tract, including, for example, an epithelial cell
of the stomach, an intestinal epithelial cell, a colonic epithelial
cell, and the like.
[0101] A "subject" is a human, but can also be an animal in need of
treatment with a compound of the disclosure, e.g., companion
animals (e.g., dogs, cats, and the like), farm animals (e.g., cows,
pigs, horses and the like) and laboratory animals (e.g., rats,
mice, guinea pigs and the like).
[0102] "Substantially systemically non-bioavailable" and/or
"substantially impermeable" as used herein (as well as variations
thereof) generally refer to situations in which a statistically
significant amount, and in some embodiments essentially all of the
compound of the present disclosure (which includes the
NHE-inhibitor small molecule), remains in the gastrointestinal
lumen. For example, in accordance with one or more embodiments of
the present disclosure, at least about 70%, about 80%, about 90%,
about 95%, about 98%, about 99%, or even about 99.5%, of the
compound remains in the gastrointestinal lumen. In such cases,
localization to the gastrointestinal lumen refers to reducing net
movement across a gastrointestinal layer of epithelial cells, for
example, by way of both transcellular and paracellular transport,
as well as by active and/or passive transport. The compound in such
embodiments is hindered from net permeation of a layer of
gastrointestinal epithelial cells in transcellular transport, for
example, through an apical membrane of an epithelial cell of the
small intestine. The compound in these embodiments is also hindered
from net permeation through the "tight junctions" in paracellular
transport between gastrointestinal epithelial cells lining the
lumen.
[0103] In this regard it is to be noted that, in one particular
embodiment, the compound is essentially not absorbed at all by the
GI tract or gastrointestinal lumen. As used herein, the terms
"substantially impermeable" or "substantially systemically
non-bioavailable" refers to embodiments wherein no detectable
amount of absorption or permeation or systemic exposure of the
compound is detected, using means generally known in the art.
[0104] In this regard it is to be further noted, however, that in
alternative embodiments "substantially impermeable" or
"substantially systemically non-bioavailable" provides or allows
for some limited absorption in the GI tract, and more particularly
the gut epithelium, to occur (e.g., some detectable amount of
absorption, such as for example at least about 0.1%, 0.5%, 1% or
more and less than about 30%, 20%, 10%, 5%, etc., the range of
absorption being for example between about 1% and 30%, or 5% and
20%, etc.; stated another way, "substantially impermeable" or
"substantially systemically non-bioavailable" refers to compounds
that exhibit some detectable permeability to an epithelium layer of
cells in the GI tract of less than about 20% of the administered
compound (e.g., less than about 15%, about 10%, or even about 5%,
and for example greater than about 0.5%, or 1%), but then are
cleared by the liver (i.e., hepatic extraction) and/or the kidney
(i.e., renal excretion).
[0105] In accordance with the present disclosure, and as further
detailed herein below, it has been found that the inhibition of
NHE-mediated antiport of sodium ions (Na.sup.+) and hydrogen ions
(H.sup.+) in the gastrointestinal tract, and more particularly the
gastrointestinal epithelia, is a powerful approach to the treatment
of various disorders that may be associated with or caused by fluid
retention and/or salt overload, and/or disorders such as heart
failure (in particular, congestive heart failure), chronic kidney
disease, end-stage renal disease, liver disease, and/or peroxisome
proliferator-activated receptor (PPAR) gamma agonist-induced fluid
retention. More specifically, it has been found that the inhibition
of the NHE-mediated antiport of sodium ions and hydrogen ions in
the GI tract increases the fecal excretion of sodium, effectively
reducing systemic levels of sodium and fluid. This, in turn,
improves the clinical status of a patient suffering from, for
example, CHF, ESRD/CKD and/or liver disease. It has further been
found that such a treatment may optionally be enhanced by the
co-administration of other beneficial compounds or compositions,
such as for example a fluid-absorbing polymer. The fluid-absorbing
polymer may optimally be chosen so that it does not block or
otherwise negatively interfere with the mechanism of action of the
co-dosed NHE-inhibiting compound.
[0106] Additionally, and also as further detailed herein below, it
has further been found that the inhibition of NHE-mediated antiport
of sodium ions (Na.sup.+) and hydrogen ions (H.sup.+) in the
gastrointestinal tract, and more particularly the gastrointestinal
epithelia, is a powerful approach to the treatment of hypertension,
that may be associated with or caused by fluid retention and/or
salt overload. More specifically, it has been found that the
inhibition of the NHE-mediated antiport of sodium ions and hydrogen
ions in the GI tract increases the fecal excretion of sodium,
effectively reducing systemic levels of sodium and fluid. This, in
turn, improves the clinical status of a patient suffering from
hypertension. Such a treatment may optionally be enhanced by the
co-administration of other beneficial compounds or compositions,
such as for example a fluid-absorbing polymer. The fluid-absorbing
polymer may optimally be chosen so that it does not block or
otherwise negatively interfere with the mechanism of action of the
co-dosed NHE-inhibiting compound.
[0107] Additionally, and also as further detailed herein below, it
has further been found that the inhibition of NHE-mediated antiport
of sodium ions (Na.sup.+) and hydrogen ions (H.sup.+) in the
gastrointestinal tract, and more particularly the gastrointestinal
epithelia, is a powerful approach to the treatment of various
gastrointestinal tract disorders, including the treatment or
reduction of pain associated with gastrointestinal tract disorders,
and more particularly to the restoration of appropriate fluid
secretion in the gut and the improvement of pathological conditions
encountered in constipation states. Applicants have further
recognized that by blocking sodium ion re-absorption, the compounds
of the present disclosure restore fluid homeostasis in the GI
tract, particularly in situations wherein fluid
secretion/absorption is altered in such a way that it results in a
high degree of feces dehydration, low gut motility, and/or a slow
transit-time producing constipation states and GI discomfort
generally. It has further been found that such a treatment may
optionally be enhanced by the co-administration of other beneficial
compounds or compositions, such as for example a fluid-absorbing
polymer. The fluid-absorbing polymer may optimally be chosen so
that it does not block or otherwise negatively interfere with the
mechanism of action of the co-dosed NHE-inhibiting compound.
[0108] Due to the presence of NHEs in other organs or tissues in
the body, the method of the present disclosure employs the use of
compounds and compositions that are desirably highly selective or
localized, thus acting substantially in the gastrointestinal tract
without exposure to other tissues or organs. In this way, any
systemic effects can be minimized (whether they are on-target or
off-target). Accordingly, it is to be noted that, as used herein,
and as further detailed elsewhere herein, "substantially active in
the gastrointestinal tract" generally refers to compounds that are
substantially systemically non-bioavailable and/or substantially
impermeable to the layer of epithelial cells, and more specifically
epithelium of the GI tract. It is to be further noted that, as used
herein, and as further detailed elsewhere herein, "substantially
impermeable" more particularly encompasses compounds that are
impermeable to the layer of epithelial cells, and more specifically
the gastrointestinal epithelium (or epithelial layer).
"Gastrointestinal epithelium" refers to the membranous tissue
covering the internal surface of the gastrointestinal tract.
Accordingly, by being substantially impermeable, a compound has
very limited ability to be transferred across the gastrointestinal
epithelium, and thus contact other internal organs (e.g., the
brain, heart, liver, etc.). The typical mechanism by which a
compound can be transferred across the gastrointestinal epithelium
is by either transcellular transit (a substance travels through the
cell, mediated by either passive or active transport passing
through both the apical and basolateral membranes) and/or by
paracellular transit, where a substance travels between cells of an
epithelium, usually through highly restrictive structures known as
"tight junctions".
[0109] Without wishing to be bound to any particular theory, it is
believed that the NHE-inhibiting compounds (e.g., NHE-3, -2 and/or
-8 inhibitors) of the present disclosure are believed to act via a
distinct and unique mechanism, to decrease paracellular
permeability of the intestine. NHE3 is expressed at high levels on
the apical surface of the gastrointestinal tract and couples
luminal Na absorption to the secretion of intracellular protons.
Inhibition of NHE3, by the NHE-inhibiting compounds (e.g., NHE-3,
-2 and/or -8 inhibitors) of the present disclosure, results in
accumulation of intracellular protons. The intracellular proton
retention accompanying NHE3 inhibition modulates the tight junction
between cells to decrease paracellular permeability which can be
measured by an increase in transepithelial electrical resistance.
Since increased paracellular and/or transcellular permeability of
the intestine is observed in many diseases including, but not
limited to a gastrointestinal motility disorder, irritable bowel
syndrome, chronic constipation, chronic idiopathic constipation,
chronic constipation occurring in cystic fibrosis patients, chronic
constipation occurring in chronic kidney disease patients,
calcium-induced constipation in osteoporotic patients,
opioid-induced constipation, multiple sclerosis-induced
constipation, parkinson's disease-induced constipation, a
functional gastrointestinal tract disorder, gastroesophageal reflux
disease, functional heartburn, dyspepsia, functional dyspepsia,
non-ulcer dyspepsia, gastroparesis, chronic intestinal
pseudo-obstruction, Crohn's disease, ulcerative colitis and related
diseases referred to as inflammatory bowel disease, colonic
pseudo-obstruction, gastric ulcers, infectious diarrhea, cancer
(colorectal), "leaky gut syndrome", cystic fibrosis
gastrointestinal disease, multi-organ failure, microscopic colitis,
necrotizing enterocolitis, allergy--atopy, food allergy, infections
(respiratory), acute inflammation (e.g., sepsis, systemic
inflammatory response syndrome), chronic inflammation (arthritis),
obesity-induced metabolic diseases (e.g., nonalcoholic
steatohepatitis, Type I diabetes, Type II diabetes, cardiovascular
disease), kidney disease, diabetic kidney disease, cirrhosis,
nonalcoholic steatohepatitis, nonalcoholic fatty acid liver
disease, Steatosis, primary sclerosing cholangitis, primary biliary
cholangitis, portal hypertension, autoimmune disease (e.g., Type I
diabetes, ankylosing spondylitis, lupus, alopecia areata,
rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic
fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis,
vasculitis, urticarial (hives), Raynaud's syndrome), Schizophrenia,
autism spectrum disorders, hepatic encephlopathy, small intestinal
bacterial overgrowth, and chronic alcoholism, and the like it is
anticipated that NHE inhibition could provide therapeutic benefit
in these diseases by decreasing paracellular and/or transcellular
permeability in the intestine
[0110] Thus in some embodiments, the present disclosure provides
methods of decreasing paracellular permeability of the intestine.
In some embodiments, the method of decreasing paracellular
permeability of the intestine comprises administration of an NHE3
inhibitor. In some embodiments, the inhibition of NHE3 results in
an accumulation of intracellular protons. In some embodiments, the
decrease in paracellular permeability is due to an increase in
intracellular protons independent of and without NHE3 inhibition.
In other words, an increase in intracellular protons without NHE3
inhibition results in a decrease in paracelllar permeability. Thus
methods of decreasing paracellular permeability comprising
increasing intracellular protons is provided. In some embodiments,
methods of treating diseases associated with paracellular
permeability are provided comprising administering an agent that
increases intracellular protons at tight junctions thereby
decreasing paracellular permeability and thus treating the disease.
Non limiting examples of such diseases include, Crohn's disease,
ulcerative colitis and related diseases referred to as inflammatory
bowel syndrome, colonic pseudo-obstruction, gastric ulcers,
infectious diarrhea, cancer (colorectal), "leaky gut syndrome",
cystic fibrosis gastrointestinal disease, multi-organ failure,
microscopic colitis, necrotizing enterocolitis, allergy--atopy,
food allergy, infections (respiratory), acute inflammation (e.g.,
sepsis, systemic inflammatory response syndrome), chronic
inflammation (arthritis), obesity-induced metabolic diseases (e.g.,
nonalcoholic steatohepatitis, Type I diabetes, Type II diabetes,
cardiovascular disease), kidney disease, diabetic kidney disease,
cirrhosis, nonalcoholic steatohepatitis, nonalcoholic fatty acid
liver disease, Steatosis, primary sclerosing cholangitis, primary
biliary cholangitis, portal hypertension, autoimmune disease (e.g.,
Type I diabetes, ankylosing spondylitis, lupus, alopecia areata,
rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic
fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis,
vasculitis, urticarial (hives), Raynaud's syndrome), Schizophrenia,
autism spectrum disorders, hepatic encephlopathy, small intestinal
bactreial overgrowth, and chronic alcoholism, and the like.
[0111] In some embodiments, the present disclosure provides methods
of modulating transcellular permeability of the intestine. In some
embodiments, the method of modulating transcellular permeability of
the intestine comprises administration of an NH.sub.4E3 inhibitor.
In some embodiments, the inhibition of NHE3 results in a substance
travelling through the cell, mediated by either passive or active
transport passing through both the apical and basolateral
membranes. Thus methods of modulating transcellular permeability
comprising mediating either passive or active transport of a
substance passing through both the apical and basolateral membranes
is provided. In some embodiments, methods of treating diseases
associated with transcellular permeability are provided comprising
administering an agent that mediates either passive or active
transport of a substance passing through both the apical and
basolateral membranes of a cell, thereby modulating transcellular
permeability and thus treating the disease. Non limiting examples
of such diseases include a gastrointestinal motility disorder,
irritable bowel syndrome, chronic constipation, chronic idiopathic
constipation, chronic constipation occurring in cystic fibrosis
patients, chronic constipation occurring in chronic kidney disease
patients, calcium-induced constipation in osteoporotic patients,
opioid-induced constipation, multiple sclerosis-induced
constipation, parkinson's disease-induced constipation, a
functional gastrointestinal tract disorder, gastroesophageal reflux
disease, functional heartburn, dyspepsia, functional dyspepsia,
non-ulcer dyspepsia, gastroparesis, chronic intestinal
pseudo-obstruction.
[0112] The compounds of the present disclosure may therefore not be
absorbed, and are thus essentially not systemically bioavailable at
all (e.g., impermeable to the gastrointestinal epithelium at all),
or they show no detectable concentration of the compound in serum.
Alternatively, the compounds may: (i) exhibit some detectable
permeability to the layer of epithelial cells, and more
particularly the epithelium of the GI tract, of less than about 20%
of the administered compound (e.g., less than about 15%, about 10%,
or even about 5%, and for example greater than about 0.5%, or 1%),
but then are rapidly cleared in the liver (i.e., hepatic
extraction) via first-pass metabolism; and/or (ii) exhibit some
detectable permeability to the layer of epithelial cells, and more
particularly the epithelium of the GI tract, of less than about 20%
of the administered compound (e.g., less than about 15%, about 10%,
or even about 5%, and for example greater than about 0.5%, or 1%),
but then are rapidly cleared in the kidney (i.e., renal
excretion).
[0113] Compounds may also be cleared from circulation unchanged
into the bile by biliary excretion. The compounds of the present
disclosure may therefore not exhibit detectable concentrations in
the bile. Alternatively, the compounds may exhibit some detectable
concentration in the bile and more particularly the epithelium of
the biliary tract and gallbladder of 10 .mu.M, less than 1 .mu.M,
less than 0.1 .mu.M, less than 0.01 .mu.M or less than about 0.001
.mu.M.
[0114] In this regard it is to be still further noted that, as used
herein, "substantially systemically non-bioavailable" generally
refers to the inability to detect a compound in the systemic
circulation of an animal or human following an oral dose of the
compound. For a compound to be bioavailable, it must be transferred
across the gastrointestinal epithelium (that is, substantially
permeable as defined above), be transported via the portal
circulation to the liver, avoid substantial metabolism in the
liver, and then be transferred into systemic circulation.
[0115] Without being held to any particular theory, the
NHE-inhibiting compounds (e.g., NHE-3, -2 and/or -8 inhibitors) of
the present disclosure are believed to act via a distinct and
unique mechanism, causing the retention of fluid and ions in the GI
tract (and stimulating fecal excretion) rather than stimulating
increased secretion of said fluid and ions. For example,
lubiprostone (Amitiza.RTM. Sucampo/Takeda) is a bicyclic fatty acid
prostaglandin E1 analog that activates the Type 2 Chloride Channel
(ClC-2) and increases chloride-rich fluid secretion from the
serosal to the mucosal side of the GI tract (see, e.g.,
Pharmacological Reviews for Amitiza.RTM., NDA package). Linaclotide
(MD-1100 acetate, Microbia/Forest Labs) is a 14 amino acid peptide
analogue of an endogenous hormone, guanylin, and indirectly
activates the Cystic Fibrosis Transmembrane Conductance Regulator
(CFTR) thereby inducing fluid and electrolyte secretion into the GI
(see, e.g., Li et al., J. Exp. Med., vol. 202 (2005), pp. 975-986).
The substantially impermeable NHE-inhibiting compounds of the
present disclosure act to inhibit the reuptake of salt and fluid
rather than promote secretion. Since the GI tract processes about 9
liters of fluid and about 800 meq of Na each day, it is anticipated
that NHE inhibition could permit the removal of substantial
quantities of systemic fluid and sodium to resorb edema and resolve
CHF symptoms.
I. Substantially Impermeable or Substantially Systemically
Non-Bioavailable NHE-Inhibiting Compounds
[0116] In one aspect, the compounds of the present disclosure are
generally represented by Formula (I):
##STR00006##
[0117] and pharmaceutically acceptable salts, prodrugs, solvates,
hydrates, isomers, and tautomers thereof,
[0118] wherein:
[0119] Linker is
--(CHR.sup.13).sub.p--Y[--(CH.sub.2).sub.r].sub.s--Z--R.sup.13--(CH.sub.2-
).sub.t--Z--;
[0120] W is independently, at each occurrence, S(O).sub.2, C(O), or
--(CH.sub.2).sub.m--;
[0121] Z is independently, at each occurrence, a bond, C(O), or
--C(O)NH--;
[0122] Y is independently, at each occurrence, O, S, NH,
N(C.sub.1-C.sub.3alkyl), or --C(O)NH--;
[0123] Q is a bond, NH, --C(O)NH--, --NHC(O)NH--,
--NHC(O)N(CH.sub.3)--, or --NHC(O)NH--(CHR.sup.13); m is an integer
from 1 to 2; n is an integer from 1 to 4;
[0124] r and p are independently, at each occurrence, integers from
0 to 8;
[0125] s is an integer from 0 to 4;
[0126] t is an integer from 0 to 4;
[0127] u is an integer from 0 to 2;
[0128] R.sup.1 and R.sup.2 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more halogen, OH, CN, --NO.sub.2, oxo,
--SR.sup.9, --OR.sup.9, --NHR.sup.9, --NR.sup.9R.sup.10,
--S(O).sub.2N(R.sup.9).sub.2--, --S(O).sub.2R.sup.9, --C(O)R.sup.9,
--C(O)OR.sup.9, --C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.9,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl; or
[0129] R.sup.1 and R.sup.2 together with the nitrogen to which they
are attached can form a heterocyclyl or heteroaryl containing 1-5
heteroatoms selected from the group consisting of N, S, P and O,
wherein the heterocyclyl or heteroaryl group is optionally
substituted with one or more halogen, OH, CN, --NO.sub.2, oxo,
--SR.sup.9, --OR.sup.9, --NHR.sup.9, --NR.sup.9R.sup.10,
--S(O).sub.2N(R.sup.9).sub.2--, --S(O).sub.2R.sup.9, --C(O)R.sup.9,
--C(O)OR.sup.9, --C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.10,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl;
[0130] R.sup.3 and R.sup.4 are independently halogen, OH, CN,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, or
--C(O)NR.sup.9R.sup.10;
[0131] R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently H,
halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.8S(O)R.sup.9;
[0132] R.sup.9 and R.sup.10 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O
[0133] X is a bond, H, N, O, CR.sup.11R.sup.12, CR.sup.11, C,
--NHC(O)NH--, or C.sub.3-C.sub.6cyclolakyl;
[0134] R.sup.11 and R.sup.12 are independently H,
C.sub.1-C.sub.6alkyl, OH, NH.sub.2, CN, or NO.sub.2;
[0135] R.sup.13 is independently, at each occurrence, a bond, H,
C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl,
wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted with one or more R.sup.19;
[0136] R.sup.14 is independently, at each occurrence, H,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6haloalkyl; or
[0137] R.sup.6 and R.sup.4 together with the atoms to which they
are attached may combine to form, independently, at each
occurrence, 5-to-6 membered heterocyclyl, wherein each
C.sub.3-C.sub.8 cycloalkyl, or heterocyclyl is optionally
substituted with one r more R.sup.19; or
[0138] R.sup.13 and R.sup.14 together with the atoms to which they
are attached may combine to form independently, at each occurrence,
C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, wherein each heterocyclyl or heteroaryl is optionally
substituted with one or more R.sup.19;
[0139] R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are
independently, at each occurrence, H, OH, NH.sub.2, or
C.sub.1-C.sub.3 alkyl, wherein the alkyl is optionally substituted
with one or more R.sup.19; and
[0140] R.sup.19 are independently, at each occurrence, H, OH,
NH.sub.2, oxo, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6Hhaloalkyl,
C.sub.1-C.sub.6alkoxy
[0141] provided that:
[0142] (1) when X is H, n is 1;
[0143] (2) when X is a bond, O, or CR.sup.11R.sup.12, n is 2;
[0144] (3) when n is 3, X is CR.sup.11 or N;
[0145] (4) when n is 4 X is C;
[0146] (5) only one of Q or X is --NHC(O)NH-- at the time,
[0147] (6) R.sup.1 and R.sup.2 together with the nitrogen to which
they are attached, cannot form a pyrrolidinyl;
[0148] (7) when R.sup.1 and R.sup.2 are methyl, R.sup.3 and R.sup.4
are halogen, and R.sup.5 and R.sup.8 are H, Linker is not
##STR00007##
[0149] (8) when R.sup.1 and R.sup.2 together with the nitrogen to
which they are attached form a piperidinyl, R.sup.3 and R.sup.4 are
halogen, and R.sup.5 and R.sup.8 are H, Linker is not
##STR00008##
[0150] (9) when R.sup.1 and R.sup.2, together with the nitrogen to
which they are attached, form 3-aminopiperidin-1-yl, R.sup.3 and
R.sup.4 are halogen, and R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
H, Linker is not
##STR00009##
[0151] In an embodiment the NHE-inhibiting compounds of Formula (I)
possess overall physicochemical properties that render them
substantially impermeable or substantially systemically
non-bioavailable.
[0152] In an embodiment, the compound of the invention has a
structure according to formula I'
##STR00010##
[0153] or a pharmaceutically acceptable salt thereof,
[0154] wherein:
[0155] Linker is
--R.sup.13--(CHR.sup.13).sub.p--[Y--(CH.sub.2).sub.r].sub.s--Z--R.sup.13--
-(CH.sub.2).sub.t--Z--;
[0156] X is a bond, H, N, O, CR.sup.11R.sup.12, CR.sup.11, C,
--NHC(O)NH--, --(CHR.sup.13).sub.p-- or
C.sub.3-C.sub.6cyclolakyl;
[0157] W is independently, at each occurrence, S(O).sub.2, C(O), or
--(CH.sub.2).sub.m--;
[0158] Z is independently, at each occurrence, a bond, C(O), or
--C(O)NH--;
[0159] Y is independently, at each occurrence, O, S, NH,
N(C.sub.1-C.sub.3alkyl), or --C(O)NH--;
[0160] Q is a bond, NH, --C(O)NH--, --NHC(O)NH--,
--NHC(O)N(CH.sub.3)--, or --NHC(O)NH--(CHR.sup.13);
[0161] m is an integer from 1 to 2;
[0162] n is an integer from 1 to 4;
[0163] r and p are independently, at each occurrence, integers from
0 to 8;
[0164] s is an integer from 0 to 4;
[0165] t is an integer from 0 to 4;
[0166] u is an integer from 0 to 2;
[0167] R.sup.1 and R.sup.2 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more halogen, OH, CN, --NO.sub.2, oxo,
--SR.sup.9, --OR.sup.9, --NHR.sup.9, --NR.sup.9R.sup.10,
--S(O).sub.2N(R.sup.9).sub.2--, --S(O).sub.2R.sup.9, --C(O)R.sup.9,
--C(O)OR.sup.9, --C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.8S(O)R.sup.9,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl; or
[0168] R.sup.1 and R.sup.2 together with the nitrogen to which they
are attached can form a heterocyclyl or heteroaryl containing 1-5
heteroatoms selected from the group consisting of N, S, P and O,
wherein the heterocyclyl or heteroaryl group is optionally
substituted with one or more halogen, OH, CN, --NO.sub.2, oxo,
--SR.sup.9, --OR.sup.9, --NHR.sup.9, --NR.sup.9R.sup.10,
--S(O).sub.2N(R.sup.9).sub.2--, --S(O).sub.2R.sup.9, --C(O)R.sup.9,
--C(O)OR.sup.9, --C(O)NR.sup.9R.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.10,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl;
[0169] R.sup.3 and R.sup.4 are independently halogen, OH, CN,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, or
--C(O)NR.sup.9R.sup.10;
[0170] R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently H,
halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.8S(O)R.sup.9;
[0171] R.sup.9 and R.sup.10 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O
[0172] R.sup.11 and R.sup.12 are independently H,
C.sub.1-C.sub.6alkyl, OH, NH.sub.2, CN, or NO.sub.2;
[0173] R.sup.13 is independently, at each occurrence, a bond, H,
C.sub.1-C.sub.6alkyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl,
wherein each cycloalkenyl, cycloalkyl, heterocyclyl, aryl, or
heteroaryl is optionally substituted with one or more R.sup.19;
[0174] R.sup.14 is independently, at each occurrence, H,
C.sub.1-C.sub.6alkyl, or C.sub.1-C.sub.6haloalkyl; or
[0175] R.sup.6 and R.sup.14 together with the atoms to which they
are attached may combine to form, independently, at each
occurrence, 5-to-6 membered heterocyclyl, wherein each
C.sub.3-C.sub.8 cycloalkyl, or heterocyclyl is optionally
substituted with one or more R.sup.19; or
[0176] R.sup.13 and R.sup.14 together with the atoms to which they
are attached may combine to form independently, at each occurrence,
C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, aryl, or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, wherein each heterocyclyl or heteroaryl is optionally
substituted with one or more R.sup.19;
[0177] R.sup.15, R.sup.16, R.sup.7, and R.sup.18 are independently,
at each occurrence, H, OH, NH.sub.2, or C.sub.1-C.sub.3 alkyl,
wherein the alkyl is optionally substituted with one or more
R.sup.19; and
[0178] R.sup.19 are independently, at each occurrence, H, OH,
NH.sub.2, oxo, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6Hhaloalkyl,
C.sub.1-C.sub.6alkoxy.
[0179] It is to be noted that, in the many structures illustrated
herein, all of the various linkages or bonds will not be shown in
every instance. However, this should not be viewed in a limiting
sense. Rather, it is to be understood that the NHE-inhibiting
molecule is bound or interconnected in some way (e.g., by a bond or
Linker) such that the resulting NHE-inhibiting compound is suitable
for use (i.e., substantially impermeable or substantially
systemically non-bioavailable in the GI tract).
[0180] In yet other embodiments, the polyvalent NHE-inhibiting
compound may be in oligomeric or polymeric form. It is to be noted
that the repeat unit in each Formula (I) generally encompasses
repeating units of various polymeric embodiments, including linear,
branched and dendritic structures, which may optionally be produced
by methods referred to herein. In each polymeric, or more general
polyvalent, embodiment, it is to be noted that each repeat unit may
be the same or different, and may or may not be linked through the
"X" moiety by a Linker, which in turn may be the same or different
when present. In this regard it is to be noted that as used herein,
"polyvalent" refers to a molecule that has multiple (e.g., 2, 4, 6,
8, 10 or more) NHE-inhibiting molecule.
[0181] In one embodiment of the invention, the Linker is
-heterocyclyl-(CHR.sup.13).sub.p--[Y--(CH.sub.2).sub.r].sub.s--. In
another embodiment of the invention, the Linker may be represented
by, but not limited to,
##STR00011##
[0182] In another embodiment, the Linker may represented, without
limitation, by
##STR00012##
[0183] In some embodiments, of the invention, R.sup.1 and R.sup.2
are C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.1 and R.sup.2
are methyl.
[0184] Yet in other embodiments of the compounds of Formula I,
R.sup.1 and R.sup.2 together with the nitrogen to which they are
attached may form a heterocyclyl or heteroaryl containing 1-5
heteroatoms selected from the group consisting of N, S, P and O. In
some embodiments of the compounds of Formula I, the heterocyclyl or
heteroaryl formed by R.sup.1 and R.sup.2 together with the nitrogen
to which they are attached is optionally substituted with one or
more H, halogen, --NR.sup.9N.sup.10, or C.sub.1-C.sub.6alkyl.
[0185] In other embodiments of the compounds of Formula I, R.sup.1
and R.sup.2 together with the nitrogen to which they are attached
can form a heterocycle. In some embodiments of the compounds of
Formula I, the heterocycle formed by R.sup.1 and R.sup.2 together
with the nitrogen to which they are attached is optionally
substituted with one or more oxo. In other embodiments of the
compounds of Formula I, R.sup.1 and R.sup.2 together with the
nitrogen to which they are attached may also form a piperidine or
piperazine. In further embodiments of the compounds of Formula I,
the piperidine or piperazine is optionally substituted with one or
more oxo, halogen, --NR.sup.9R.sup.10, or C.sub.1-C.sub.6alkyl. In
a particular embodiment, the piperazine is substituted with
methyl.
[0186] In some embodiments of the compounds of Formula I, R.sup.9
and R.sup.10 are C.sub.1-C.sub.6alkyl. In other embodiments,
R.sup.9 and R.sup.10 are methyl. In some embodiments of the
compounds of Formula I, R.sup.3 is halogen, CN,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, or C.sub.1-C.sub.6haloalkoxy. In some
embodiments of the compounds of Formula I, R.sup.3 is halogen, CN,
or C.sub.1-C.sub.6alkyl. In an embodiment, R.sup.3 is CN. In some
embodiments. R.sup.3 is F, Cl, CN, or methyl.
[0187] In some embodiments of the compounds of Formula I, R.sup.4
is halogen or C.sub.1-C.sub.6alkyl.
[0188] In some embodiments of the compounds of Formula I, R.sup.4
is F, Cl, or methyl. In an embodiment, R.sup.3 is CN and R.sup.4 is
C.sub.1.
[0189] In other embodiments of the compounds of Formula I, R.sup.5
is H, halogen, C.sub.1-C.sub.6alkyl, or OR.sup.9. In yet other
embodiments, R.sup.5 is 1-1, F, or methyl.
[0190] In another embodiment of the invention, R.sup.6, R.sup.7,
and R.sup.8 are H, halogen, or C.sub.1-C.sub.6alkyl. In another
embodiment, R.sup.6, R.sup.7, and R.sup.8 are all H. It has be
observed that compounds of the invention incorporating a halogen or
alkyl substituent at R.sup.6 while R.sup.5, R.sup.7 and R.sup.8 are
each H exhibit less interaction with cytochrome enzymes.
Accordingly, in an embodiment, R.sup.5, R.sup.7 and R.sup.8 are
each H and R.sup.6 is halogen or C.sub.1-6alkyl. In an embodiment,
R.sup.5, R.sup.7 and R.sup.8 are each H and R.sup.6 is F. In an
embodiment, R.sup.5, R.sup.7 and R.sup.8 are each H and R.sup.6 is
Me.
[0191] In another embodiment of the compounds of Formula I, Q is
--NHC(O)NH--. In a particular embodiment, Q is --NHC(O)NH-- and the
Linker is
-heterocyclyl-(CHR.sup.13).sub.p--[Y--(CH.sub.2).sub.r].sub.s--- .
In a particular embodiment, Q is --NHC(O)NH--, the Linker is
-heterocyclyl-(CHR.sup.3).sub.p--[Y--(CH.sub.2).sub.r].sub.s-- and
u is 0. In a particular embodiment, Q is --NHC(O)NH--, the Linker
is -heterocyclyl-(CHR.sup.13).sub.p--[Y--(CH.sub.2).sub.r].sub.s--,
u is 0 and n is 2. In a particular embodiment, Q is --NHC(O)NH--,
the Linker is
-heterocyclyl-(CHR.sup.13).sub.p--[Y--(CH.sub.2).sub.r].sub.s--, u
is 0, n is 2 and X is --(CHR.sup.13).sub.p-- or
C.sub.3-C.sub.6cyclolakyl. In another embodiment, Q is a bond.
[0192] In one embodiment of the compounds of Formula I, R.sup.15,
R.sup.16, R.sup.17, and R.sup.18 are all H. In one embodiment of
the compounds of Formula I, R.sup.15 and R.sup.17 are H. In one
embodiment of the compounds of Formula I, R.sup.16 and R.sup.18 are
OH. In yet another embodiment of the compounds of Formula I,
R.sup.15 and R.sup.17 are H and R.sup.16 and R.sup.1K are OH.
[0193] In one embodiment of the compounds of Formula I, Y is O, r
is 2, and s is 1. In another embodiment, Y is O, r is 2, and s is
2. In some embodiments, s is 0. In some embodiments, Z is C(O).
[0194] In some embodiments of the compounds of Formula I, R.sup.13
is H, C.sub.1-C.sub.6 alkyl, heterocyclyl or heteroaryl. In some
embodiments of the compounds of Formula I, the heterocyclyl or
heteroaryl of R is optionally substituted with one or more
R.sup.19. In some embodiments, R.sup.13 is heterocyclyl optionally
substituted with one or more R.sup.19. In some embodiments,
R.sup.19 is oxo. In some embodiments of the compounds of Formula I,
n is 2. In other embodiments of the compounds of Formula I, n is 3
Or 4.
[0195] In one embodiment of the invention, the compounds of Formula
I have the Formula Ia or Ia':
##STR00013##
[0196] In one embodiment of the invention, the compounds of Formula
I have the Formula Ib or Ib':
##STR00014##
wherein the ring Het represents R.sup.1 and R.sup.2 together with
the nitrogen to which they are attached can form a heterocyclyl or
heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, wherein the heterocyclyl or heteroaryl
group is optionally substituted with one or more halogen, OH, CN,
--NO.sub.2, oxo, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10), --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10,
--S(O)R.sup.9, --S(O)NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.10,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl.
[0197] In one embodiment of the invention, the compounds of Formula
I have the Formula Ic or Ic':
##STR00015##
wherein Het B represents a C.sub.3-C.sub.8 cycloalkyl,
heterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms
selected from the group consisting of N, S, P and O, wherein each
heterocyclyl or heteroaryl is optionally substituted with one or
more R.sup.19.
[0198] In one embodiment of the invention, the compounds of Formula
I have the Formula Id or Id':
##STR00016##
wherein Het is R.sup.13 which represents
C.sub.4-C.sub.8cycloalkenyl, C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, or heteroaryl, wherein each cycloalkenyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more R.sup.19.
[0199] In one embodiment of the invention, the compounds of Formula
I have the Formula Ie or Ie':
##STR00017##
[0200] wherein the ring Het A represents R.sup.1 and R.sup.2
together with the nitrogen to which they are attached can form a
heterocyclyl or heteroaryl containing 1-5 heteroatoms selected from
the group consisting of N, S, P and O, wherein the heterocyclyl or
heteroaryl group is optionally substituted with one or more
halogen, OH, CN, --NO.sub.2, oxo, --SR.sup.9, --OR.sup.9,
--NHR.sup.9, --NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.11,
--S(O)R.sup.9, --S(O)NR.sup.9R.sup.10, --NR.sup.9S(O)R.sup.10,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl; and Het is R.sup.13 which represents
C.sub.4-C.sub.8cycloalkenyl, C.sub.3-C.sub.8cycloalkyl,
heterocyclyl, aryl, or heteroaryl, wherein each cycloalkenyl,
cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally
substituted with one or more R.sup.19.
[0201] In one embodiment of the invention, the compounds of Formula
I have the Formula If or If':
##STR00018##
[0202] In one embodiment of the invention, the compounds of Formula
I have the Formula
##STR00019##
[0203] In one embodiment of the invention, the compounds of Formula
I have the Formula Ih or Ih':
##STR00020##
wherein: Het represents R.sup.6 and R.sup.14 together with the
atoms to which they are attached forming, independently, at each
occurrence, a 5-to-6 membered heterocyclyl.
[0204] In one embodiment of the invention, the compounds of Formula
I have the Formula Ii or Ii':
##STR00021##
[0205] In other embodiments, compounds of Formula I include, but
are not limited to,
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl-
]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy-
)ethyl] carbamoyl]amino)butyl]urea: [0206]
3-[2-(2-[2-[(4-[[(1S,2S)-2[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-d-
ihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]
ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]-
ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0207]
3-[2-(2-[2-[(4-[[(1S,2
S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden--
1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1-
S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inde-
n-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl
urea; [0208]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[-
4-([[2-(2-[2-[(4-[[(1S,2S)-2-(3R)-3-aminopiperidin-1-yl]-6-chloro-4-cyano--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0209]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methox-
y-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-
-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-met-
hoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl-
]carbamoyl]amino)butyl]urea; [0210]
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-fluoro-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)-
ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlo-
ro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]eth-
oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0211]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)-
ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlo-
ro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]eth-
oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0212]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-cyano--
2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlor-
o-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0213]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methox-
y-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido
ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperid-
in-1-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene-
)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino) butyl]urea;
[0214]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-(fluoro
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2--
[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]-
urea: [0215]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro--
1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-
-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1--
yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0216]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-
-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-ind-
en-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]-
urea; [0217]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]
ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0218]
1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[-
4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethoxy)-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]car-
bamoyl]amino)butyl]urea; [0219]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-
-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[-
2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden--
1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]ure-
a; [0220]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-fluoro-2,3-
-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethy-
l]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-d-
ihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-
carbamoyl]amino) butyl]urea; [0221]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methyl
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6--
chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylb-
enzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0222]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-[4-([[2-
-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-dimethylamino)-2,3-dihydro-1H-inde-
n-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy) ethyl]
carbamoyl]amino)butyl]urea; [0223]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2-
,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)et-
hyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoro-
methyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]-
ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0224]
1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)--
2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(tri
fluoromethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido-
]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0225]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]
ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylam-
ino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-
ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0226]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-y-
l]oxy]-3-methyl
benzene)sulfonamido]ethoxy]ethoxy)ethy]carbamoyl]amino)butyl]urea
dihydrochloride; [0227]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-y-
l]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)but-
yl]urea; [0228]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro--
1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-
-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea; [0229]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin--
1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethy-
l]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)pip-
eridin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]etho-
xy)ethyl]carbamoyl]amino)butyl]urea; [0230]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin--
1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]et-
hoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethyl-
amino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfo-
namido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0231]
3-[2-(2-[2-[(4[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-dimethylamino)piperidin-1--
yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]etho-
xy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylam-
ino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0232]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy-
)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethyl]amino)p-
iperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-
ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0233]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]etho-
xy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethy-
lamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylben-
zene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0234]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-(fluorobenzene)sulfonamido]eth-
oxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimeth-
ylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobe-
nzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0235]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-
-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]b-
enzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0236]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2--
(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]
carbamoyl]amino)butyl]urea; [0237]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2--
(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)b-
utyl]urea; [0238]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[-
2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden--
1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]ure-
a; [0239]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,-
3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)eth-
yl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-
-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethy-
l]carbamoyl]amino)butyl]urea; [0240]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-ind-
en-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]ami-
no)butyl]urea; [0241]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-i-
nden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]
carbamoyl]amino)butyl]urea; [0242]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)-
ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlo-
ro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]eth-
oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0243]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperi-
din-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethox-
y]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenze-
ne)sulfonamido]ethoxy]ethoxy)ethyl](carbamoyl]amino)butyl]urea;
[0244]
3-[2-(2-[2-[(4-[[(1S,1S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperi-
din-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethox-
y]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-(fluorobenz-
ene)sulfon amido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0245]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-
-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1--
yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0246]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-d-
ihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-
-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-24
piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamid-
o]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0247]
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea; [0248]
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethox-
y)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3--
dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methox-
y]ethoxy)ethyl(carbamoyl]amino) butyl]urea; [0249]
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethox-
y)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino-
)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene) sulfonyl]
pyrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0250]
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)--
2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]me-
thoxy]ethoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-
-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]p-
yrrolidin-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
[0251]
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]e-
thoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimet-
hylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolid-
in-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0252]
3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-
-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylam-
ino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3--
yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea; [0253]
3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-
-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylam-
ino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3--
yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea; [0254]
3-[(4-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihyd-
ro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyr-
idin-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(di-
methylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrro-
lidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea:
[0255]
3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihyd-
ro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyr-
idin-2-yl)methyl]-1-[4-([[4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dim-
ethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrol-
idin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea;
[0256]
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2-
S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylb-
enzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)
carbamoyl]amino]butyl)urea; [0257]
3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethy-
l)-1(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-di-
hydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethox-
y]ethyl)carbamoyl]amino]butyl)urea; [0258]
3-(2-[2-[(3S)-3-[[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy-
]ethyl)-1-(4-[[(2-[2-[(3S)-3-[[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylam-
ino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-
-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; [0259]
3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamin-
o)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-
-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea; [0260]
1-([1-[2(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-[4-[[([1-
-[2-(2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihyd-
ro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)
ethyl]-1H-1,2,3-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea;
[0261]
(2R,3R,4R,5S)--N.sup.1,N.sup.6-Bis([1-[2-(2-[2-[(4-[[(1S,2)-2-[(3R)-3-ami-
nopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfo-
namido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahyd-
roxyhexanediamide; [0262]
3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)m-
ethyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dich-
loro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-tri-
azol-4-yl)methyl]carbamoyl]amino)butyl]urea; [0263]
3[(1-[6-(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihy-
dro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triazol-4-yl)met-
hyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-((3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-triaz-
ol-4-yl)methyl(carbamoyl]amino)butyl]urea; [0264]
(4R,4aS,8S,8aR)--N.sup.4,N.sup.8-Bis([1-(4-[4-((1S,2S)-2-[(3R)-3-aminopip-
eridin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenyl
sulfonamide]butyl)-1H-1,2,3-triazol-4-yl(methyl)-2,2,6,6-tetramethyl-tetr-
ahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide; [0265]
(4R,4aS,8S,8aR)--N.sup.4,N.sup.8-Bis([1-(6-[4-((1S,2S)-2-[(3R)-3-amino
piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonami-
do]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-1-tetrahydro-[-
1,3]dioxino[5,4-d][[1,3]dioxine-4,8-dicarboxamide; [0266]
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydr-
o-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[-
(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]ben-
zene) sulfonamido]octyl]carbamoyl)amino]butyl]urea; [0267]
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydr-
o-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-
-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]o-
ctyl]carbamoyl)amino]butyl]urea; [0268]
3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1--
yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(-
dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]octyl]carbamoyl)amino]butyl]urea; [0269]
3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1--
yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,1S)-4,6-dic-
hloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]octyl]carbamoyl)amino]butyl]urea; [0270]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]
carbamoyl]amino)butyl]urea; [0271]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2M-2-methylpiperidin-1-yl]-2,3--
dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy](ethoxy)ethyl]carbamoyl-
]amino)butyl]urea; [0272]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[-
4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]car-
bamoyl]amino)butyl]urea; [0273]
1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carba-
moyl]amino)butyl]urea; [0274]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyelo[3.2.1]octan-8-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy](benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[-
4-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carb-
amoyl]amino)butyl]urea; [0275]
1-[2-(2-[2-[(4-[[(1S,2S)-2-[8-Azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carba-
moyl]amino)butyl]urea; [0276]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihy-
dro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H--
inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)but-
yl]urea; [0277]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea; [0278]
3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihy-
dro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H--
inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)but-
yl]urea; [0279]
3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea; [0280] 4-[(1S,2S)-4,6-dichloro-1-[4-1
(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[4-(dimethylcarbamo-
yl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)eth-
oxy]ethoxy]ethyl)
sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine-1-ca-
rboxamide; [0281] 4-[(1S,2
S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2
S)-4,6-dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]am-
ino)butyl]carbamoyl]amino)eth
oxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]-N-
,N-dimethylpiperazine-1-carboxamide; [0282]
3-[2-(2-[2-[(4[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino]-
piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichlo-
ro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inde-
n-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]u-
rea; [0283]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3,5-dimethyl
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2--
[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-
,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]u-
rea; hydrochloride; [0284]
1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)
ethyl]-3[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-di-
hydro-1H-inden-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)eth-
yl]carbamoyl]amino)butyl]urea; [0285]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3--
aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimet-
hylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]
carbamoyl]amino)butyl]urea; [0286]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydr-
o-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]--
1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carb-
amoyl]amino)butyl]urea; [0287]
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]eth-
oxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,-
6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride;
[0288]
1-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]car-
bamoyl]amino)butyl]urea; [0289]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dic-
hloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)sulfonamido]ethox-
y]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0290]
4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl(oxy)-
-N-[26-(|4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-
-yl]oxy)-3,5-difluorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,-
11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide; [0291]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]eth-
oxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,-
6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0292]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H--
inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea; [0293]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]eth-
oxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,-
6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0294]
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H--
inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea; [0295]
1(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethoxy-
]ethyl)-3-[4-[[(2-[2[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2-
,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-
-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea;
[0296]
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2-
,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-
-1-yl]ethoxy]ethyl)-3-[4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2--
(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido-
]-2-oxopyrrolidin-1-yl(ethoxy]ethyl)carbamoyl]amino]butyl)urea;
[0297]
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethox-
y)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-
-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0298]
3-[2-(2-[[(3S)-1-[(4-[[(1S,2)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy-
)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-
-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3--
yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; [0299]
3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethy-
l]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethox-
y]ethyl]carbamoyl)amino]butyl]urea; [0300]
1-(2-[(2S)-2-[4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl-3-(4-(-
[[2-[(2-[2-[(4-(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dih-
ydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamoyl]-
amino]butyl)urea; hydrochloride; [0301]
3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-
-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichl-
oro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl-
)carbamoyl]amino]butyl)urea; [0302]
3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4-
,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea
dihydrochloride: [0303]
3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4-
,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbut-
oxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea; [0304]
1-[2-(2-[2-[(4-[[((3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-
-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]-3-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dih-
ydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea; hydrochloride; [0305]
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethy-
l]-3[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethox-
y)ethyl]carbamoyl]amino)butyl]urea; [0306]
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl-
]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy-
)ethyl]carbamoyl]amino)butyl]urea; [0307]
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl-
]-3[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)-
ethyl]carbamoyl]amino)butyl]urea; [0308]
4-([(1S,2S)-2-[(R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-ind-
en-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl(oxy)-2-chlorophenyl]sulfonamido)-10,17-dioxo-3-
,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]-2-chlorobenzenesulfonamide-
; [0309]
4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden--
1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1--
yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluo-
robenzenesulfonamide; tetra(trifluoroacetate); [0310]
4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy-
)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-d-
ihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-
-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzen-
esulfonamide; tetra(trifluoroacetate); [0311]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl-
)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-d-
ioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamid-
e; tetra(trifluoroacetate); [0312]
4-([1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]-
oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl-
)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-d-
ioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamid-
e; tetra(trifluoroacetate); [0313]
4-[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]-
oxy)-N--[(R)-1-(20-[(S)-2-([4-[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-
-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1-yl-
]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluoro-
benzenesulfonamide; tetra(trifluoroacetate); [0314]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamide)pyrrolidin-1--
yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluo-
robenzenesulfonamide; tetra(trifluoroacetate); [0315]
4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-
-N--[(S)-1-(20-[(S)-3-(.parallel.4-([(1S,2S)-4,6-dichloro-2-(dimethylamino-
)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-y-
l]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluor-
obenzenesulfonamide; tetra(trifluoroacetate); [0316]
4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-
-N--[(R)-1-(20-[(R)-3-([4-[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-di-
oxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenesu-
lfonamide; tetra(trifluoroacetate); [0317]
4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-
-dihydro-1H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2--
[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,-
13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;
tetra(trifluoroacetate); [0318]
4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-
-dihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2--
[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,-
13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;
tetra(trifluoroacetate); [0319]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo--
5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;
[0320]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-4,11,-
14-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonami-
de; [0321]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H--
inden-1-yl]oxy)-N--[(S)-1-[(2S,13S)-14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cya-
no-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyr-
rolidin-1-yl]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl-
]pyrrolidin-3-yl]benzenesulfonamide; [0322]
N.sup.1,N.sup.14-bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-
-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide; [0323]
N.sup.1,N.sup.14-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-
-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide;
[0324]
N.sup.1,N.sup.18-Bis(1-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin--
1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-d-
ioxo-5,7,12,14-tetraazaoctadecanediamide; [0325]
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3--
dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfona-
mido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenes-
ulfonamide; [0326]
-([(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(d-
imethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonam-
ido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenesu-
lfonamide; [0327]
4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dih-
ydro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidin-1-yl)-7,14-dioxo-3,18--
dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide;
[0328]
N.sup.1,N.sup.18-Bis([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-
-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazao-
ctadecanediamide; [0329]
N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden--
1-yl]oxy)phenyl]sulfonyl)-1-[16-(4[([4-[(1S,2S)-6-chloro-4-cyano-2-(pipera-
zin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperidi-
n-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide;
[0330]
4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H--
inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-
-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidi-
n-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]ben-
zenesulfonamide; [0331]
4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(1,4-diazep-
an-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-
-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesul-
fonamide; [0332]
4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-
-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
in-3-yl]benzenesulfonamide; [0333]
4-([(1S,2S)-6-chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-
-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
in-3-yl]benzenesulfonamide; [0334]
4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cya-
no-2,3-dihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20)-[(S)-3-([4-([(1S,2S)-2-[(-
1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H-
-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa--
6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; [0335]
4-([(1S,2S)-2-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cya-
no-2,3-dihydro-1H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1-
S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H--
inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6-
,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; [0336]
4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(-
R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl
oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-t-
etraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide; [0337]
4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(20)-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[-
(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonami-
do)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrroli-
din-3-yl]benzenesulfonamide; [0338]
4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(-
S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
in-3-yl]benzenesulfonamide; [0339]
4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(20[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S-
)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido-
)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidi-
n-3-yl]benzenesulfonamide; [0340]
4-([(1S,2S)-6-chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cy-
ano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)p-
henyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraaz-
aicosyl)pyrrolidin-3-yl]benzenesulfonamide; [0341]
4-([(1S,2S)-6-chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy)-N--[(R)-[-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cy-
ano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)p-
henyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraaz-
aicosyl)pyrrolidin-3-yl]benzenesulfonamide; [0342]
4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxopiperidin-1-yl]--
7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzen-
esulfonamide; [0343]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-[(1S,2S)-6-chloro-4-cyano-2-
-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy]-
ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonami-
de; [0344]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H--
inden-1-yl]oxy)-N--[(R)-1-(18-[(r)-3-([4-([(1S,1S)-6-chloro-4-cyano-2-(pip-
erazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-
-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzene-
sulfonamide; [0345]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)benzenesulfonamide; [0346]
N-(2-[2-(2-Aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(pipe-
razin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;
[0347]
N-[1-(4-Aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(pip-
erazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide;
[0348]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)benzenesulfonamide;
[0349]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-ind-
en-1-yl]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfon-
amide; [0350]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide-
; [0351]
4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy)phenyl]sulfonamido)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydro-
xyhexan-2-yl]piperidine-1-carboxamide; [0352]
4-(3-[4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H--
inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-([(1S,2S)-6-ch-
loro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfo-
nyl)butanamide; [0353]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2-
,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl-
)ureido]butanoyl)piperidin-4-yl]benzenesulfonamide; [0354]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diaza-
nonadecyl]benzenesulfonamide; [0355]
4-([(1S,2S)-6-Chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,-
16,18-tetraazahexacosyl]benzenesulfonamide; [0356]
4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,-
16,18-tetraazahexacosyl]benzenesulfonamide; [0357]
1,1'-(Butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-o-
xobutyl)urea], [0358]
1,1'-(Butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-o-
xobutyl)urea]; [0359]
N,N'-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-([(1-
S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-
,4-dihydroisoquinoline-2(1H)-carboxamide]; [0360]
N,N-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-([(1S-
,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,-
4-dihydroisoquinoline-2(1H)-carboxamide]; [0361]
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(-
R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidi-
n-3-yl]benzenesulfonamide; [0362]
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-f
(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonam-
ido)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrroli-
din-3-yl]benzenesulfonamide; [0363]
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-meth-
ylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperid-
in-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benz-
enesulfonamide; [0364]
N.sup.1,N.sup.14-Bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-met-
hylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrol-
idin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide,
[0365] 4-([(1S,2S)-6-Chloro-4-cyano-2-1
(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([-
4-([(1S,2S)-6-chloro-4-cyano-2-1
(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonam-
ido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperid-
in-4-yl]benzenesulfonamide; [0366]
4-([(1S,2S)-4,6-Dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-in-
den-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-met-
hylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrol-
idin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-
benzenesulfonamide; [0367]
N.sup.1,N.sup.14-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylp-
iperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-
-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide:
[0368]
1,1'-(Butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(pipera-
zin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl-
]urea); and [0369]
1,1'-(Butane-1,4-diyl)bis(3[I2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(pipera-
zin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl-
]urea). [0370]
(1S,2S)-1-(4-{[(3S)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4-carboxy-6-
-chloro-2-
[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]ben-
zenesulfonamido)-1-hydroxy-1.lamda..sup.4-Pyrrolidin-1-yl]ethoxy]ethyl)car-
bamoyl]amino}butyl)carbamoyl]amino}ethoxy)ethyl]-1-hydroxy-1.lamda..sup.4--
pyrrolidin-3-yl]sulfamoyl}phenoxy)-6-chloro-2-[(3R)-3-methylpiperazin-1-yl-
]-2,3-dihydro-1H-indene-4-carboxylic acid; [0371]
3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-
-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-.sup.2H.sub.4)benzenesulfonami-
do)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-({[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chlo-
ro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(-
2,3,5,6-.sup.2H.sub.4)benzenesulfonamido)pyrrolidin-1-yl]ethoxy]ethyl)carb-
amoyl]amino}(1,1,2,2,3,3,4,4-.sup.2H.sub.8)butyl)urea; [0372]
3-(2-{2-[2-(4-{[(1S,2S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]--
2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-
-{[(2-{2-[2-(4-{[(1 S,2
S)-4-cyano-6-methyl-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden--
1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea-
; [0373]
3-(2-{2-[(3S)-3-[4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperaz-
in-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-
ethoxy}ethyl)-1-(4-({[(2-[2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-me-
thylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrro-
lidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea; [0374]
N-{2-[(3S)-3-[4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,-
3-dihydro-1H-inden-1-yl]oxy}/benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethy-
l}-2-({[4-({[({(2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpipera-
zin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl-
]-2-oxoethyl}carbamoyl)methyl]carbamoyl]amino)butyl]carbamoyl}
amino)acetamide; [0375]
3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-[(1
s,4s)-4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-d-
ihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]-
amino}cyclohexyl]urea: [0376]
1,3-bis(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihy-
dro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)urea;
[0377]
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-ident-1-yl-
]oxy)-N-[19-([4-([1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diazan-
onadecyl]benzenesulfonamide; [0378]
3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-1(1r,4r)-4-{[(2-
-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-ind-
en-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}cyclohe-
xyl]urea; [0379]
3-(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-
-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]etho-
xy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-met-
hylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrol-
idin-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-
.sup.2H.sub.8)butyl)urea; [0380]
3-{4-[(3S)-3-[4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl-
]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-4-oxob-
utyl}-1-{4-[({4-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpipe-
razin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy})
benzenesulfonamido)pyrrolidin-1-yl]-4-oxobutyl}carbamoyl)amino]butyl}urea-
; [0381]
3-{4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-
-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzenesulfonamido)piperidin-1-yl]-4-ox-
obutyl}-1-{4-[({4-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperaz-
in-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]--
4-oxobutyl}carbamoyl)amino]butyl}urea; [0382]
N-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2-({[4--
({[({2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydr-
o-1H-inden-1-yl]oxy]benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamo-
yl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamide; [0383]
3-(2-{2-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]--
2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]ethoxy}eth-
yl)-1-(4-{[(2-{2-[4-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazi-
n-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)piperidin-1-yl]et-
hoxy}ethyl)carbamoyl]amino}butyl)urea; [0384]
3-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-1-{4-[(-
{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}carbamoyl)a-
mino]butyl} urea; and [0385]
(3S)--N-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy}benzenesulfonyl)-1-[2-(2-{[(4-{[(2-{2-[(3S)-3-[(4-{[(1S,2S)--
6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benzenes-
ulfonyl)carbamoyl]pyrrolidin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)carba-
moyl]amino}ethoxy)ethyl]pyrrolidine-3-carboxamide.
[0386] In other embodiments, W is S(O).sub.2, C(O), or
--(CH.sub.2).sub.m--. In other embodiments, W is S(O).sub.2. In
other embodiments, W is C(O). In other embodiments, W is
--(CH.sub.2).sub.2--. In other embodiments, W is
--(CH.sub.2)--.
[0387] In some embodiments, Y is O, S, NH, N(C.sub.1-C.sub.3alkyl),
or --C(O)NH--. In some embodiments, Y is O. In some embodiments, Y
is S. In some embodiments, Y is NH. In some embodiments, Y is
N(C.sub.1-C.sub.6alkyl). In some embodiments, Y is --C(O)NH--. In
some embodiments, Y is O, S, NH, or N(C.sub.1-C.sub.3alkyl). In
some embodiments, Y is O, S, or NIH. In some embodiments, Y is O or
S.
[0388] In some embodiments, Q is a bond, NH, --C(O)NH--,
--NHC(O)NH--, --NHC(O)N(CH.sub.3)--, or --NHC(O)NH--(CHR.sup.13).
In some embodiments, Q is a bond, NH, --C(O)NH--, --NHC(O)NH--, or
--NHC(O)N(CH.sub.3)--. In some embodiments, Q is a bond, NH,
--C(O)NH--, or --NHC(O)NH--. In some embodiments, Q is a bond, NH,
or --C(O)NH--. In some embodiments, Q is a bond or NH. In some
embodiments, Q is a bond. In some embodiments, Q is --NHC(O)NH--.
In some embodiments, Q is --C(O)NH--. In some embodiments, Q is
--NHC(O)NH--. In some embodiments, Q is --NHC(O)N(CH.sub.3)--. In
some embodiments, Q is --NHC(O)NH--(CHR.sup.13).
[0389] In some embodiments, R.sup.1 and R.sup.2 are independently
H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl. In
some embodiments, R.sup.1 and R.sup.2 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, or aryl. In some
embodiments, R.sup.1 and R.sup.2 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, or heterocyclyl. In some embodiments,
R.sup.1 and R.sup.2 are independently H, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, or heteroaryl. In some embodiments, R.sup.1 and R.sup.2 are
independently H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl, or
C.sub.3-C.sub.8cycloalkyl. In some embodiments, R.sup.1 and R.sup.2
are independently H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, or C.sub.2-C.sub.6alkynyl. In some
embodiments, R.sup.1 and R.sup.2 are independently H,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, or
C.sub.4-C.sub.8cycloalkenyl. In some embodiments, R.sup.1 and
R.sup.2 are independently H, C.sub.1-C.sub.6alkyl, or
C.sub.2-C.sub.6alkenyl. In some embodiments, R.sup.1 and R.sup.2
are independently H or C.sub.1-C.sub.6alkyl. In some embodiments,
R.sup.1 and R.sup.2 are independently H, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, or heteroaryl wherein each alkyl, alkenyl, cycloalkenyl,
alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is
optionally substituted with one or more halogen, OH, CN,
--NO.sub.2, oxo, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, C(O)R.sup.9, --C(O)OR.sup.9,
--C(O)NR.sup.9R.sup.10, --NR.sup.9S(O).sub.2R.sup.10,
--S(O)R.sup.9, --S(O)NR.sup.9R.sup.10, --NRRS(O)R.sup.9,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, heterocycle, aryl, or
heteroaryl.
[0390] In another embodiment, R.sup.3 is halogen, OH, CN,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, or
--C(O)NR.sup.9R.sup.10. In one embodiment, R.sup.3 is halogen, OH,
CN, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, or C.sub.1-C.sub.6haloalkoxy. In one
embodiment, R.sup.3 is halogen, OH, CN, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, or C.sub.1-C.sub.6haloalkyl. In one
embodiment, R.sup.3 is halogen, OH, CN, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6alkoxy. In one embodiment, R.sup.3 is halogen, OH,
CN, or C.sub.1-C.sub.6alkyl. R.sup.3 is halogen, OH, or CN. In one
embodiment, R.sup.3 is halogen or OH. In one embodiment, R.sup.3 is
halogen. R.sup.3 is OH. In one embodiment, R.sup.3 is CN. In one
embodiment, R.sup.3 is C.sub.1-C.sub.6alkyl. In one embodiment,
R.sup.3 is C.sub.1-C.sub.6alkoxy. In one embodiment, R.sup.3 is
C.sub.1-C.sub.6haloalkyl. In one embodiment, R.sup.3 is
C.sub.1-C.sub.6haloalkoxy. In one embodiment, R.sup.4 is
--C(O)NR.sup.9R.sup.10.
[0391] In another embodiment, R.sup.4 is halogen, OH, CN,
C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, or
--C(O)NR.sup.9R.sup.10. In one embodiment, R.sup.4 is halogen, OH,
CN, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkyl, or C.sub.1-C.sub.6haloalkoxy. In one
embodiment, R.sup.4 is halogen, OH, CN, C.sub.1-C.sub.6alkyl,
C.sub.1-C.sub.6alkoxy, or C.sub.1-C.sub.6haloalkyl. In one
embodiment, R.sup.4 is halogen, OH, CN, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6alkoxy. In one embodiment, R.sup.4 is halogen, OH,
CN, or C.sub.1-C.sub.6alkyl. R.sup.3 is halogen, OH, or CN. In one
embodiment, R.sup.4 is halogen or OH. In one embodiment, R.sup.4 is
halogen. R.sup.3 is OH. In one embodiment, R.sup.4 is CN. In one
embodiment, R.sup.4 is C.sub.1-C.sub.6alkyl. In one embodiment,
R.sup.4 is C.sub.1-C.sub.6alkoxy. In one embodiment, R.sup.4 is
C.sub.1-C.sub.6haloalkyl, In one embodiment, R.sup.4 is
C.sub.1-C.sub.6haloalkoxy. In one embodiment, R.sup.4 is
--C(O)NR.sup.9R.sup.10.
[0392] In one embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8
are independently H, halogen, OH, CN, --NO.sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.10,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10, --NR.sup.8S(O)R.sup.9. In one embodiment,
R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently H,
halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.10, --C(O)OR.sup.9,
--NR.sup.9S(O).sub.2R.sup.10, --S(O)R.sup.9,
--S(O)NR.sup.9R.sup.10. In one embodiment, R.sup.5, R.sup.6,
R.sup.7, and Rx are independently H, halogen, OH, CN, --NO.sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9,
--NR.sup.9S(O).sub.2. In one embodiment, R.sup.10. R.sup.5,
R.sup.6, R.sup.7, and Rx are independently H, halogen, OH, CN,
--NO.sub.2, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10,--S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9, --C(O)OR.sup.9. In one
embodiment, R.sup.5, R.sup.6, R.sup.7, and Rx are independently H,
halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9, --C(O)R.sup.9. In one embodiment, R.sup.5,
R.sup.6, R.sup.7, and Rx are independently H, halogen, OH, CN,
--NO.sub.2, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--,
--S(O).sub.2R.sup.9. In one embodiment, R.sup.5, R.sup.6, R.sup.7,
and Rx are independently H, halogen, OH, CN, --NO.sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10, --S(O).sub.2N(R.sup.9).sub.2--. In one
embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently H, halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9,
--NR.sup.9R.sup.10. In one embodiment, R.sup.5, R.sup.6, R.sup.7,
and R.sup.8 are independently H, halogen, OH, CN, --NO.sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, --SR.sup.9, --OR.sup.9, --NHR.sup.9. In one embodiment,
R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently H,
halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, heterocyclyl,
aryl, heteroaryl containing 1-5 heteroatoms selected from the group
consisting of N, S, P and O, --SR.sup.9, --OR.sup.9. In one
embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently 11, halogen, OH, CN, --NO.sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O, --SR.sup.9. In one embodiment, R.sup.5, R.sup.6,
R.sup.7, and R.sup.8 are independently H, halogen, OH, CN,
--NO.sub.2, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, aryl, or heteroaryl
containing 1-5 heteroatoms selected from the group consisting of N,
S, P and O. In one embodiment, R.sup.5, R.sup.6, R.sup.7, and
R.sup.8 are independently 11, halogen, OH, CN, --NO.sub.2,
C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.4-C.sub.8cycloalkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.3-C.sub.8cycloalkyl, heterocyclyl, or aryl. In one
embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently H, halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.8cycloalkyl, or heterocyclyl.
In one embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently H, halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl,
C.sub.2-C.sub.6alkynyl, or C.sub.3-C.sub.8cycloalkyl. In one
embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently H, halogen, OH, CN, --NO.sub.2, C.sub.1-C.sub.6alkyl,
C.sub.2-C.sub.6alkenyl, C.sub.4-C.sub.8cycloalkenyl, or
C.sub.2-C.sub.6alkynyl. In one embodiment, R.sup.5, R.sup.6,
R.sup.7, and R.sup.8 are independently H, halogen, OH, CN,
--NO.sub.2, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, or
C.sub.4-C.sub.8cycloalkenyl. In one embodiment, R.sup.5, R.sup.6,
R.sup.7, and R.sup.8 are independently H, halogen, OH, CN,
--NO.sub.2, C.sub.1-C.sub.6alkyl, or C.sub.2-C.sub.6alkenyl. In one
embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently H, halogen, OH, CN, --NO.sub.2, or
C.sub.1-C.sub.6alkyl. In one embodiment, R.sup.5, R.sup.6, R.sup.7,
and R.sup.8 are independently H, halogen, OH, CN, or--NO.sub.2. In
one embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently H, halogen, OH, or CN. In one embodiment, R.sup.5,
R.sup.6, R.sup.7, and R.sup.8 are independently H, halogen, or OH.
In one embodiment, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are
independently H or halogen.
[0393] In one embodiment, R.sup.5, R.sup.16, R.sup.17, and R.sup.18
are independently, at each occurrence, H, OH, NH.sub.2, or
C.sub.1-C.sub.3 alkyl. In a further embodiment, R.sup.15, R.sup.16,
R.sup.17, and R.sup.18 are independently, at each occurrence, H,
OH, or NH.sub.2. In a further embodiment, R.sup.15, R.sup.16,
R.sup.17, and R.sup.18 are independently, at each occurrence, H or
OH. In a further embodiment, R.sup.16, R.sup.17, and R.sup.18 are
independently, at each occurrence, H, OH, NH.sub.2, or
C.sub.1-C.sub.3 alkyl, wherein the alkyl is optionally substituted
with one or more R.sup.19.
[0394] In one embodiment, X is a bond, H, N, O, CR.sup.11R.sup.12,
CR.sup.11, C, --NIC(O)NH--, or C.sub.3-C.sub.6cyclolalkyl. In one
embodiment, X is a bond, H, N, O, CR.sup.11R.sup.12, CR.sup.11, C,
or --NHC(O)NH--. In one embodiment, X is a bond, H, N, O,
CR.sup.11R.sup.12, CR.sup.11, or C. In one embodiment, X is a bond,
H, N, O, CR.sup.11R.sup.12, or CR.sup.11. In one embodiment, X is a
bond, H, N, O, or CR.sup.11R.sup.12. In one embodiment, X is a
bond, H, N, or O. X is a bond, H, or N. In one embodiment, X is a
bond or H. in one embodiment, X is a bond. In another embodiment X
is H and n is 1. In another embodiment, X is N when n is 3. In
another embodiment, X is O and n is 2. In another embodiment, X is
CR.sup.11R.sup.12 and n is 2. In another embodiment, X is CR.sup.11
and n is 3. In another embodiment, X is C and n is 4. In another
embodiment, X is --NHC(O)NH--. In another embodiment, X is
C.sub.3-C.sub.6cyclolalkyl.
[0395] In some embodiments, R.sup.4 is H, C.sub.1-C.sub.6alkyl, or
C.sub.1-C.sub.6haloalkyl. In some embodiments, R.sup.4 is H or
C.sub.1-C.sub.6alkyl. In some embodiments, R.sup.14 is H. In some
embodiments, R.sup.14 is C.sub.1-C.sub.6alkyl. In some embodiments,
R.sup.14 is C.sub.1-C.sub.6haloalkyl.
[0396] In yet other embodiments, R.sup.6 and R.sup.14 together with
the atoms to which they are attached may combine to form, a 5-to-6
membered heterocyclyl. In other embodiments, R.sup.6 and R.sup.14
together with the atoms to which they are attached may combine to
form, independently, at each occurrence, 5-to-6 membered
heterocyclyl, wherein the heterocyclyl is optionally substituted
with one or more R.sup.19.
[0397] In other embodiments, R.sup.13 and R.sup.14 together with
the atoms to which they are attached may combine to form
independently, at each occurrence, C.sub.3-C.sub.8 cycloalkyl,
heterocyclyl, aryl, or heteroaryl. In other embodiments, R.sup.13
and R.sup.14 together with the atoms to which they are attached may
combine to form independently, at each occurrence, C.sub.3-C.sub.8
cycloalkyl, heterocyclyl, or aryl. In some embodiments, R.sup.13
and R.sup.14 together with the atoms to which they are attached may
combine to form independently, at each occurrence, C.sub.3-C.sub.8
cycloalkyl or heterocyclyl. In some embodiments, R.sup.13 and
R.sup.14 together with the atoms to which they are attached may
combine to form independently, at each occurrence, C.sub.3-C.sub.8
cycloalkyl. In some embodiments, R.sup.13 and R.sup.14 together
with the atoms to which they are attached may combine to form
independently, at each occurrence, heterocyclyl. In some
embodiments, R.sup.13 and R.sup.14 together with the atoms to which
they are attached may combine to form independently, at each
occurrence, aryl. In some embodiments, R.sup.13 and R.sup.14
together with the atoms to which they are attached may combine to
form independently, at each occurrence, heteroaryl.
[0398] In other embodiments, R.sup.13 and R.sup.14 together with
the atoms to which they are attached may combine to form
independently, at each occurrence, C.sub.3-C.sub.8 cycloalkyl,
heterocyclyl, aryl, or heteroaryl, wherein each heterocyclyl or
heteroaryl is optionally substituted with one or more R.sup.19. In
other embodiments, R.sup.13 and R.sup.14 together with the atoms to
which they are attached may combine to form independently, at each
occurrence, C.sub.3-C.sub.8 cycloalkyl, heterocyclyl, or aryl,
wherein each heterocyclyl is optionally substituted with one or
more R.sup.19. In some embodiments, R.sup.13 and R.sup.14 together
with the atoms to which they are attached may combine to form
independently, at each occurrence, C.sub.3-C.sub.8 cycloalkyl or
heterocyclyl, wherein each heterocyclyl is optionally substituted
with one or more R.sup.19. In some embodiments, R.sup.13 and
R.sup.14 together with the atoms to which they are attached may
combine to form independently, at each occurrence, C.sub.3-C.sub.8
cycloalkyl. In some embodiments, R.sup.13 and R.sup.14 together
with the atoms to which they are attached may combine to form
independently, at each occurrence, heterocyclyl, wherein each
heterocyclyl is optionally substituted with one or more R.sup.11.
In some embodiments, R.sup.13 and R.sup.14 together with the atoms
to which they are attached may combine to form independently, at
each occurrence, aryl. In some embodiments, R.sup.13 and R.sup.14
together with the atoms to which they are attached may combine to
form independently, at each occurrence, heteroaryl, wherein each
heteroaryl is optionally substituted with one or more R.sup.19.
[0399] In some embodiments, u is 0, 1, or 2. In some embodiments, u
is 0 or 1. In some embodiments, u is 0. In some embodiments, u is
1. In some embodiments, u is 2.
[0400] In some embodiments, n is 1, 2, 3, or 4. In some
embodiments, n is 1, 2, or 3. In some embodiments, n is 1 or 2. In
some embodiments, n is 1. In some embodiments, n is 2. In some
embodiments, n is 3. In some embodiments, n is 4.
[0401] In some embodiments, s is 0, 1, 2, 3, or 4. In some
embodiments, s is 0, 1, 2, or 3. In some embodiments, s is 0, 1, or
2. In some embodiments, s is 0 or 1. In some embodiments, s is 0.
In some embodiments, s is 1. In some embodiments, s is 2. In some
embodiments, s is 3. In some embodiments, s is 4.
[0402] In some embodiments, r is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In
some embodiments, r is 0, 1, 2, 3, 4, 5, 6, or 7. In some
embodiments, r is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, r is
0, 1, 2, 3, 4, or 5. In some embodiments, r is 0, 1, 2, 3, or 4. In
some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 0,
1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r
is 0. In some embodiments, r is 1. In some embodiments, r is 2. In
some embodiments, r is 3. In some embodiments, r is 4. In some
embodiments, r is 5. In some embodiments, r is 6. In some
embodiments, r is 7. In some embodiments, r is 8.
[0403] In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In
some embodiments, p is 0, 1, 2, 3, 4, 5, 6, or 7. In some
embodiments, p is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, p is
0, 1, 2, 3, 4, or 5. In some embodiments, p is 0, 1, 2, 3, or 4. In
some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0,
1, or 2. In some embodiments, p is 0 or 1. In some embodiments, p
is 0. In some embodiments, p is 1. In some embodiments, p is 2. In
some embodiments, p is 3. In some embodiments, p is 4. In some
embodiments, p is 5. In some embodiments, p is 6. In some
embodiments, p is 7. In some embodiments, p is 8.
[0404] In designing and making the substantially impermeable or
substantially systemically non-bioavailable NHE-inhibiting
compounds of the present invention that may be utilized for the
treatments detailed in the instant disclosure.
[0405] Another aspect, compounds of the present invention with
extended hydrocarbon functionalities may collapse upon themselves
in an intramolecular fashion, causing an increased enthalpic
barrier for interaction with the desired biological target.
Accordingly, when designing "X" and Linkers moieties, these are
designed to be resistant to hydrophobic collapse. For example,
conformational constraints such as rigid monocyclic, bicyclic or
polycyclic rings can be installed in a "X" and Linker moiety to
increase the rigidity of the structure. Unsaturated bonds, such as
alkenes and alkynes, may also or alternatively be installed. Such
modifications may ensure the NHE-inhibiting compound is accessible
for productive binding with its target. Furthermore, the
hydrophilicity of the Linkers may be improved by adding hydrogen
bond donor or acceptor motifs, or ionic motifs such as amines that
are protonated in the GI, or acids that are deprotonated. Such
modifications will increase the hydrophilicity of the "X" and
Linker moieties and help prevent hydrophobic collapse. Furthermore,
such modifications will also contribute to the impermeability of
the resulting compounds by increasing tPSA.
[0406] One skilled in the art may also consider a variety of
functional groups that will allow the facile and specific
attachment of the rest of the molecule of the compounds of Formula
I to the "X" moiety and/or Linker. These functional groups can
include electrophiles, which can react with nucleophilic groups,
and/or nucleophiles, which can react with electrophilic "X" and
Linker moieties. NHE-inhibiting compounds of Formula I may also be
similarly derivatized with, for example, boronic acid groups. The
NHE-inhibiting compounds of Formula I may also contain olefins via
olefin metathesis chemistry, or alkynes or azides which can then
react with appropriate other "X" and Linker via [2+3]
cycloaddition.
[0407] It is to be noted that one skilled in the art can envision a
number of "X" and Linker moieties that may be functionalized with
an appropriate electrophile or nucleophile. Shown below are a
series of such compounds selected based on several design
considerations, including solubility, steric effects, and their
ability to confer, or be consistent with, favorable
structure-activity relationships. In this regard it is to be
further noted, however, that the structures provided below, and
above, are for illustration purposes only, and therefore should not
be viewed in a limiting sense.
[0408] Exemplary electrophilic and nucleophilic Linker moieties
include, but are not limited to, the Linker moieties illustrated in
the Examples and the following:
##STR00022## ##STR00023##
[0409] The linking moiety, Linker, in each of the described
embodiments can also be a chemical bond or other moiety, for
example that can be hydrophilic and/or hydrophobic. In one
embodiment, the linking moiety can be a polymer moiety grafted onto
a polymer backbone, for example, using living free radical
polymerization approaches known in the art.
[0410] In another embodiment, "X" moieties illustrated in the
compounds of Formula I may also include, but are not limited to,
ether moieties, ester moieties, sulfide moieties, disulfide
moieties, amine moieties, aryl moieties, alkoxy]moieties, etc.,
such as, for example, the following:
##STR00024## ##STR00025##
wherein the broken bonds (i.e., those having a wavy bond, , through
them) are points of connection to the rest of the molecule of
Formula I when n>1, where said points of connection can be made
using chemistries and functional groups known to the art of
medicinal chemistry; and further wherein each p', q', r' and s' is
an independently selected integer ranging from about 0 to about 48,
from about 0 to about 36, or from about 0 to about 24, or from
about 0 to about 16. In some instances, each p, q, r and s can be
an independently selected integer ranging from about 0 to 12.
Additionally, R' can be a substituent moiety generally selected
from halide, hydroxyl, amine, thiol, ether, carbonyl, carboxyl,
ester, amide, carbocyclic, heterocyclic, and moieties comprising
combinations thereof.
[0411] In another approach, the "X" moiety of formula I may be a
dendrimer, defined as a repeatedly branched molecule (see, e.g., J.
M. J. Frechet, D. A. Tomalia, Dendrimers and Other Dendritic
Polymers, John Wiley & Sons, Ltd. NY, NY, 2001) and
schematically represented below:
[0412] In this approach, the rest of the NHE-inhibiting molecule is
attached through Linker to one, several or optionally all termini
located at the periphery of the dendrimer. In another approach, a
dendrimer building block named dendron, and illustrated above, is
used as "X" moiety, wherein the rest of NHE-inhibiting molecule is
attached to one, several or optionally all termini located at the
periphery of the dendron. The number of generations herein is
typically between about 0 and about 6, and between about 0 and
about 3. (Generation is defined in, for example, J. M. J. Frechet,
D. A. Tomalia, Dendrimers and Other Dendritic Polymers, John Wiley
& Sons, Ltd. NY, NY.) Dendrimer and/or dendron structures are
well known in the art and include, for example, those shown in or
illustrated by: (i) J. M. J. Frechet, D. A. Tomalia, Dendrimers and
Other Dendritic Polymers, John Wiley & Sons, Ltd. NY, NY; (ii)
George R Newkome, Charles N. Moorefield and Fritz Vogtle,
Dendrimers and Dendrons: Concepts, Syntheses, Applications, VCH
Verlagsgesellschaft Mbh; and, (iii) Boas, U., Christensen, J. B.,
Heegaard, P.M.H., Dendrimers in Medicine and Biotechnology: New
Molecular Tools, Springer, 2006.
[0413] In yet another approach, the "X" moiety may be a polymer
moiety or an oligomer moiety. The polymer or oligomer may, in each
case, be independently considered and comprise repeat units
consisting of a repeat moiety selected from alkyl (e.g.,
--CH.sub.2--), substituted alkyl (e.g., --CHR--, wherein, for
example, R is hydroxy), alkenyl, substituted alkenyl, alkynyl,
substituted alkynyl, phenyl, aryl, heterocyclic, amine, ether,
sulfide, disulfide, hydrazine, and any of the foregoing substituted
with oxygen, sulfur, sulfonyl, phosphonyl, hydroxyl, alkoxyl,
amine, thiol, ether, carbonyl, carboxyl, ester, amide, alkyl,
alkenyl, alkynyl, aryl, heterocyclic, as well as moieties
comprising combinations thereof. In still another approach, the "X"
moiety comprises repeat units resulting from the polymerization of
ethylenic monomers (e.g., such as those ethylenic monomers listed
elsewhere herein below).
[0414] Preferred polymers for polymeric moieties useful in
constructing substantially impermeable or substantially
systemically non-bioavailable NHE-inhibiting compounds that are
multivalent, for use in the treatment various treatment methods
disclosed herein, can be prepared by any suitable technique, such
as by free radical polymerization, condensation polymerization,
addition polymerization, ring-opening polymerization, and/or can be
derived from naturally occurring polymers, such as saccharide
polymers. Further, in some embodiments, any of these polymer
moieties may be functionalized.
[0415] Examples of polysaccharides useful in preparation of such
compounds include but are not limited to materials from vegetable
or animal origin, including cellulose materials, hemicellulose,
alkyl cellulose, hydroxyalkyl cellulose, carboxymethylcellulose,
sulfoethylcellulose, starch, xylan, amylopectine, chondroitin,
hyarulonate, heparin, guar, xanthan, mannan, galactomannan, chitin,
and/or chitosan. More preferred, in at least some instances, are
polymer moieties that do not degrade, or that do not degrade
significantly, under the physiological conditions of the GI tract
(such as, for example, carboxymethylcellulose, chitosan, and
sulfoethylcellulose).
[0416] When free radical polymerization is used, the polymer moiety
can be prepared from various classes of monomers including, for
example, acrylic, methacrylic, styrenic, vinylic, and dienic, whose
typical examples are given thereafter: styrene, substituted
styrene, alkyl acrylate, substituted alkyl acrylate, alkyl
methacrylate, substituted alkyl methacrylate, acrylonitrile,
methacrylonitrile, acrylamide, methacrylamide, N-alkylacrylamide,
N-alkylmethacrylamide, N,N-dialkylacrylamide,
N,N-dialkylmethacrylamide, isoprene, butadiene, ethylene, vinyl
acetate, and combinations thereof. Functionalized versions of these
monomers may also be used and any of these monomers may be used
with other monomers as comonomers. For example, specific monomers
or comonomers that may be used in this disclosure include methyl
methacrylate, ethyl methacrylate, propyl methacrylate (all
isomers), butyl methacrylate (all isomers), 2-ethylhexyl
methacrylate, isobornyl methacrylate, methacrylic acid, benzyl
methacrylate, phenyl methacrylate, methacrylonitrile,
.alpha.-methylstyrene, methyl acrylate, ethyl acrylate, propyl
acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl
acrylate, isobornyl acrylate, acrylic acid, benzyl acrylate, phenyl
acrylate, acrylonitrile, styrene, glycidyl methacrylate,
2-hydroxyethyl methacrylate, hydroxypropyl methacrylate (all
isomers), hydroxybutyl methacrylate (all isomers),
N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl
methacrylate, triethyleneglycol methacrylate, itaconic anhydride,
itaconic acid, glycidyl acrylate, 2-hydroxyethyl acrylate,
hydroxypropyl acrylate (all isomers), hydroxybutyl acrylate (all
isomers), N,N-dimethylaminoethyl acrylate, N,N-diethylaminoethyl
acrylate, triethyleneglycol acrylate, methacrylamide,
N-methylacrylamide, N,N-dimethylacrylamide,
N-tert-butylmethacrylamide, N--N-butylmethacrylamide,
N-methylolmethacrylamide, N-ethylolmethacrylamide,
N-tert-butylacrylamide, N--N-butylacrylamide, N-methylolacrylamide,
N-ethylolacrylamide, 4-acryloylmorpholine, vinyl benzoic acid (all
isomers), diethylaminostyrene (all isomers), .alpha.-methylvinyl
benzoic acid (all isomers), diethylamino .alpha.-methylstyrene (all
isomers), p-vinylbenzenesulfonic acid, p-vinylbenzenesulfonic
sodium salt, alkoxy and alkyl silane functional monomers, maleic
anhydride, N-phenylmaleimide, N-butylmaleimide, butadiene,
isoprene, chloroprene, ethylene, vinyl acetate, vinylformamide,
allylamine, vinylpyridines (all isomers), fluorinated acrylate,
methacrylates, and combinations thereof. Main chain heteroatom
polymer moieties can also be used, including polyethyleneimine and
polyethers such as polyethylene oxide and polypropylene oxide, as
well as copolymers thereof.
[0417] In one particular embodiment, the polymer to which the
NHE-inhibiting molecule is attached, or otherwise a part of, is a
polyol (e.g., a polymer having a repeat unit of, for example, a
hydroxy]-substituted alkyl, such as --CH(OH)--). Polyols, such as
mono- and disaccharides, with or without reducing or reducible end
groups thereon, may be good candidates, for example, for installing
additional functionality that could render the compound
substantially impermeable.
[0418] In one particular embodiment, the NHE-inhibiting molecule is
attached at one or both ends of the polymer chain. More
specifically, in yet another alternative approach to the polyvalent
embodiment of the present disclosure, a macromolecule (e.g., a
polymer or oligomer) having the generic following exemplary
structures
##STR00026##
which may be exemplified, designed, and/or constructed as described
for the moieties:
##STR00027##
[0419] It is understood that any embodiment of the compounds of the
present invention, as set forth above, and any specific substituent
set forth herein in such compounds, as set forth above, may be
independently combined with other embodiments and/or substituents
of such compounds to form embodiments of the inventions not
specifically set forth above. In addition, in the event that a list
of substituents is listed for any particular substituent in a
particular embodiment and/or claim, it is understood that each
individual substituent may be deleted from the particular
embodiment and/or claim and that the remaining list of substituents
will be considered to be within the scope of the invention.
Furthermore, it is understood that in the present description,
combinations of substituents and/or variables of the depicted
formulae are permissible only if such contributions result in
stable compounds.
[0420] B. Permeability
[0421] In this regard it is to be noted that, in various
embodiments, the ability of a compound to be substantially
systemically non-bioavailable is based on the compound charge,
size, and/or other physicochemical parameters (e.g., polar surface
area, number of hydrogen bond donors and/or acceptors therein,
number of freely rotatable bonds, etc.). More specifically, it is
to be noted that the absorption character of a compound can be
selected by applying principles of pharmacodynamics, for example,
by applying Lipinski's rule, also known as "the rule of five."
Although not a rule, but rather a set of guidelines, Lipinski shows
that small molecule drugs with (i) a molecular weight, (ii) a
number of hydrogen bond donors, (iii) a number of hydrogen bond
acceptors, and/or (iv) a water/octanol partition coefficient
(Moriguchi Log P), greater than a certain threshold value,
generally do not show significant systemic concentration (i.e., are
generally not absorbed to any significant degree). (See, e.g.,
Lipinski et al., Advanced Drug Delivery Reviews, 46, 2001 3-26,
incorporated herein by reference.) Accordingly, substantially
systemically non-bioavailable compounds (e.g., substantially
systemically non-bioavailable NHE-inhibiting compounds) can be
designed to have molecular structures exceeding one or more of
Lipinski's threshold values. (See also Lipinski et al.,
Experimental and Computational Approaches to Estimate Solubility
and Permeability in Drug Discovery and Development Settings, Adv.
Drug Delivery Reviews, 46:3-26 (2001); and Lipinski, Drug-like
Properties and the Causes of Poor Solubility and Poor Permeability,
J. Pharm. & Toxicol. Methods, 44:235-249 (2000), incorporated
herein by reference.) In some embodiments, for example, a
substantially impermeable or substantially systemically
non-bioavailable NHE-inhibiting compound of the present disclosure
can be constructed to feature one or more of the following
characteristics: (i) a MW greater than about 500 Da, about 1000 Da,
about 2500 Da, about 5000 Da, about 10,000 Da or more (in the
non-salt form of the compound); (ii) a total number of NH and/or OH
and/or other potential hydrogen bond donors greater than about 5,
about 10, about 15 or more; (iii) a total number of O atoms and/or
N atoms and/or other potential hydrogen bond acceptors greater than
about 5, about 10, about 15 or more; and/or (iv) a Moriguchi
partition coefficient greater than about 10.sup.5 (i.e., Log P
greater than about 5, about 6, about 7, etc.), or alternatively
less than about 10 (i.e., a Log P of less than 1, or even 0).
[0422] In addition to the parameters noted above, the molecular
polar surface area (i.e., "PSA"), which may be characterized as the
surface belonging to polar atoms, is a descriptor that has also
been shown to correlate well with passive transport through
membranes and, therefore, allows prediction of transport properties
of drugs. It has been successfully applied for the prediction of
intestinal absorption and Caco2 cell monolayer penetration. (For
Caco2 cell monolayer penetration test details, see for example the
description of the Caco2 Model provided in Example 31 of U.S. Pat.
No. 6,737,423, the entire contents of which are incorporated herein
by reference for all relevant and consistent purposes, and the text
of Example 31 in particular, which may be applied for example to
the evaluation or testing of the compounds of the present
disclosure.) PSA is expressed in {acute over (.ANG.)}.sup.2
(squared angstroms) and is computed from a three-dimensional
molecular representation. A fast calculation method is now
available (see, e.g., Ertl et al., Journal of Medicinal Chemisiry,
2000, 43, 3714-3717, the entire contents of which are incorporated
herein by reference for all relevant and consistent purposes) using
a desktop computer and commercially available chemical graphic
tools packages, such as ChemDraw. The term "topological PSA" (tPSA)
has been coined for this fast-calculation method. tPSA is well
correlated with human absorption data with common drugs (see, e.g.,
Table 1, below):
TABLE-US-00001 TABLE 1 name % FA.sup.a TPSA.sup.b metoprolol 102
50.7 nordiazepam 99 41.5 diazepam 97 32.7 oxprenolol 97 50.7
phenazone 97 26.9 oxazepam 97 61.7 alprenolol 96 41.9 practolol 95
70.6 pindolol 92 57.3 ciprofloxacin 69 74.6 metolazone 64 92.5
tranexamic acid 55 63.3 atenolol 54 84.6 sulpiride 36 101.7
mannitol 26 121.4 foscarnet 17 94.8 sulfasalazine 12 141.3
olsalazine 2.3 139.8 lactulose 0.6 197.4 raffinose 0.3 268.7
(from Ertl et al., J. Med. Chem., 2000, 43:3714-3717). Accordingly,
in some preferred embodiments, the compounds of the present
disclosure may be constructed to exhibit a tPSA value greater than
about 100 .ANG..sup.2, about 120 .ANG..sup.2, about 130
.ANG..sup.2, or about 140 .ANG..sup.2, and in some instances about
150 .ANG..sup.2, about 200 .ANG..sup.2, about 250 .ANG..sup.2,
about 270 .ANG..sup.2, about 300 .ANG..sup.2, about 400
.ANG..sup.2, or even about 500 .ANG..sup.2, such that the compounds
are substantially impermeable or substantially systemically
non-bioavailable (as defined elsewhere herein).
[0423] Because there are exceptions to Lipinski's "rule," or the
tPSA model, the permeability properties of the compounds of the
present disclosure may be screened experimentally. The permeability
coefficient can be determined by methods known to those of skill in
the art, including for example by Caco-2 cell permeability assay
and/or using an artificial membrane as a model of a
gastrointestinal epithelial cell. (As previously noted above, see
for example U.S. Pat. No. 6,737,423, Example 31 for a description
of the Caco-2 Model, which is incorporated herein by reference). A
synthetic membrane impregnated with, for example, lecithin and/or
dodecane to mimic the net permeability characteristics of a
gastrointestinal mucosa, may be utilized as a model of a
gastrointestinal mucosa. The membrane can be used to separate a
compartment containing the compound of the present disclosure from
a compartment where the rate of permeation will be monitored. Also,
parallel artificial membrane permeability assays (PAMPA) can be
performed. Such in vitro measurements can reasonably indicate
actual permeability in vivo. (See, for example, Wohnsland et al.,
J. Med. Chem., 2001, 44:923-930; Schmidt et al., Millipore Corp.
Application Note, 2002, no AN1725EN00, and no AN1728EN00,
incorporated herein by reference.)
[0424] Accordingly, in some embodiments, the compounds utilized in
the methods of the present disclosure may have a permeability
coefficient, Papp, of less than about 100.times.10.sup.-6 cm/s, or
less than about 10.times.10.sup.-6 cm/s, or less than about
1.times.10.sup.-6 cm/s, or less than about 0.1.times.10.sup.-6
cm/s, when measured using means known in the art (such as for
example the permeability experiment described in Wohnsland et al.,
J. Med. Chem., 2001, 44, 923-930, the contents of which is
incorporated herein by reference).
[0425] As previously noted, in accordance with the present
disclosure, a NHE-inhibiting compound is modified as described
above to hinder the net absorption through a layer of gut
epithelial cells, rendering the resulting compound substantially
systemically non-bioavailable. In various embodiments, the
compounds of the present disclosure are substantially impermeable
or substantially systemically non-bioavailable. More specifically,
the NHE-inhibiting can be a dimer, multimer or polymer moiety, such
that the resulting compound is substantially impermeable or
substantially systemically non-bioavailable. The dimer, multimer or
polymer may be of a molecular weight greater than about 500 Daltons
(Da), about 1000 Da, about 2500 Da, about 5000 Da, about 10,000 Da
or more, and in particular may have a molecular weight in the range
of about 1000 Daltons (Da) to about 500,000 Da, or in the range of
about 5000 to about 200,000 Da, and may have a molecular weight
that is sufficiently high to essentially preclude any net
absorption through a layer of gut epithelial cells of the
compound.
[0426] C. Persistent Inhibitory, Effect
[0427] In other embodiments, the substantially impermeable or
substantially systemically non-bioavailable NHE-inhibiting
compounds utilized in the treatment methods of the present
disclosure may additionally exhibit a persistent inhibitor effect.
This effect manifests itself when the inhibitory action of a
compound at a certain concentration in equilibrium with the
epithelial cell (e.g., at or above its inhibitory concentration,
IC) does not revert to baseline (i.e., sodium transport without
inhibitor) after the compound is depleted by simple washing of the
luminal content.
[0428] This effect can be interpreted as a result of the tight
binding of the NHE-inhibiting compounds to the NHE protein at the
intestinal apical side of the gut epithelial cell. The binding can
be considered as quasi-irreversible to the extent that, after the
compound has been contacted with the gut epithelial cell and
subsequently washed off said gut epithelial cell, the flux of
sodium transport is still significantly lower than in the control
without the compound. This persistent inhibitory effect has the
clear advantage of maintaining drug activity within the GI tract
even though the residence time of the active in the upper GI tract
is short, and when no entero-biliary recycling process is effective
to replenish the compound concentration near its site of
action.
[0429] Such a persistent inhibitory effect has an obvious advantage
in terms of patient compliance, but also in limiting drug exposure
within the GI tract.
[0430] The persistence effect can be determined using in vitro
methods; in one instance, cell lines expressing NHE transporters
are split in different vials and treated with a NHE-inhibiting
compound and sodium solution to measure the rate of sodium uptake.
The cells in one set of vials are washed for different periods of
time to remove the inhibitor, and sodium uptake measurement is
repeated after the washing. Compounds that maintain their
inhibitory effect after multiple/lengthy washing steps (compared to
the inhibitory effect measured in the vials where washing does not
occur) are persistent inhibitors. Persistence effect can also be
characterized ex vivo by using the everted sac technique, whereby
transport of Na is monitored using an excised segment of GI
perfused with a solution containing the inhibitor and shortly after
flushing the bathing solution with a buffer solution free from
inhibitor. A persistence effect can also be characterized in vivo
by observing the time needed for sodium balance to return to normal
when the inhibitor treatment is discontinued. The limit of the
method resides in the fact that apical cells (and therefore apical
NHE transporters) are sloughed off after a period of 3 to 4 days,
the typical turnover time of gut epithelial cells. A persistence
effect can be achieved by increasing the residence time of the
active compound at the apical surface of the gut epithelial cells;
this can be obtained by designing NHE antiport inhibitors with
several NHE-inhibiting molecule or oligomer (wherein "several" as
used herein typically means at least about 2, about 4, about 6 or
more). Examples of such structures in the context of analogs of the
antibiotic vancomycin are given in Griffin, et al., J. Am. Chem.
Soc., 2003, 125, 6517-6531. Alternatively the compound comprises
groups that contribute to increase the affinity towards the gut
epithelial cell so as to increase the time of contact with the gut
epithelial cell surface. Such groups are referred to as being
"mucoadhesive." More specifically, the "X" and Linker moieties can
be substituted by such mucoadhesive groups, such as polyacrylates,
partially deacetylated chitosan or polyalkylene glycol. (See also
Patil, S. B. et al., Curr. Drug. Deliv., 2008, Oct. 5(4), pp.
312-8.) Compounds of the invention incorporating a cyano group at
the 4-position of the indane ring system of formula I unexpectedly
exhibited superior persistent inhibition of NHE3 in the cell-based
assay described in example 181 herein in comparison to compounds
incorporating other groups at said positions 4 and 6. For example,
compounds incorporating 4-cyano and 6-chloro groups demonstrated
superior persistent inhibition compared to the analagous compound
having a 4,6-dichloro substituted indane ring system. See following
table. The following pairs of compounds differ only in the
4-position substituent (either chloro (X-Cl) or cyano (X-CN)):
[0431] (A-Cl)
3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-
-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}e-
thyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2
S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl-
]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino}butyl-
)urea; and [0432] (A-CN)
3-(2-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-
-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]etho-
xy}ethyl)-1-(4-{[(2-{2-[(3R)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-met-
hylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrol-
idin-1-yl]ethoxy}ethyl)carbamoyl]amino}butyl)urea. [0433] (B-Cl)
N-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazin-1-yl]-2,-
3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl-
]-2-({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-methylpiperazi-
n-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]--
2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamid-
e; and [0434] (B-CN) N-{2-[(3
S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-di-
hydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]-2-oxoethyl}-2--
({[4-({[({2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazi-
n-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]--
2-oxoethyl}carbamoyl)methyl]carbamoyl}amino)butyl]carbamoyl}amino)acetamid-
e. [0435] (C-Cl)
3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl-
)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy-
}ethyl)carbamoyl]amino}butyl)urea; and [0436] (C-CN)
3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperid-
in-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy)ethoxy}et-
hyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamin-
o)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]-
ethoxy}ethyl)carbamoyl]amino}butyl)urea. [0437] (C-Cl)
3-(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl-
)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy-
}ethyl)carbamoyl]amino}butyl)urea; and [0438] (C-CN)
3-(2-[2-[(3S)-3-[4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihy-
dro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-yl]ethoxy}e-
thyl)-1-(4-{[(2-[2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl-
)-2,3-dihydro-1H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)pyrrolidin-1-y-
l]ethoxy}ethyl)carbamoyl]amino}butyl)urea. [0439] (D-Cl)
3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-in-
den-1-yl]oxy}-3-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-
-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy}-3-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl-
)urea; and
[0440] (D-CN)
3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy}-3-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(-
2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-in-
den-1-yl]oxy}-3-fluorobenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]ami-
no}butyl)urea. [0441] (E-Cl)
3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piperidin-1-
-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-
-1-(4-{[(2-{2-[2-[(4-({(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)piper-
idin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}-
ethyl)carbamoyl]amino}butyl)urea; and [0442] (E-CN)
3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperid-
in-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}et-
hyl)-1-(4-{[(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamin-
o)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]-
ethoxy}ethyl)carbamoyl]amino}butyl)urea. [0443] (F-Cl)
3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-in-
den-1-yl]oxy}-3-methylbenzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-
-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy}-3-methylbenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl-
)urea; and [0444] (F-CN)
3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy}-3-methylbenzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(-
2-{2-[2-(4-{[(1S,2
S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}-3-m-
ethylbenzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea.
[0445] (G-Cl)
3-(2-{2-[2-(4-{[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-in-
den-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2-{2-[2-(4-{[-
(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy}benz-
enesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)urea; and
[0446] (G-CN)
3-(2-{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)-1-(4-{[(2--
{2-[2-(4-{[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inde-
n-1-yl]oxy}benzenesulfonamido)ethoxy]ethoxy}ethyl)carbamoyl]amino}butyl)ur-
ea.
TABLE-US-00002 [0446] pIC50 Standard Percent Compound (persistent)
Deviation n Inhibition A-Cl 8.6 0.2 3 101 A-CN 9.2 0.1 2 101 B-Cl
9.2 0 2 102 B-CN 9.9 0.1 6 110 C-Cl 8.4 0.1 2 90 C-CN 9.3 0.3 3 106
D-Cl 8.4 0.1 2 -- D-CN 9.3 0.1 2 74 E-Cl 8.3 0.3 5 99 E-CN 8.9 0.8
4 36 F-Cl 7.7 0.2 5 104 F-CN 8.6 0.1 2 88 G-Cl 8.2 0.1 2 82 G-CN
9.0 0.2 2 --
[0447] Accordingly, in an embodiment of the invention there is
provided a compound having a structure according to any one of
formula (I') and (Ia') through (Ii').
[0448] D. GI Enzyme Resistance
[0449] Because the compounds utilized in the treatment methods of
the present disclosure are substantially systemically
non-bioavailable, and/or exhibit a persistent inhibitory effect, it
is also desirable that, during their prolonged residence time in
the gut, these compounds sustain the hydrolytic conditions
prevailing in the upper GI tract. In such embodiments, compounds of
the present disclosure are resistant to enzymatic metabolism. For
example, administered compounds are resistant to the activity of
P450 enzymes, glucurosyl transferases, sulfotransferases,
glutathione S-transferases, and the like, in the intestinal mucosa,
as well as gastric (e.g., gastric lipase, and pepsine), pancreatic
(e.g., trypsin, triglyceride pancreatic lipase, phospholipase A2,
endonucleases, nucleotidases, and alpha-amylase), and brush-border
enzymes (e.g., alkaline phosphatase, glycosidases, and proteases)
generally known in the art.
[0450] The compounds that are utilized in methods of the present
disclosure are also resistant to metabolism by the bacterial flora
of the gut; that is, the compounds are not substrates for enzymes
produced by bacterial flora. In addition, the compounds
administered in accordance with the methods of the present
disclosure may be substantially inactive towards the
gastrointestinal flora, and do not disrupt bacterial growth or
survival. As a result, in various embodiments herein, the minimal
inhibitory concentration (or "MIC") against GI flora is desirably
greater than about 15 .mu.g/ml, about 30 .mu.g/ml, about 60
.mu.g/ml, about 120 .mu.g/ml, or even about 240 .mu.g/ml, the MIC
in various embodiments being for example between about 16 and about
32 .mu.g/ml, or between about 64 and about 128 .mu.g/ml, or greater
than about 256 .mu.g/ml.
[0451] To one skilled in the art of medicinal chemistry, metabolic
stability can be achieved in a number of ways. Functionality
susceptible to P450-mediated oxidation can be protected by, for
example, blocking the point of metabolism with a halogen or other
functional group. Alternatively, electron withdrawing groups can be
added to a conjugated system to generally provide protection to
oxidation by reducing the electrophilicity of the compound.
Proteolytic stability can be achieved by avoiding secondary amide
bonds, or by incorporating changes in stereochemistry or other
modifications that prevent the drug from otherwise being recognized
as a substrate by the metabolizing enzyme.
[0452] E. Sodium and/or Fluid Output
[0453] It is also to be noted that, in various embodiments of the
present disclosure, one or more of the NHE-inhibiting compounds
detailed herein, when administered either alone or in combination
with one or more additional pharmaceutically active compounds or
agents (including, for example, a fluid-absorbing polymer) to a
patient in need thereof, may act to increase the patient's daily
fecal output of sodium by at least about 20, about 30 mmol, about
40 mmol, about 50 mmol, about 60 mmol, about 70 mmol, about 80
mmol, about 90 mmol, about 100 mmol, about 125 mmol, about 150 mmol
or more, the increase being for example within the range of from
about 20 to about 150 mmol/day, or from about 25 to about 100
mmol/day, or from about 30 to about 60 mmol/day
[0454] Additionally, or alternatively, it is also to be noted that,
in various embodiments of the present disclosure, one or more of
the NHE-inhibiting compounds detailed herein, when administered
either alone or in combination with one or more additional
pharmaceutically active compounds or agents (including, for
example, a fluid-absorbing polymer) to a patent in need thereof,
may act to increase the patient's daily fluid output by at least
about 100 ml, about 200 ml, about 300 ml, about 400 ml, about 500
ml, about 600 ml, about 700 ml, about 800 ml, about 900 ml, about
1000 ml or more, the increase being for example within the range of
from about 100 to about 1000 ml/day, or from about 150 to about 750
ml/day, or from about 200 to about 500 nl/day (assuming isotonic
fluid).
[0455] F. C.sub.max and IC.sub.50
[0456] It is also to be noted that, in various embodiments of the
present disclosure, one or more of the NHE-inhibiting compounds
detailed herein, when administered either alone or in combination
with one or more additional pharmaceutically active compounds or
agents (including, for example, a fluid-absorbing polymer) to a
patient in need thereof at a dose resulting in at least a 10%
increase in fecal water content, has a C.sub.max that is less than
the IC.sub.50 for NHE-3, more specifically, less than about
10.times. (10 times) the IC.sub.50, and, more specifically still,
less than about 100.times. (100 times) the IC.sub.50.
[0457] Additionally, or alternatively, it is also to be noted that,
in various embodiments of the present disclosure, one or more of
the NHE-inhibiting compounds detailed herein, when administered
either alone or in combination with one or more additional
pharmaceutically active compounds or agents (including, for
example, a fluid-absorbing polymer) to a patient in need thereof,
may have a C.sub.max of less than about 10 ng/ml, about 7.5 ng/ml,
about 5 ng/ml, about 2.5 ng/ml, about 1 ng/ml, or about 0.5 ng/ml,
the C.sub.max being for example within the range of about 1 ng/ml
to about 10 ng/ml, or about 2.5 ng/ml to about 7.5 ng/ml.
[0458] Additionally, or alternatively, it is also to be noted that,
in various embodiments of the present disclosure, one or more of
the NHE-inhibiting compounds detailed herein, when administered
either alone or in combination with one or more additional
pharmaceutically active compounds or agents (including, for
example, a fluid-absorbing polymer) to a patient in need thereof,
may have a IC.sub.50 of less than about 10 .mu.M, about 7.5 .mu.M,
about 5 .mu.M, about 2.5 .mu.M, about 1 .mu.M, or about 0.5 .mu.M,
the IC.sub.50 being for example within the range of about 1 .mu.M
to about 10 .mu.M, or about 2.5 .mu.M to about 7.5 .mu.M.
[0459] Additionally, or alternatively, it is also to be noted that,
in various embodiments of the present disclosure, one or more of
the NHE-inhibiting compounds detailed herein, when administered to
a patient in need thereof, may have a ratio of IC.sub.50:C.sub.max,
wherein IC.sub.50 and C.sub.max are expressed in terms of the same
units, of at least about 10, about 50, about 100, about 250, about
500, about 750, or about 1000.
[0460] Additionally, or alternatively, it is also to be noted that,
in various embodiments of the present disclosure, wherein one or
more of the NHE-inhibiting compounds as detailed herein is orally
administered to a patent in need thereof, within the therapeutic
range or concentration, the maximum compound concentration detected
in the serum, defined as C.sub.max, is lower than the NHE
inhibitory concentration IC.sub.50 of said compound. As previously
noted, as used herein, IC.sub.50 is defined as the quantitative
measure indicating the concentration of the compound required to
inhibit 50% of the NHE-mediated Na/H antiport activity in a cell
based assay.
III. Pharmaceutical Compositions and Methods of Treatment
[0461] A Compositions and Methods
[0462] 1. Fluid Retention and/or Salt Overload Disorders
[0463] Another aspect of the invention is directed to method for
inhibiting NHE-mediated antiport of sodium and hydrogen ions. The
method comprises administering to a mammal in need thereof a
pharmaceutically effective amount of a compound or pharmaceutical
composition of Formula I. In one embodiment, the method comprises
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or
Ii or a combination thereof.
[0464] Another aspect of the invention is directed to method for
treating a disorder associated with fluid retention or salt
overload. The method comprises administering to a mammal in need
thereof a pharmaceutically effective amount of a compound or
pharmaceutical composition of Formula I. In one embodiment, the
method of treating a disorder associated with fluid retention or
salt overload comprises administering to a mammal in need thereof a
pharmaceutically effective amount of a compound Ia, Ib, Ic, Id, Ie,
If, Ig, Ih, or Ii or a combination thereof.
[0465] In one embodiment, a method for treating a disorder selected
from the group consisting of heart failure (such as congestive
heart failure), chronic kidney disease, end-stage renal disease,
liver disease, and peroxisome proliferator-activated receptor
(PPAR) gamma agonist-induced fluid retention is provided, the
method comprising administering to a mammal in need thereof a
pharmaceutically effective amount of a compound or pharmaceutical
composition as set forth above. In another embodiment, the disorder
is, but not limited to, a gastrointestinal motility disorder,
irritable bowel syndrome, chronic constipation, chronic idiopathic
constipation, chronic constipation occurring in cystic fibrosis
patients, chronic constipation occurring in chronic kidney disease
patients, calcium-induced constipation in osteoporotic patients,
opioid-induced constipation, a functional gastrointestinal tract
disorder, gastroesophageal reflux disease, functional heartburn,
dyspepsia, functional dyspepsia, non-ulcer dyspepsia,
gastroparesis, chronic intestinal pseudo-obstruction, Crohn's
disease, ulcerative colitis and related diseases referred to as
inflammatory bowel syndrome, colonic pseudo-obstruction, gastric
ulcers, infectious diarrhea, cancer (colorectal), "leaky gut
syndrome", cystic fibrosis gastrointestinal disease, multi-organ
failure, microscopic colitis, necrotizing enterocolitis,
allergy--atopy, food allergy, infections (respiratory), acute
inflammation (e.g., sepsis, systemic inflammatory response
syndrome), chronic inflammation (arthritis), obesity-induced
metabolic diseases (e.g., nonalcoholic steatohepatitis, Type I
diabetes, Type II diabetes, cardiovascular disease), kidney
disease, diabetic kidney disease, cirrhosis, nonalcoholic
steatohepatitis, nonalcoholic fatty acid liver disease, Steatosis,
primary sclerosing cholangitis, primary biliary cholangitis, portal
hypertension, autoimmune disease (e.g., Type I diabetes, ankylosing
spondylitis, lupus, alopecia areata, rheumatoid arthritis,
polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome,
Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticarial
(hives), Raynaud's syndrome), Schizophrenia, autism spectrum
disorders, hepatic encephlopathy, chronic alcoholism, and the
like.
[0466] In another embodiment, a method for treating hypertension is
provided, the method comprising administering to a mammal in need
thereof a pharmaceutically effective amount of a compound or
pharmaceutical composition as set forth above.
[0467] In further embodiments, the method comprises administering a
pharmaceutically effective amount of the compound to the mammal in
order to increase the mammal's daily fecal output of sodium and/or
fluid. In further embodiments, the method comprises administering a
pharmaceutically effective amount of the compound to the mammal in
order to increase the mammal's daily fecal output of sodium by at
least about 30 mmol, and/or fluid by at least about 200 ml. In
further embodiments, the mammal's fecal output of sodium and/or
fluid is increased without introducing another type of cation in a
stoichiometric or near stoichiometric fashion via an ion exchange
process. In further embodiments, the method further comprises
administering to the mammal a fluid-absorbing polymer to absorb
fecal fluid resulting from the use of the compound that is
substantially active in the gastrointestinal tract to inhibit
NHE-mediated antiport of sodium ions and hydrogen ions therein.
[0468] In further embodiments, the compound or composition is
administered to treat hypertension. In further embodiments, the
compound or composition is administered to treat hypertension
associated with dietary salt intake. In further embodiments,
administration of the compound or composition allows the mammal to
intake a more palatable diet. In further embodiments, the compound
or composition is administered to treat fluid overload. In further
embodiments, the fluid overload is associated with congestive heart
failure. In further embodiments, the fluid overload is associated
with end stage renal disease. In further embodiments, the fluid
overload is associated with peroxisome proliferator-activated
receptor (PPAR) gamma agonist therapy. In further embodiments, the
compound or composition is administered to treat sodium overload.
In further embodiments, the compound or composition is administered
to reduce interdialytic weight gain in ESRD patients. In further
embodiments, the compound or composition is administered to treat
edema. In further embodiments, the edema is caused by chemotherapy,
pre-menstrual fluid overload or preeclampsia.
[0469] In further embodiments, the compound or composition is
administered to treat gastric ulcers. In further embodiments, the
compound or composition is administered to treat infectious
diarrhea. In further embodiments, the compound or composition is
administered to treat cancer (colorectal). In further embodiments,
the compound or composition is administered to treat "leaky gut
syndrome". In further embodiments, the compound or composition is
administered to treat cystic fibrosis gastrointestinal disease. In
further embodiments, the compound or composition is administered to
treat multi-organ failure. In further embodiments, the compound or
composition is administered to treat microscopic colitis. In
further embodiments, the compound or composition is administered to
treat necrotizing enterocolitis. In further embodiments, the
compound or composition is administered to treat atopy. In further
embodiments, the compound or composition is administered to treat
food allergy. In further embodiments, the compound or composition
is administered to treat respiratory infections. In further
embodiments, the compound or composition is administered to treat
acute inflammation (e.g., sepsis, systemic inflammatory response
syndrome). In further embodiments, the compound or composition is
administered to treat chronic inflammation (e.g., arthritis). In
further embodiments, the compound or composition is administered to
treat obesity-induced metabolic diseases (e.g., nonalcoholic
steatohepatitis, Type I diabetes, Type II diabetes, cardiovascular
disease). In further embodiments, the compound or composition is
administered to treat kidney disease. In further embodiments, the
compound or composition is administered to treat diabetic kidney
disease. In further embodiments, the compound or composition is
administered to treat cirrhosis. In further embodiments, the
compound or composition is administered to treat steatohepatitis.
In further embodiments, the compound or composition is administered
to treat nonalcoholic fatty acid liver disease. In further
embodiments, the compound or composition is administered to treat
steatosis. In further embodiments, the compound or composition is
administered to treat primary sclerosing cholangitis. In further
embodiments, the compound or composition is administered to treat
primary biliary cholangitis. In further embodiments, the compound
or composition is administered to treat portal hypertension. In
further embodiments, the compound or composition is administered to
treat autoimmune disease (e.g., Type I diabetes, ankylosing
spondylitis, lupus, alopecia areata, rheumatoid arthritis,
polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome,
Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticarial
(hives), or Raynaud's syndrome). In further embodiments, the
compound or composition is administered to treat Schizophrenia. In
further embodiments, the compound or composition is administered to
treat autism spectrum disorders. In further embodiments, the
compound or composition is administered to treat hepatic
encephlopathy. In further embodiments, the compound or composition
is administered to treat chronic alcoholism.
[0470] In further embodiments, the compound or composition is
administered orally, by rectal suppository, or enema.
[0471] In further embodiments, the method comprises administering a
pharmaceutically effective amount of the compound or composition in
combination with one or more additional pharmaceutically active
compounds or agents. In further embodiments, the one or more
additional pharmaceutically active compounds or agents is selected
from the group consisting of a diuretic, cardiac glycoside, ACE
inhibitor, angiotensin-2 receptor antagonist, aldosterone
antagonist, aldosterone synthase inhibitor, renin inhibitor,
calcium channel blocker, beta blocker, alpha blocker, central alpha
agonist, vasodilator, blood thinner, anti-platelet agent,
lipid-lowering agent, and peroxisome proliferator-activated
receptor (PPAR) gamma agonist agent. In further embodiments, the
diuretic is selected from the group consisting of a high ceiling
loop diuretic, a benzothiadiazide diuretic, a potassium sparing
diuretic, and an osmotic diuretic. In further embodiments, the
pharmaceutically effective amount of the compound or composition,
and the one or more additional pharmaceutically active compounds or
agents, are administered as part of a single pharmaceutical
preparation. In further embodiments, the pharmaceutically effective
amount of the compound or composition, and the one or more
additional pharmaceutically active compounds or agents, are
administered as individual pharmaceutical preparations. In further
embodiments, the individual pharmaceutical preparation is
administered sequentially. In further embodiments, the individual
pharmaceutical preparation is administered simultaneously.
[0472] In another embodiment, a method for treating a
gastrointestinal tract disorder is provided, the method comprising
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound or pharmaceutical composition as set
forth above.
[0473] In further embodiments, the gastrointestinal tract disorder
is a gastrointestinal motility disorder. In further embodiments,
the gastrointestinal tract disorder is irritable bowel syndrome. In
further embodiments, the gastrointestinal tract disorder is chronic
constipation. In further embodiments, the gastrointestinal tract
disorder is chronic idiopathic constipation. In further
embodiments, the gastrointestinal tract disorder is chronic
constipation occurring in cystic fibrosis patients. In further
embodiments, the gastrointestinal tract disorder is opioid-induced
constipation. In further embodiments, the gastrointestinal tract
disorder is a functional gastrointestinal tract disorder. In
further embodiments, the gastrointestinal tract disorder is
selected from the group consisting of chronic intestinal
pseudo-obstruction and colonic pseudo-obstruction. In further
embodiments, the gastrointestinal tract disorder is Crohn's
disease. In further embodiments, the gastrointestinal tract
disorder is ulcerative colitis. In further embodiments, the
gastrointestinal tract disorder is a disease referred to as
inflammatory bowel disease. In further embodiments, the
gastrointestinal tract disorder is associated with chronic kidney
disease (stage 4 or 5). In further embodiments, the
gastrointestinal tract disorder is constipation induced by calcium
supplement. In further embodiments, the gastrointestinal tract
disorder is constipation, and the constipation to be treated is
associated with the use of a therapeutic agent. In further
embodiments, the gastrointestinal tract disorder is constipation,
and the constipation to be treated is associated with a neuropathic
disorder. In further embodiments, the gastrointestinal tract
disorder is constipation, and the constipation to be treated is
post-surgical constipation (postoperative ileus). In further
embodiments, the gastrointestinal tract disorder is constipation,
and the constipation to be treated is idiopathic (functional
constipation or slow transit constipation). In further embodiments,
the gastrointestinal tract disorder is constipation, and the
constipation to be treated is associated with neuropathic,
metabolic or an endocrine disorder (e.g., diabetes mellitus, renal
failure, hypothyroidism, hyperthyroidism, hypocalcaemia, Multiple
Sclerosis, Parkinson's disease, spinal cord lesions,
neurofibromatosis, autonomic neuropathy, Chagas disease,
Hirschsprung's disease or cystic fibrosis, and the like). In
further embodiments, the gastrointestinal tract disorder is
constipation, and the constipation to be treated is due the use of
drugs selected from analgesics (e.g., opioids), antihypertensives,
anticonvulsants, amidepressants, antispasmodics and
antipsychotics.
[0474] In other embodiments, the gastrointestinal tract disorder is
associated with gastric ulcers, infectious diarrhea, cancer
(colorectal), "leaky gut syndrome", cystic fibrosis
gastrointestinal disease, multi-organ failure, microscopic colitis,
necrotizing enterocolitis, allergy--atopy, food allergy, infections
(respiratory), acute inflammation (e.g., sepsis, systemic
inflammatory response syndrome), chronic inflammation (e.g.,
arthritis), obesity-induced metabolic diseases (e.g., nonalcoholic
steatohepatitis, Type I diabetes, Type II diabetes, cardiovascular
disease), kidney disease, diabetic kidney disease, cirrhosis,
nonalcoholic steatohepatitis, nonalcoholic fatty acid liver
disease, Steatosis, primary sclerosing cholangitis, primary biliary
cholangitis, portal hypertension, autoimmune (e.g., Type I
diabetes, ankylosing spondylitis, lupus, alopecia areata,
rheumatoid arthritis, polymyalgia rheumatica, fibromyalgia, chronic
fatigue syndrome, Sjogren's syndrome, vitiligo, thyroiditis,
vasculitis, urticarial (hives), or Raynaud's syndrome),
Schizophrenia, autism spectrum disorders, hepatic encephlopathy,
small intestitinal bacterial overgrowth, or chronic alcoholism.
[0475] In another embodiment, a method for treating irritable bowel
syndrome is provided, the method comprising administering to a
mammal in need thereof a pharmaceutically effective amount of a
compound or pharmaceutical composition as set forth above.
[0476] In further embodiments of the above embodiments, the
compound or composition is administered to treat or reduce pain
associated with a gastrointestinal tract disorder. In further
embodiments, the compound or composition is administered to treat
or reduce visceral hypersensitivity associated with a
gastrointestinal tract disorder. In further embodiments, the
compound or composition is administered to treat or reduce
inflammation of the gastrointestinal tract. In further embodiments,
the compound or composition is administered to reduce
gastrointestinal transit time.
[0477] Compounds of the invention inhibit Transient Receptor
Potential Cation channel subfamily C, member 6 (TRPC6).
Accordingly, compounds of the invention are useful for treating
diseases, disorders and conditions mediated with abherent TRPC6
activity, for example, cardiac hypertrophy kidney diseases, in
particular, glomerular diseases.
[0478] In further embodiments, the compound or composition is
administered either orally or by rectal suppository.
[0479] In further embodiments, the method comprises administering a
pharmaceutically effective amount of the compound or composition,
in combination with one or more additional pharmaceutically active
compounds or agents. In further embodiments, the one or more
additional pharmaceutically active agents or compounds are an
analgesic peptide or agent. In further embodiments, the one or more
additional pharmaceutically active agents or compounds are selected
from the group consisting of a laxative agent selected from a
bulk-producing agent (e.g. psyllium husk (Metamucil)),
methylcellulose (Citrucel), polycarbophil, dietary fiber, apples,
stool softeners/surfactant (e.g., docusate, Colace, Diocto), a
hydrating or osmotic agent (e.g., dibasic sodium phosphate,
magnesium citrate, magnesium hydroxide (Milk of magnesia),
magnesium sulfate (which is Epsom salt), monobasic sodium
phosphate, sodium biphosphate), and a hyperosmotic agent (e.g.,
glycerin suppositories, sorbitol, lactulose, and polyethylene
glycol (PEG)). In further embodiments, the pharmaceutically
effective amount of the compound or composition, and the one or
more additional pharmaceutically active compounds or agents, are
administered as part of a single pharmaceutical preparation. In
further embodiments, the pharmaceutically effective amount of the
compound or composition, and the one or more additional
pharmaceutically active compounds or agents, are administered as
individual pharmaceutical preparations. In further embodiments, the
individual pharmaceutical preparation is administered sequentially.
In further embodiments, the individual pharmaceutical preparation
is administered simultaneously.
[0480] Another aspect of the invention is directed to
pharmaceutical compositions comprising a compound of Formula I and
a pharmaceutically acceptable carrier. In one embodiment, the
pharmaceutical composition comprise a compound of Formula Ia, Ib,
Ic, Id, Ie, If, Ig, Ih, or Ii and a pharmaceutically acceptable
carrier. In another embodiment, the pharmaceutical composition
described herein may be used to inhibit NHE-mediated antiport of
sodium and hydrogen ions. In another embodiment, the pharmaceutical
composition described herein may be used to treat disorders
associated with fluid retention or salt overload
[0481] A pharmaceutical composition or preparation that may be used
in accordance with the present disclosure for the treatment of
various disorders associated with fluid retention and/or salt
overload in the gastrointestinal tract (e.g., hypertension, heart
failure (in particular, congestive heart failure), chronic kidney
disease, end-stage renal disease, liver disease and/or peroxisome
proliferator-activated receptor (PPAR) gamma agonist-induced fluid
retention) comprises, in general, the substantially impermeable or
substantially systemically non-bioavailable NHE-inhibiting compound
of the present disclosure, as well as various other optional
components as further detailed herein below (e.g., pharmaceutically
acceptable excipients, etc.). The compounds utilized in the
treatment methods of the present disclosure, as well as the
pharmaceutical compositions comprising them, may accordingly be
administered alone, or as part of a treatment protocol or regiment
that includes the administration or use of other beneficial
compounds (as further detailed elsewhere herein). In some
particular embodiments, the NHE-inhibiting compound, including any
pharmaceutical composition comprising the compound, is administered
with a fluid-absorbing polymer (as more fully described below).
[0482] Subjects "in need of treatment" with a compound of the
present disclosure, or subjects "in need of NHE inhibition" include
subjects with diseases and/or conditions that can be treated with
substantially impermeable or substantially systemically
non-bioavailable NHE-inhibiting compounds, with or without a
fluid-absorbing polymer, to achieve a beneficial therapeutic and/or
prophylactic result. A beneficial outcome includes a decrease in
the severity of symptoms or delay in the onset of symptoms,
increased longevity and/or more rapid or more complete resolution
of the disease or condition. For example, a subject in need of
treatment may be suffering from hypertension; from salt-sensitive
hypertension which may result from dietary salt intake; from a risk
of a cardiovascular disorder (e.g., myocardial infarction,
congestive heart failure and the like) resulting from hypertension;
from heart failure (e.g., congestive heart failure) resulting in
fluid or salt overload; from chronic kidney disease resulting in
fluid or salt overload, from end stage renal disease resulting in
fluid or salt overload; from liver disease resulting in fluid or
salt overload; from peroxisome proliferator-activated receptor
(PPAR) gamma agonist-induced fluid retention; or from edema
resulting from congestive heart failure or end stage renal disease.
In various embodiments, a subject in need of treatment typically
shows signs of hypervolemia resulting from salt and fluid retention
that are common features of congestive heart failure, renal failure
or liver alopeccia. Fluid retention and salt retention manifest
themselves by the occurrence of shortness of breath, edema, ascites
or interdialytic weight gain. Other examples of subjects that would
benefit from the treatment are those suffering from congestive
heart failure and hypertensive patients and, particularly, those
who are resistant to treatment with diuretics, i.e., patients for
whom very few therapeutic options are available. A subject "in need
of treatment" also includes a subject with hypertension,
salt-sensitive blood pressure and subjects with systolic/diastolic
blood pressure greater than about 130-139/85-89 mm Hg.
[0483] Administration of NHE-inhibiting compounds, with or without
administration of fluid-absorbing polymers, may be beneficial for
patients put on "non-added salt" dietary regimen (i.e., 60-100 mmol
of Na per day), to liberalize their diet while keeping a neutral or
slightly negative sodium balance (i.e., the overall uptake of salt
would be equal of less than the secreted salt). In that context,
"liberalize their diet" means that patients treated may add salt to
their meals to make the meals more palatable, or/and diversify
their diet with salt-containing foods, thus maintaining a good
nutritional status while improving their quality of life.
[0484] The treatment methods described herein may also help
patients with edema associated with chemotherapy, pre-menstrual
fluid overload and preeclampsia (pregnancy-induced
hypertension).
[0485] Accordingly, it is to be noted that the present disclosure
is further directed to methods of treatment involving the
administration of the compound of the present disclosure, or a
pharmaceutical composition comprising such a compound. Such methods
may include, for example, a method for treating hypertension, the
method comprising administering to the patient a substantially
impermeable or substantially systemically non-bioavailable
NHE-inhibiting compound, or a pharmaceutical composition comprising
it. The method may be for reducing fluid overload associated with
heart failure (in particular, congestive heart failure), the method
comprising administering to the patient a substantially impermeable
or substantially systemically non-bioavailable NHE-inhibiting
compound or pharmaceutical composition comprising it. The method
may be for reducing fluid overload associated with end stage renal
disease, the method comprising administering to the patient a
substantially impermeable or substantially systemically
non-bioavailable NHE-inhibiting compound or composition comprising
it. The method may be for reducing fluid overload associated with
peroxisome proliferator-activated receptor (PPAR) gamma agonist
therapy, the method comprising administering to the patient a
substantially impermeable or substantially systemically
non-bioavailable NHE-inhibiting compound or composition comprising
it. Additionally, or alternatively, the method may be for
decreasing the activity of an intestinal NHE transporter in a
patient, the method comprising: administering to the patient a
substantially impermeable or substantially systemically
non-bioavailable NHE-inhibiting compound, or a composition
comprising it. In another embodiment, the disease to be treated,
includes, but is not limited to, heart failure (such as congestive
heart failure), chronic kidney disease, end-stage renal disease,
liver disease, and peroxisome proliferator-activated receptor
(PPAR) gamma agonist-induced fluid retention is provided,
gastrointestinal motility disorder, irritable bowel syndrome,
chronic constipation, chronic idiopathic constipation, chronic
constipation occurring in cystic fibrosis patients, chronic
constipation occurring in chronic kidney disease patients,
calcium-induced constipation in osteoporotic patients,
opioid-induced constipation, a functional gastrointestinal tract
disorder, gastroesophageal reflux disease, functional heartburn,
dyspepsia, functional dyspepsia, non-ulcer dyspepsia,
gastroparesis, chronic intestinal pseudo-obstruction, Crohn's
disease, ulcerative colitis and related diseases referred to as
inflammatory bowel syndrome, colonic pseudo-obstruction, gastric
ulcers, infectious diarrhea, cancer (colorectal), "leaky gut
syndrome", cystic fibrosis gastrointestinal disease, multi-organ
failure, microscopic colitis, necrotizing enterocolitis,
allergy--atopy, food allergy, infections (respiratory), acute
inflammation (e.g., sepsis, systemic inflammatory response
syndrome), chronic inflammation (arthritis), obesity-induced
metabolic diseases (e.g., nonalcoholic steatohepatitis, Type I
diabetes, Type II diabetes, cardiovascular disease), kidney
disease, diabetic kidney disease, cirrhosis, nonalcoholic
steatohepatitis, nonalcoholic fatty acid liver disease, Steatosis,
primary sclerosing cholangitis, primary biliary cholangitis, portal
hypertension, autoimmune disease (e.g., Type I diabetes, ankylosing
spondylitis, lupus, alopecia areata, rheumatoid arthritis,
polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome,
Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticarial
(hives), Raynaud's syndrome), Schizophrenia, autism spectrum
disorders, hepatic encephlopathy, small intestitinal bacterial
overgrowth, and chronic alcoholism, and the like.
[0486] 2. Gastrointestinal Tract Disorders
[0487] Another aspect of the invention is directed to method for
treating a disorder associated with gastrointestinal tract. The
method comprises administering to a mammal in need thereof a
pharmaceutically effective amount of a compound or pharmaceutical
composition of Formula I. In one embodiment, the method of treating
a disorder associated with gastrointestinal tract comprises
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or
Ii or a combination thereof.
[0488] A pharmaceutical composition or preparation that may be used
in accordance with the present disclosure for the treatment of
various gastrointestinal tract disorders, including the treatment
or reduction of pain associated with gastrointestinal tract
disorders, comprises, the substantially impermeable or
substantially systemically non-bioavailable NHE-inhibiting compound
of the present disclosure, as well as various other optional
components as further detailed herein below (e.g., pharmaceutically
acceptable excipients, etc.). The compounds utilized in the
treatment methods of the present disclosure, as well as the
pharmaceutical compositions comprising them, may accordingly be
administered alone, or as part of a treatment protocol or regiment
that includes the administration or use of other beneficial
compounds (as further detailed elsewhere herein). In some
particular embodiments, the NHE-inhibiting compound, including any
pharmaceutical composition comprising the compound, is administered
with a fluid-absorbing polymer (as more fully described below).
[0489] Subjects "in need of treatment" with a compound of the
present disclosure, or subjects "in need of NHE inhibition" include
subjects with diseases and/or conditions that can be treated with
substantially impermeable or substantially systemically
non-bioavailable NHE-inhibiting compounds, with or without a
fluid-absorbing polymer, to achieve a beneficial therapeutic and/or
prophylactic result. A beneficial outcome includes a decrease in
the severity of symptoms or delay in the onset of symptoms,
increased longevity and/or more rapid or more complete resolution
of the disease or condition. For example, a subject in need of
treatment is suffering from a gastrointestinal tract disorder; the
patient is suffering from a disorder selected from the group
consisting of: a gastrointestinal motility disorder, irritable
bowel syndrome, chronic constipation, chronic idiopathic
constipation, chronic constipation occurring in cystic fibrosis
patients, chronic constipation occurring in chronic kidney disease
patients, calcium-induced constipation in osteoporotic patients,
opioid-induced constipation, a functional gastrointestinal tract
disorder, gastroesophageal reflux disease, functional heartburn,
dyspepsia, functional dyspepsia, non-ulcer dyspepsia,
gastroparesis, chronic intestinal pseudo-obstruction, Crohn's
disease, ulcerative colitis and related diseases referred to as
inflammatory bowel syndrome, colonic pseudo-obstruction, gastric
ulcers, infectious diarrhea, cancer (colorectal), "leaky gut
syndrome", cystic fibrosis gastrointestinal disease, multi-organ
failure, microscopic colitis, necrotizing enterocolitis, atopy,
food allergy, infections (respiratory), acute inflammation (e.g.,
sepsis, systemic inflammatory response syndrome), chronic
inflammation (e.g., arthritis), obesity-induced metabolic diseases
(e.g., nonalcoholic steatohepatitis, Type I diabetes, Type I1
diabetes, cardiovascular disease), kidney disease, diabetic kidney
disease, cirrhosis, nonalcoholic steatohepatitis, nonalcoholic
fatty acid liver disease, Steatosis, primary sclerosing
cholangitis, primary biliary cholangitis, portal hypertension,
autoimmune disease (e.g., Type I diabetes, ankylosing spondylitis,
lupus, alopecia areata, rheumatoid arthritis, polymyalgia
rheumatica, fibromyalgia, chronic fatigue syndrome, Sjogren's
syndrome, vitiligo, thyroiditis, vasculitis, urticarial (hives),
Raynaud's syndrome), Schizophrenia, autism spectrum disorders,
hepatic encephlopathy, small intestitinal bacterial overgrowth, and
chronic alcoholism, and the like.
[0490] In various preferred embodiments, the constipation to be
treated is: associated with the use of a therapeutic agent;
associated with a neuropathic disorder; post-surgical constipation
(postoperative ileus); associated with a gastrointestinal tract
disorder; idiopathic (functional constipation or slow transit
constipation); associated with neuropathic, metabolic or endocrine
disorder (e.g., diabetes mellitus, renal failure, hypothyroidism,
hyperthyroidism, hypocalcaemia, Multiple Sclerosis, Parkinson's
disease, spinal cord lesions, neurofibromatosis, autonomic
neuropathy, Chagas disease, Hirschsprung's disease or cystic
fibrosis, and the like). Constipation may also be the result of
surgery (postoperative ileus) or due the use of drugs such as
analgesics (e.g., opioids), antihypertensives, anticonvulsants,
amidepressants, antispasmodics and antipsychotics.
[0491] In yet other embodiments, the constipation is associated
with gastric ulcers, infectious diarrhea, cancer (colorectal),
"leaky gut syndrome", cystic fibrosis gastrointestinal disease,
multi-organ failure, microscopic colitis, necrotizing
enterocolitis, atopy, food allergy, infections (respiratory), acute
inflammation (e.g., sepsis, systemic inflammatory response
syndrome), chronic inflammation (e.g., arthritis), obesity-induced
metabolic diseases (e.g., nonalcoholic steatohepatitis, Type I
diabetes, Type II diabetes, cardiovascular disease), kidney
disease, diabetic kidney disease, cirrhosis, nonalcoholic
steatohepatitis, nonalcoholic fatty acid liver disease, Steatosis,
primary sclerosing cholangitis, primary biliary cholangitis, portal
hypertension, autoimmune disease (e.g., Type I diabetes, ankylosing
spondylitis, lupus, alopecia areata, rheumatoid arthritis,
polymyalgia rheumatica, fibromyalgia, chronic fatigue syndrome,
Sjogren's syndrome, vitiligo, thyroiditis, vasculitis, urticarial
(hives), Raynaud's syndrome), Schizophrenia, autism spectrum
disorders, hepatic encephlopathy, small intestitinal bacterial
overgrowth, and chronic alcoholism, and the like.
[0492] Accordingly, it is to be noted that the present disclosure
is further directed to methods of treatment involving the
administration of the compound of the present disclosure, or a
pharmaceutical composition comprising such a compound. Such methods
may include, for example, a method for increasing gastrointestinal
motility in a patient, the method comprising administering to the
patient a substantially non-permeable or substantially
non-bioavailable NHE-inhibiting compound, or a pharmaceutical
composition comprising it. Additionally, or alternatively, the
method may be for decreasing the activity of an intestinal NHE
transporter in a patient, the method comprising administering to
the patient a substantially non-permeable or substantially
non-bioavailable NHE-inhibiting compound, or a pharmaceutical
composition comprising it. Additionally, or alternatively, the
method may be for treating a gastrointestinal tract disorder, a
gastrointestinal motility disorder, irritable bowel syndrome,
chronic calcium-induced constipation in osteoporotic patients,
chronic constipation occurring in cystic fibrosis patients, chronic
constipation occurring in chronic kidney disease patients, a
functional gastrointestinal tract disorder, gastroesophageal reflux
disease, functional heartburn, dyspepsia, functional dyspepsia,
non-ulcer dyspepsia, gastroparesis, chronic intestinal
pseudo-obstruction, colonic pseudo-obstruction, Crohn's disease,
ulcerative colitis, inflammatory bowel disease, the method
comprising administering an antagonist of the intestinal NHE, and
more specifically, a substantially non-permeable or substantially
non-bioavailable NHE-inhibiting compound, or a pharmaceutical
composition comprising it, either orally or by rectal suppository.
Additionally, or alternatively, the method may be for treating or
reducing pain, including visceral pain, pain associated with a
gastrointestinal tract disorder or pain associated with some other
disorder, the method comprising administering to a patient a
substantially non-permeable or substantially non-bioavailable
NHE-inhibiting compound, or a pharmaceutical composition comprising
it Additionally, or alternatively, the method may be for treating
inflammation, including inflammation of the gastrointestinal tract,
e.g., inflammation associated with a gastrointestinal tract
disorder or infection or some other disorder, the method comprising
administering to a patient a substantially non-permeable or
substantially non-bioavailable NHE-inhibiting compound, or a
pharmaceutical composition comprising it.
[0493] 3. Metabolic Disorders
[0494] A pharmaceutical composition or preparation that may be used
in accordance with the present disclosure for the treatment of
various metabolic disorders including the treatment or reduction of
type II diabetes mellitus (T2DM), metabolic syndrome, and/or
symptoms associated with such disorders comprises, in general, the
substantially impermeable or substantially systemically
non-bioavailable NHE-inhibiting compound of the present disclosure,
as well as various other optional components as further detailed
herein below (e.g., pharmaceutically acceptable excipients, etc.).
The compounds utilized in the treatment methods of the present
disclosure, as well as the pharmaceutical compositions comprising
them, may accordingly be administered alone, or as part of a
treatment protocol or regiment that includes the administration or
use of other beneficial compounds (as further detailed elsewhere
herein). In another embodiment, the pharmaceutical composition can
be used to treat other metabolic diseases such as non-alcoholic
steatohepatitis, diabetes Type I and II, and cardiovascular
diseases.
[0495] Obesity is becoming a worldwide epidemic. In the United
States, approximately 2/3rds of the population is either overweight
(body mass index [BMI] 25 to 29.9) or obese (BMI.gtoreq.30) (Ogden,
C L et al, "Prevalence of overweight and obesity in the united
states, 1999-2004" JAMA 2006, 295, 1549-1555). Obesity is a major
risk factor for the development of diabetes and related
complications, including cardiovascular disease and chronic kidney
disease (CKD). The prevalence of T2DM has increased alarmingly in
the United States. The American Diabetes Associated (ADA) estimates
that more than 23 million U.S. adults aged 20 years or older have
diabetes, with T2DM accounting for approximately 95% of these
cases. The World Health Organization (WHO) has put the number of
persons with diabetes worldwide at approximately 170 million
(Campbell, R. K. "Type 2 diabetes: where we are today: an overview
of disease burden, current treatments, and treatment strategies"
Journal of the American Pharmacists Association 2009, 49(5),
S3-S9).
[0496] Obesity is also a major risk factor for the development of
metabolic syndrome, and subsequently the development of CKD.
Metabolic syndrome, previously known as Syndrome X, the
plurimetabolic syndrome, the dysmetabolic syndrome, and other
names, consists of a clustering of metabolic abnormalities
including abdominal obesity, hypertriglyceridemia, low levels of
high-density lipoprotein (HDL) cholesterol, elevated blood pressure
(BP), and elevations in fasting glucose or diabetes (Townsend, R.
R. et al "Metabolic Syndrome, Components, and Cardiovascular
Disease Prevalence in Chronic Kidney Disease: Findings from the
Chronic Renal Insufficiency Cohort (CRIC) Study" American Journal
of Nephrology 2011, 33, 477-484). Metabolic syndrome is common in
patients with CKD and an important risk factor for the development
and progression of CKD.
[0497] Hemodynamic factors appear to play a significant role in
obesity-induced renal dysfunction. Hypertension, which is closely
linked to obesity, appears to be a major cause of renal dysfunction
in obese patients (Wahba, I. M. et al "Obesity and
obesity-initiated metabolic syndrome: mechanistic links to chronic
kidney disease" Clinical Journal of the American Society of
Nephrology 2007, 2, 550-562). Studies in animals and in humans have
shown that obesity is associated with elevated glomerular
Filtration rate (GFR) and increased renal blood flow. This likely
occurs because of afferent arteriolar dilation as a result of
proximal salt reabsorption, coupled with efferent renal arteriolar
vasoconstriction as a result of elevated angiotensin II levels.
These effects may contribute to hyperfiltration, glomerulomegaly,
and later focal glomerulosclerosis. Even though GFR is increased in
obesity, urinary sodium excretion in response to a saline load is
often delayed, and individuals exhibit an abnormal pressure
natriuresis, indicating avid proximal tubular sodium reabsorption.
In addition, increased fat distribution can cause increased
intra-abdomial pressure, leading to renal vein compression, thus
raising renal venous pressure and diminishing renal perfusion. In
creased fat, through a variety of mechanisms, can cause elevated
renal interstitial fluid hydrostatic fluid and may stimulate renal
sodium retention the thereby contribute to hypertension
(Wahba_2007).
[0498] In view of the above, there exists a need in the art for
agents that can divert sodium and fluid from a subject via
mechanisms that either avoid the kidney, or do not depend upon
normal kidney function. A subject with metabolic disease, including
T2DM, metabolic syndrome, and the like, is a human, but can also be
an animal in need of treatment with a compound of the disclosure,
e.g., companion animals (e.g., dogs, cats, and the like), farm
animals (e.g., cows, pigs, horses and the like) and laboratory
animals (e.g., rats, mice, guinea pigs and the like).
[0499] The compounds utilized in the treatment methods of the
present disclosure, as well as the pharmaceutical compositions
comprising them, may accordingly be administered alone, or as part
of a combination therapy or regimen that includes the
administration or use of other therapeutic compounds related to the
treatment of metabolic disorders such as T2DM and metabolic
syndrome. In some particular embodiments, the NHE-inhibiting
compound, including any pharmaceutical composition comprising the
compound, is administered with a fluid absorbing polymer.
[0500] 3. Urinary Protein Excretion
[0501] The compounds described herein have been shown to reduce
urinary protein (e.g. albumin) excretion in a dose-dependent
manner. FIG. 2 illustrates the effects of two NHE3 inhibitors,
NHE3-1 and NHE3-2, a compound of the present disclosure, on urinary
albumin excretion in rats. Accordingly, another aspect of the
invention is directed to method for lowering urinary protein
excretion in a mammal and disorders associated with elevated
urinary protein excretion. The method comprises administering to a
mammal in need thereof a pharmaceutically effective amount of a
compound or pharmaceutical composition of Formula I. In one
embodiment, the method of treating a disorder associated with
elevated urinary protein excretion comprises administering to a
mammal in need thereof a pharmaceutically effective amount of a
compound Ia, Ib, Ic, Id, Ie, If, Ig, Ih, or Ii or a combination
thereof. In one embodiment, the protein is albumin.
[0502] B. Combination Therapies
[0503] 1. Fluid Retention and/or Salt Overload Disorders
[0504] As previously noted, the compounds described herein can be
used alone or in combination with other agents. For example, the
compounds can be administered together with a diuretic (i.e., High
Ceiling Loop Diuretics, Benzothiadiazide Diuretics, Potassium
Sparing Diuretics, Osmotic Diuretics), cardiac glycoside, ACE
inhibitor, angiotensin-2 receptor antagonist, aldosterone
antagonist, aldosterone synthase inhibitor, renin inhibitor,
calcium channel blocker, beta blocker, alpha blocker, central alpha
agonist, vasodilator, blood thinner, anti-platelet agent,
lipid-lowering agent, peroxisome proliferator-activated receptor
(PPAR) gamma agonist agent or compound or with a fluid-absorbing
polymer as more fully described below. The agent can be covalently
attached to a compound described herein or it can be a separate
agent that is administered together with or sequentially with a
compound described herein in a combination therapy.
[0505] Combination therapy can be achieved by administering two or
more agents, e.g., a substantially non-permeable or substantially
systemically non-bioavailable NHE-inhibiting compound described
herein and a diuretic, cardiac glycoside, ACE inhibitor,
angiotensin-2 receptor antagonist, aldosterone antagonist,
aldosterone synthase inhibitor, renin inhibitor, calcium channel
blocker, beta blocker, alpha blocker, central alpha agonist,
vasodilator, blood thinner, anti-platelet agent or compound, each
of which is formulated and administered separately, or by
administering two or more agents in a single formulation. Other
combinations are also encompassed by combination therapy. For
example, two agents can be formulated together and administered in
conjunction with a separate formulation containing a third agent.
While the two or more agents in the combination therapy can be
administered simultaneously, they need not be. For example,
administration of a first agent (or combination of agents) can
precede administration of a second agent (or combination of agents)
by minutes, hours, days, or weeks. Thus, the two or more agents can
be administered within minutes of each other or within 1, 2, 3, 6,
9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5,
6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6,
7, 8, 9, or weeks of each other. In some cases, even longer
intervals are possible. While in many cases it is desirable that
the two or more agents used in a combination therapy be present in
within the patient's body at the same time, this need not be
so.
[0506] Combination therapy can also include two or more
administrations of one or more of the agents used in the
combination. For example, if agent X and agent Y are used in a
combination, one could administer them sequentially in any
combination one or more times, e.g., in the order X-Y-X, X-X-Y,
Y-X-Y, Y-Y-X, X-X-Y-Y, etc.
[0507] The compounds described herein can be used in combination
therapy with a diuretic. Among the useful diuretic agents are, for
example: High Ceiling Loop Diuretics [Furosemide (Lasix),
Ethacrynic Acid (Edecrin), Bumetanide (Bumex)|, Benzothiadiazide
Diuretics [Hydrochlorothiazide (Hydrodiuril), Chlorothiazide
(Diuril), Clorthalidone (Hygroton), Benzthiazide (Aguapres),
Bendroflumethiazide (Naturetin), Methyclothiazide (Aguatensen),
Polythiazide (Renese), Indapamide (Lozol), Cyclothiazide
(Anhydron), Hydroflumethiazide (Diucardin), Metolazone (Diulo),
Qumethazone (Hydromox), Trichlormethiazide (Naqua)], Potassium
Sparing Diuretics[Spironolactone (Aldactone), Triamterene
(Dyrenium), Amiloride (Midamor)], and Osmotic Diuretics [Mannitol
(Osmitrol)]. Diuretic agents in the various classes are known and
described in the literature.
[0508] Cardiac glycosides (cardenolides) or other digitalis
preparations can be administered with the compounds of the
disclosure in co-therapy. Among the useful cardiac glycosides are,
for example: Digitoxin (Crystodigin), Digoxin (Lanoxin) or
Deslanoside (Cedilanid-D). Cardiac glycosides in the various
classes are described in the literature.
[0509] Angiotensin Converting Enzyme Inhibitors (ACE Inhibitors)
can be administered with the compounds of the disclosure in
co-therapy. Among the useful ACE inhibitors are, for example:
Captopril (Capoten), Enalapril (Vasotec), Lisinopril (Prinivil).
ACE inhibitors in the various classes are described in the
literature.
[0510] Angiotensin-2 Receptor Antagonists (also referred to as
AT.sub.1-antagonists or angiotensin receptor blockers, or ARB's)
can be administered with the compounds of the disclosure in
co-therapy. Among the useful Angiotensin-2 Receptor Antagonists
are, for example: Candesartan (Atacand), Eprosartan (Teveten),
Irbesartan (Avapro), Losartan (Cozaar), Telmisartan (Micardis),
Valsartan (Diovan). Angiotensin-2 Receptor Antagonists in the
various classes are described in the literature.
[0511] Calcium channel blockers such as Amlodipine (Norvasc,
Lotrel), Bepridil (Vascor), Diltiazem (Cardizem, Tiazac),
Felodipine (Plendil), Nifedipine (Adalat, Procardia), Nimodipine
(Nimotop), Nisoldipine (Sular), Verapamil (Calan, Isoptin, Verelan)
and related compounds described in, for example, EP 625162B1, U.S.
Pat. Nos. 5,364,842, 5,587,454, 5,824,645, 5,859,186, 5,994,305,
6,087,091, 6,136,786, WO 93/13128 A1, EP 1336409 A1, EP 835126 A1,
EP 835126 B1, U.S. Pat. Nos. 5,795,864, 5,891,849, 6,054,429, WO
97/01351 A1, the entire contents of which are incorporated herein
by reference for all relevant and consistent purposes, can be used
with the compounds of the disclosure.
[0512] Beta blockers can be administered with the compounds of the
disclosure in co-therapy. Among the useful beta blockers are, for
example: Acebutolol (Sectral), Atenolol (Tenormin), Betaxolol
(Kerlone), Bisoprolol/hydrochlorothiazide (Ziac), Bisoprolol
(Zebeta), Carteolol (Cartrol), Metoprolol (Lopressor, Toprol XL),
Nadolol (Corgard), Propranolol (Inderal), Sotalol (Betapace),
Timolol (Blocadren). Beta blockers in the various classes are
described in the literature.
[0513] PPAR gamma agonists such as thiazolidinediones (also called
glitazones) can be administered with the compounds of the
disclosure in co-therapy. Among the useful PPAR agonists are, for
example: rosiglitazone (Avandia), pioglitazone (Actos) and
rivoglitazone.
[0514] Aldosterone antagonists can be administered with the
compounds of the disclosure in co-therapy. Among the useful
Aldosterone antagonists are, for example: eplerenone,
spironolactone, and canrenone.
[0515] Renin inhibitor can be administered with the compounds of
the disclosure in co-therapy. Among the useful Renin inhibitors is,
for example: aliskiren.
[0516] Alpha blockers can be administered with the compounds of the
disclosure in co-therapy. Among the useful Alpha blockers are, for
example: Doxazosin mesylate (Cardura), Prazosin hydrochloride
(Minipress). Prazosin and polythiazide (Minizide), Terazosin
hydrochloride (Hytrin). Alpha blockers in the various classes are
described in the literature.
[0517] Central alpha agonists can be administered with the
compounds of the disclosure in co-therapy. Among the useful Central
alpha agonists are, for example: Clonidine hydrochloride
(Catapres), Clonidine hydrochloride and chlorthalidone (Clorpres,
Combipres), Guanabenz Acetate (Wytensin), Guanfacine hydrochloride
(Tenex), Methyldopa (Aldomet), Methyldopa and chlorothiazide
(Aldochlor), Methyldopa and hydrochlorothiazide (Aldoril). Central
alpha agonists in the various classes are described in the
literature.
[0518] Vasodilators can be administered with the compounds of the
disclosure in co-therapy. Among the useful vasodilators are, for
example: Isosorbide dinitrate (Isordil), Nesiritide (Natrecor),
Hydralazine (Apresoline), Nitrates/nitroglycerin, Minoxidil
(Loniten). Vasodilators in the various classes are described in the
literature.
[0519] Blood thinners can be administered with the compounds of the
disclosure in co-therapy. Among the useful blood thinners are, for
example: Warfarin (Coumadin) and Heparin. Blood thinners in the
various classes are described in the literature.
[0520] Anti-platelet agents can be administered with the compounds
of the disclosure in co-therapy. Among the useful anti-platelet
agents are, for example: Cyclooxygenase inhibitors (Aspirin),
Adenosine diphosphate (ADP) receptor inhibitors [Clopidogrel
(Plavix), Ticlopidine (Ticlid)], Phosphodiesterase inhibitors
[Cilostazol (Pletal)], Glycoprotein IIB/IIIA inhibitors [Abciximab
(ReoPro), Eptifibatide (Integrilin), Tirofiban (Aggrastat),
Defibrotide], Adenosine reuptake inhibitors [Dipyridamole
(Persantine)]. Anti-platelet agents in the various classes are
described in the literature.
[0521] Lipid-lowering agents can be administered with the compounds
of the disclosure in co-therapy. Among the useful lipid-lowering
agents are, for example: Statins (HMG CoA reductase inhibitors),
|Atorvastatin (Lipitor), Fluvastatin (Lescol), Lovastatin (Mevacor,
Altoprev), Pravastatin (Pravachol), Rosuvastatin Calcium (Crestor),
Simvastatin (Zocor)j, Selective cholesterol absorption inhibitors
[ezetimibe (Zetia)], Resins (bile acid sequestrant or bile
acid-binding drugs) [Cholestyramine (Questran, Questran Light,
Prevalite, Locholest, Locholest Light), Colestipol (Colestid),
Colesevelam Hcl (WelChol)], Fibrates (Fibric acid derivatives)
[Gemfibrozil (Lopid), Fenofibrate (Antara, Lolibra, Tricor, and
Triglide), Clofibrate (Atromid-S)], Niacin (Nicotinic acid).
Lipid-lowering agents in the various classes are described in the
literature.
[0522] The compounds of the disclosure can be used in combination
with peptides or peptide analogs that activate the Guanylate
Cyclase-receptor in the intestine and results in elevation of the
intracellular second messenger, or cyclic guanosine monophosphate
(cGMP), with increased chloride and bicarbonate secretion into the
intestinal lumen and concomitant fluid secretion. Example of such
peptides are Linaclotide (MD-1100 Acetate), endogenous hormones
guanylin and uroguanylin and enteric bacterial peptides of the heat
stable enterotoxin family (ST peptides) and those described in U.S.
Pat. Nos. 5,140,102, 5,489,670, 5,969,097, WO 2006/001931A2, WO
2008/002971A2, WO 2008/106429A2, US 2008/0227685A1 and U.S. Pat.
No. 7,041,786, the entire contents of which are incorporated herein
by reference for all relevant and consistent purposes.
[0523] The compounds of the disclosure can be used in combination
with type-2 chloride channel agonists, such as Amitiza
(Lubiprostone) and other related compounds described in U.S. Pat.
No. 6,414,016, the entire contents of which are incorporated herein
by reference for all relevant and consistent purposes.
[0524] The compounds described herein can be used in combination
therapy with agents used for the treatment of obesity, T2DM,
metabolic syndrome and the like. Among the useful agents include:
insulin; insulin secretagogues, such as sulphonylureas;
glucose-lowering effectors, such as metformin; activators of the
peroxisome proliferator-activated receptor .gamma. (PPAR.gamma.),
such as the thiazolidinediones; incretin-based agents including
dipeptidyl peptidase-4 inhibitors such as sitagliptin, and
synthetic incretin mimetics such as liraglutide and exenatide;
alpha-glucosidase inhibitors, such as acarbose; glinides, such as
repaglinide and nateglinide, and the like.
[0525] The compounds of the disclosure can be used in combination
with P2Y2 receptor agonists, such as those described in EP
1196396B1 and U.S. Pat. No. 6,624,150, the entire contents of which
are incorporated herein by reference for all relevant and
consistent purposes.
[0526] Other agents include natriuretic peptides such as
nesiritide, a recombinant form of brain-natriuretic peptide (BNP)
and an atrial-natriuretic peptide (ANP). Vasopressin receptor
antagonists such as tolvaptan and conivaptan may be co-administered
as well as phosphate binders such as renagel, renleva, phoslo and
fosrenol. Other agents include phosphate transport inhibitors (as
described in U.S. Pat. Nos. 4,806,532; 6,355,823; 6,787,528;
7,119,120; 7,109,184; U.S. Pat. Pub. No. 2007/021509; 2006/0280719;
2006/0217426; International Pat. Pubs. WO 2001/005398, WO
2001/087294, WO 2001/082924, WO 2002/028353, WO 2003/048134, WO
2003/057225, WO2003/080630, WO 2004/085448, WO 2004/085382;
European Pat. Nos. 1465638 and 1485391; and JP Patent No.
2007131532, or phosphate transport antagonists such as
Nicotinamide.
[0527] 2. Gastrointestinal Tract Disorders
[0528] As previously noted, the compounds described herein can be
used alone or in combination with other agents. For example, the
compounds can be administered together with an analgesic peptide or
compound. The analgesic peptide or compound can be covalently
attached to a compound described herein or it can be a separate
agent that is administered together with or sequentially with a
compound described herein in a combination therapy.
[0529] Combination therapy can be achieved by administering two or
more agents, e.g., a substantially non-permeable or substantially
non-bioavailable NHE-inhibiting compound described herein and an
analgesic peptide or compound, each of which is formulated and
administered separately, or by administering two or more agents in
a single formulation. Other combinations are also encompassed by
combination therapy. For example, two agents can be formulated
together and administered in conjunction with a separate
formulation containing a third agent. While the two or more agents
in the combination therapy can be administered simultaneously, they
need not be. For example, administration of a first agent (or
combination of agents) can precede administration of a second agent
(or combination of agents) by minutes, hours, days, or weeks. Thus,
the two or more agents can be administered within minutes of each
other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each
other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each
other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In
some cases, even longer intervals are possible. While in many cases
it is desirable that the two or more agents used in a combination
therapy be present in within the patient's body at the same time,
this need not be so.
[0530] Combination therapy can also include two or more
administrations of one or more of the agents used in the
combination. For example, if agent X and agent Y are used in a
combination, one could administer them sequentially in any
combination one or more times, e.g., in the order X-Y-X, X-X-Y,
Y-X-Y, Y-Y-X, X-X-Y-Y, etc.
[0531] The compounds described herein can be used in combination
therapy with an analgesic agent, e.g., an analgesic compound or an
analgesic peptide. The analgesic agent can optionally be covalently
attached to a compound described herein. Among the useful analgesic
agents are, for example: Ca channel blockers, 5HT3 agonists (e.g.,
MCK-733), 5HT4 agonists (e.g., tegaserod, prucalopride), and 5HT1
receptor antagonists, opioid receptor agonists (loperamide,
fedotozine, and fentanyl), NK1 receptor antagonists, CCK receptor
agonists (e.g., loxiglumide), NK1 receptor antagonists, NK3
receptor antagonists, norepinephrine-serotonin reuptake inhibitors
(NSR1), vanilloid and cannabanoid receptor agonists, and
sialorphin. Analgesics agents in the various classes are described
in the literature.
[0532] Opioid receptor antagonists and agonists can be administered
with the compounds of the disclosure in co-therapy or linked to the
compound of the disclosure, e.g., by a covalent bond. For example,
opioid receptor antagonists such as naloxone, naltrexone, methyl
nalozone, nalmefene, cypridime, beta funaltrexamine, naloxonazine,
naltrindole, and nor-binaltorphimine are thought to be useful in
the treatment of opioid-induced constipaption (OIC). It can be
useful to formulate opioid antagonists of this type in a delayed or
sustained release formulation, such that initial release of the
antagonist is in the mid to distal small intestine and/or ascending
colon. Such antagonists are described in U.S. Pat. No. 6,734,188
(WO 01/32180 A2), the entire contents of which are incorporated
herein by reference for all relevant and consistent purposes.
Enkephalin pentapeptide (HOE825; Tyr-D-Lys-Gly-Phe-L-homoserine) is
an agonist of the .mu.- and .gamma.-opioid receptors and is thought
to be useful for increasing intestinal motility (Eur. J. Pharm.,
219:445, 1992), and this peptide can be used in conjunction with
the compounds of the disclosure. Also useful is trimebutine which
is thought to bind to mu/delta/kappa opioid receptors and activate
release of motilin and modulate the release of gastrin, vasoactive
intestinal peptide, gastrin and glucagons. K-opioid receptor
agonists such as fedotozine, ketocyclazocine, and compounds
described in US 2005/0176746 (WO 03/097051 A2), the entire contents
of which are incorporated herein by reference for all relevant and
consistent purposes, can be used with or linked to the compounds of
the disclosure. In addition, .mu.-opioid receptor agonists, such as
morphine, diphenyloxylate, frakefamide
(H-Tyr-D-Ala-Phe(F)-Phe-NH.sub.2, disclosed in WO 01/019849 A1, the
entire contents of which are incorporated herein by reference for
all relevant and consistent purposes) and loperamide can be
used.
[0533] Tyr-Arg (kyotorphin) is a dipeptide that acts by stimulating
the release of met-enkephalins to elicit an analgesic effect (J.
Biol. Chem. 262:8165, 1987). Kyotorphin can be used with or linked
to the compounds of the disclosure. CCK receptor agonists such as
caerulein from amphibians and other species are useful analgesic
agents that can be used with or linked to the compounds of the
disclosure.
[0534] Conotoxin peptides represent a large class of analgesic
peptides that act at voltage gated Ca channels, NMDA receptors or
nicotinic receptors. These peptides can be used with or linked to
the compounds of the disclosure.
[0535] Peptide analogs of thymulin (U.S. Pat. No. 7,309,690 or FR
2830451, the entire contents of which are incorporated herein by
reference for all relevant and consistent purposes) can have
analgesic activity and can be used with or linked to the compounds
of the disclosure.
[0536] CCK (CCKa or CCKb) receptor antagonists, including
loxiglumide and dexloxiglumide (the R-isomer of loxiglumide) (U.S.
Pat. No. 5,130,474 or WO 88/05774, the entire contents of which are
incorporated herein by reference for all relevant and consistent
purposes) can have analgesic activity and can be used with or
linked to the compounds of the disclosure.
[0537] Other useful analgesic agents include 5-HT4 agonists such as
tegaserod/zelnorm and lirexapride. Such agonists are described in:
EP1321142 A1, WO 03/053432A], EP 505322 A1, EP 505322 BI, EP 507672
A1, EP 507672 BI, U.S. Pat. Nos. 5,510,353 and 5,273,983, the
entire contents of which are incorporated herein by reference for
all relevant and consistent purposes.
[0538] Calcium channel blockers such as zicyanotide and related
compounds described in, for example, EP 625162B1, U.S. Pat. Nos.
5,364,842, 5,587,454, 5,824,645, 5,859,186, 5,994,305, 6,087,091,
6,136,786, WO 93/13128 A1, EP 1336409 A1, EP 835126 A1, EP 835126
BI, U.S. Pat. Nos. 5,795,864, 5,891,849, 6,054,429, WO 97/0135 A1,
the entire contents of which are incorporated herein by reference
for all relevant and consistent purposes, can be used with or
linked to the compounds of the disclosure.
[0539] Various antagonists of the NK-1, NK-2, and NK-3 receptors
(for a review see Giardina et al. 2003 Drugs 6:758) can be can be
used with or linked to the compounds of the disclosure.
[0540] NK1 receptor antagonists such as: aprepitant (Merck & Co
Inc), vofopitant, ezlopitant (Pfizer, Inc.), R-673 (Hoffmann-La
Roche Ltd), SR-14033 and related compounds described in, for
example, EP 873753 A1, U.S. 20010006972 A1, U.S. 20030109417 A1, WO
01/52844 A1, the entire contents of which are incorporated herein
by reference for all relevant and consistent purposes, can be used
with or linked to the compounds of the disclosure.
[0541] NK-2 receptor antagonists such as nepadutant (Menarini
Ricerche SpA), saredutant (Sanofi-Synthelabo), SR-144190
(Sanofi-Synthelabo) and UK-290795 (Pfizer Inc) can be used with or
linked to the compounds of the disclosure.
[0542] NK3 receptor antagonists such as osanetant
(Sanofi-Synthelabo), talnetant and related compounds described in,
for example, WO 02/094187 A2, EP 876347 A1, WO 97/21680 A1, U.S.
Pat. No. 6,277,862, WO 98/11090, WO 95/28418, WO 97/19927, and
Boden et al. (J Med. Chem. 39:1664-75, 1996), the entire contents
of which are incorporated herein by reference for all relevant and
consistent purposes, can be used with or linked to the compounds of
the disclosure.
[0543] Norepinephrine-serotonin reuptake inhibitors such as
milnacipran and related compounds described in WO 03/077897 A1, the
entire contents of which are incorporated herein by reference for
all relevant and consistent purposes, can be used with or linked to
the compounds of the disclosure.
[0544] Vanilloid receptor antagonists such as arvanil and related
compounds described in WO 01/64212 A1, the entire contents of which
are incorporated herein by reference for all relevant and
consistent purposes, can be used with or linked to the compounds of
the disclosure.
[0545] The compounds can be used in combination therapy with a
phosphodiesterase inhibitor (examples of such inhibitors can be
found in U.S. Pat. No. 6,333,354, the entire contents of which are
incorporated herein by reference for all relevant and consistent
purposes).
[0546] The compounds can be used alone or in combination therapy to
treat disorders associated with chloride or bicarbonate secretion
that may lead to constipation, e.g., Cystic Fibrosis.
[0547] The compounds can also or alternatively be used alone or in
combination therapy to treat calcium-induced constipation effects.
Constipation is commonly found in the geriatric population,
particularly patients with osteoporosis who have to take calcium
supplements. Calcium supplements have shown to be beneficial in
ostoporotic patients to restore bone density but compliance is poor
because of constipation effects associated therewith.
[0548] The compounds of the current disclosure have can be used in
combination with an opioid. Opioid use is mainly directed to pain
relief, with a notable side-effect being GI disorder, e.g.
constipation. These agents work by binding to opioid receptors,
which are found principally in the central nervous system and the
gastrointestinal tract. The receptors in these two organ systems
mediate both the beneficial effects, and the undesirable side
effects (e.g. decrease of gut motility and ensuing constipation).
Opioids suitable for use typically belong to one of the following
exemplary classes: natural opiates, alkaloids contained in the
resin of the opium poppy including morphine, codeine and thebaine;
semi-synthetic opiates, created from the natural opioids, such as
hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine,
diacetylmorphine (Heroin), nicomorphine, dipropanoylmorphine,
benzylmorphine and ethylmorphine; fully synthetic opioids, such as
fentanyl, pethidine, methadone, tramadol and propoxyphene;
endogenous opioid peptides, produced naturally in the body, such as
endorphins, enkephalins, dynorphins, and endomorphins.
[0549] The compound of the disclosure can be used alone or in
combination therapy to alleviate GI disorders encountered with
patients with renal failure (stage 3-5). Constipation is the second
most reported symptom in that category of patients (Murtagh et al.,
2006; Murtagh et al., 2007a; Murtagh et al., 2007b). Without being
held by theory, it is believed that kidney failure is accompanied
by a stimulation of intestinal Na re-absorption (Hatch and Freel,
2008). A total or partial inhibition of such transport by
administration of the compounds of the disclosure can have a
therapeutic benefit to improve GI transit and relieve abdominal
pain. In that context, the compounds of the disclosure can be used
in combination with Angiotensin-modulating agents: Angiotensin
Converting Enzyme (ACE) inhibitors (e.g. captopril, enalopril,
lisinopril, ramipril) and Angiotensin II receptor antagonist
therapy (also referred to as AT.sub.1-antagonists or angiotensin
receptor blockers, or ARB's); diuretics such as loop diuretics
(e.g. furosemide, bumetanide), Thiazide diuretics (e.g.
hydrochlorothiazide, chlorthalidone, chlorthiazide) and
potassium-sparing diuretics: amiloride; beta blockers: bisoprolol,
carvedilol, nebivolol and extended-release metoprolol; positive
inotropes: Digoxin, dobutamine; phosphodiesterase inhibitors such
as milrinone; alternative vasodilators: combination of isosorbide
dinitrate/hydralazine; aldosterone receptor antagonists:
spironolactone, eplerenone; natriuretic peptides: Nesiritide, a
recombinant form of brain-natriuretic peptide (BNP),
atrial-natriuretic peptide (ANP); vasopressin receptor antagonists:
Tolvaptan and conivaptan; phosphate binder (Renagel, Renleva,
Phoslo, Fosrenol); phosphate transport inhibitor such as those
described in U.S. Pat. Nos. 4,806,532, 6,355,823, 6,787,528, WO
2001/005398, WO 2001/087294, WO 2001/082924, WO 2002/028353, WO
2003/048134, WO 2003/057225, U.S. Pat. No. 7,119,120, EP 1465638,
US Appl. 2007/021509, WO 2003/080630, U.S. Pat. No. 7,109,184, US
Appl. 2006/0280719, EP 1485391, WO 2004/085448, WO 2004/085382, US
Appl. 2006/0217426, JP 2007/131532, the entire contents of which
are incorporated herein by reference for all relevant and
consistent purposes, or phosphate transport antagonist
(Nicotinamide).
[0550] The compounds of the disclosure can be used in combination
with peptides or peptide analogs that activate the Guanylate
Cyclase-receptor in the intestine and results in elevation of the
intracellular second messenger, or cyclic guanosine monophosphate
(cGMP), with increased chloride and bicarbonate secretion into the
intestinal lumen and concomitant fluid secretion. Example of such
peptides are Linaclotide (MD-1100 Acetate), endogenous hormones
guanylin and uroguanylin and enteric bacterial peptides of the heat
stable enterotoxin family (ST peptides) and those described in U.S.
Pat. Nos. 5,140,102, 5,489,670, 5,969,097, WO 2006/001931A2, WO
2008/002971 A2, WO 2008/106429A2, US 2008/0227685A1 and U.S. Pat.
No. 7,041,786, the entire contents of which are incorporated herein
by reference for all relevant and consistent purposes.
[0551] The compounds of the disclosure can be used in combination
with type-2 chloride channel agonists, such as Amitiia
(Lubiprostone) and other related compounds described in U.S. Pat.
No. 6,414,016, the entire contents of which are incorporated herein
by reference for all relevant and consistent purposes.
[0552] The compounds of the disclosure can be used in combination
with P2Y2 receptor agonists, such as those described in EP
1196396B1 and U.S. Pat. No. 6,624,150, the entire contents of which
are incorporated herein by reference for all relevant and
consistent purposes.
[0553] The compounds of the disclosure can be used in combination
with laxative agents such as bulk-producing agents, e.g. psyllium
husk (Metamucil), methylcellulose (Citrucel), polycarbophil,
dietary fiber, apples, stool softeners/surfactant such as docusate
(Colace, Diocto); hydrating agents (osmotics), such as dibasic
sodium phosphate, magnesium citrate, magnesium hydroxide (Milk of
magnesia), magnesium sulfate (which is Epsom salt), monobasic
sodium phosphate, sodium biphosphate; hyperosmotic agents: glycerin
suppositories, sorbitol, lactulose, and polyethylene glycol (PEG).
The compounds of the disclosure can be also be used in combination
with agents that stimulate gut peristalsis, such as Bisacodyl
tablets (Dulcolax), Casanthranol, Senna and Aloin, from Aloe
Vera.
[0554] In one embodiment, the compounds of the disclosure
accelerate gastrointestinal transit, and more specifically in the
colon, without substantially affecting the residence time in the
stomach, i.e. with no significant effect on the gastric emptying
time. Even more specifically the compounds of the invention restore
colonic transit without the side-effects associated with delayed
gastric emptying time, such as nausea. The GI and colonic transit
are measured in patients using methods reported in, for example:
Burton D D, Camilleri M, Mullan B P, et al., J. Nucl. Med., 1997;
38:1807-1810; Cremonini F, Mullan B P, Camilleri M, et al.,
Aliment. Pharmacol. Ther., 2002; 16:1781-1790; Camilleri M,
Zinsmeister A R, Gastroenterology, 1992; 103:36-42; Bouras E P,
Camilleri M, Burton D D, et al., Gastroenterology, 2001;
120:354-360; Coulie B, Szarka L A, Camilleri M, et al.,
Gastroenterology, 2000; 119:41-50; Prather C M, Camilleri M,
Zinsmeister A R, et al., Gastroenterology, 2000; 118:463-468; and,
Camilleri M, McKinzie S, Fox J, et al., Clin. Gastroenterol.
Hepatol., 2004; 2:895-904.
[0555] C. Polymer Combination Therapy
[0556] The NHE-inhibiting compounds described therein may be
administered to patients in need thereof in combination with a
fluid-absorbing polymer ("FAP"). The intestinal fluid-absorbing
polymers useful for administration in accordance with embodiments
of the present disclosure may be administered orally in combination
with non-absorbable NHE-inhibiting compounds (e.g., a NHE-3
inhibitor) to absorb the intestinal fluid resulting from the action
of the sodium transport inhibitors. Such polymers swell in the
colon and bind fluid to impart a consistency to stools that is
acceptable for patients. The fluid-absorbing polymers described
herein may be selected from polymers with laxative properties, also
referred to as bulking agents (i.e., polymers that retain some of
the intestinal fluid in the stools and impart a higher degree of
hydration in the stools and facilitate transit). The
fluid-absorbing polymers may also be optionally selected from
pharmaceutical polymers with anti-diarrhea function, i.e., agents
that maintain some consistency to the stools to avoid watery stools
and potential incontinence.
[0557] The ability of the polymer to maintain a certain consistency
in stools with a high content of fluid can be characterized by its
"water holding power." Wenzl et al. (in Determinants of decreased
fecal consistency in patients with diarrhea; Gastroenterology, v.
108, no. 6, p. 1729-1738 (1995)) studied the determinants that
control the consistency of stools of patients with diarrhea and
found that they were narrowly correlated with the water holding
power of the feces. The water holding power is determined as the
water content of given stools to achieve a certain level of
consistency (corresponding to "formed stool" consistency) after the
reconstituted fecal matter has been centrifuged at a certain g
number. Without being held to any particular theory, has been found
that the water holding power of the feces is increased by ingestion
of certain polymers with a given fluid absorbing profile. More
specifically, it has been found that the water-holding power of
said polymers is correlated with their fluid absorbency under load
(AUL); even more specifically the AUL of said polymers is greater
than 15 g of isotonic fluid/g of polymer under a static pressure of
5 kPa, or under a static pressure of 10 kPa.
[0558] The FAP utilized in the treatment method of the present
disclosure also has a AUL of at least about 10 g, about 15 g, about
20 g, about 25 g or more of isotonic fluid/g of polymer under a
static pressure of about 5 kPa, or about 10 kPA, and may have a
fluid absorbency of about 20 g, about 25 g or more, as determined
using means generally known in the art. Additionally or
alternatively, the FAP may impart a minimum consistency to fecal
matter and, in some embodiments, a consistency graded as "soft" in
the scale described in the test method below, when fecal non
water-soluble solid fraction is from 10% to 20%, and the polymer
concentration is from 1% to 5% of the weight of stool. The
determination of the fecal non water-soluble solid fraction of
stools is described in Wenz et al. The polymer may be uncharged or
may have a low charge density (e.g., 1-2 meq/gr). Alternatively or
in addition, the polymer may be delivered directly to the colon
using known delivery methods to avoid premature swelling in the
esophagus.
[0559] In one embodiment of the present disclosure, the FAP is a
"superabsorbent" polymer (i.e., a lightly crosslinked, partially
neutralized polyelectrolyte hydrogel similar to those used in baby
diapers, feminine hygiene products, agriculture additives, etc.).
Superabsorbent polymers may be made of a lightly crosslinked
polyacrylate hydrogel. The swelling of the polymer is driven
essentially by two effects: (i) the hydration of the polymer
backbone and entropy of mixing and (ii) the osmotic pressure
arising from the counter-ions (e.g., Na ions) within the gel. The
gel swelling ratio at equilibrium is controlled by the elastic
resistance inherent to the polymer network and by the chemical
potential of the bathing fluid, i.e., the gel will de-swell at
higher salt concentration because the background electrolyte will
reduce the apparent charge density on the polymer and will reduce
the difference of free ion concentrations inside and outside the
gel that drives osmotic pressure. The swelling ratio SR (g of fluid
per g of dry polymer and synonymously "fluid absorbency") may vary
from 1000 in pure water down to 30 in 0.9% NaCl solution
representative of physiological saline (i.e., isotonic). SR may
increase with the degree of neutralization and may decrease with
the crosslinking density. SR generally decreases with an applied
load with the extent of reduction dependent on the strength of the
gel, i.e., the crosslinking density. The salt concentration within
the gel, as compared with the external solution, may be lower as a
result of the Donnan effect due to the internal electrical
potential.
[0560] The fluid-absorbing polymer may include crosslinked
polyacrylates which are fluid absorbent such as those prepared from
.alpha.,.beta.-ethylenically unsaturated monomers, such as
monocarboxylic acids, polycarboxylic acids, acrylamide and their
derivatives. These polymers may have repeating units of acrylic
acid, methacrylic acid, metal salts of acrylic acid, acrylamide,
and acrylamide derivatives (such as
2-acrylamido-2-methylpropanesulfonic acid) along with various
combinations of such repeating units as copolymers. Such
derivatives include acrylic polymers which include hydrophilic
grafts of polymers such as polyvinyl alcohol. Examples of suitable
polymers and processes, including gel polymerization processes, for
preparing such polymers are disclosed in U.S. Pat. Nos. 3,997,484;
3,926,891; 3,935,099; 4,090,013; 4,093,776; 4,340,706; 4,446,261;
4,683,274; 4,459,396; 4,708,997; 4,076,663; 4,190,562; 4,286,082;
4,857,610; 4,985,518; 5,145,906; 5,629,377 and 6,908,609 which are
incorporated herein by reference for all relevant and consistent
purposes (in addition, see Buchholz, F. L. and Graham, A. T.,
"Modern Superabsorbent Polymer Technology," John Wiley & Sons
(1998), which is also incorporated herein by reference for all
relevant and consistent purposes). A class of preferred polymers
for treatment in combination with NHE-inhibitors is
polyelectrolytes.
[0561] The degree of crosslinking can vary greatly depending upon
the specific polymer material; however, in most applications the
subject superabsorbent polymers are only lightly crosslinked, that
is, the degree of crosslinking is such that the polymer can still
absorb over 10 times its weight in physiological saline (i.e., 0.9%
saline). For example, such polymers typically include less than
about 0.2 mole % crosslinking agent.
[0562] In some embodiments, the FAP's utilized for treatment are
Calcium Carbophil (Registry Number: 9003-97-8, also referred as
Carbopol EX-83), and Carpopol 934P.
[0563] In some embodiments, the fluid-absorbing polymer is prepared
by high internal phase emulsion ("HIPE") processes. The HIPE
process leads to polymeric foam slabs with a very large porous
fraction of interconnected large voids (about 100 microns) (i.e.,
open-cell structures). This technique produces flexible and
collapsible foam materials with exceptional suction pressure and
fluid absorbency (see U.S. Pat. Nos. 5,650,222; 5,763,499 and
6,107,356, which are incorporated herein for all relevant and
consistent purposes). The polymer is hydrophobic and, therefore,
the surface should be modified so as to be wetted by the aqueous
fluid. This is accomplished by post-treating the foam material by a
surfactant in order to reduce the interfacial tension. These
materials are claimed to be less compliant to loads, i.e., less
prone to de-swelling under static pressure.
[0564] In some embodiments, fluid-absorbing gels are prepared by
aqueous free radical polymerization of acrylamide or a derivative
thereof, a crosslinker (e.g., methylene-bis-acrylamide) and a free
radical initiator redox system in water. The material is obtained
as a slab. Typically, the swelling ratio of crosslinked
polyacrylamide at low crosslinking density (e.g., 2%-4% expressed
as weight % of methylene-bis-acrylamide) is between 25 and 40 (F.
Horkay, Macromolecules, 22, pp. 2007-09 (1989)). The swelling
properties of these polymers have been extensively studied and are
essentially the same of those of crosslinked polyacrylic acids at
high salt concentration. Under those conditions, the osmotic
pressure is null due to the presence of counter-ions and the
swelling is controlled by the free energy of mixing and the network
elastic energy. Stated differently, a crosslinked polyacrylamide
gel of same crosslink density as a neutralized polyacrylic acid
will exhibit the same swelling ratio (i.e., fluid absorbing
properties) and it is believed the same degree of deswelling under
pressure, as the crosslinked polyelectrolyte at high salt content
(e.g., 1 M). The properties (e.g., swelling) of neutral hydrogels
will not be sensitive to the salt environment as long as the
polymer remains in good solvent conditions. Without being held to
any particular theory, it is believed that the fluid contained
within the gel has the same salt composition than the surrounding
fluid (i.e., there is no salt partitioning due to Donnan
effect).
[0565] Another subclass of fluid-absorbing polymers that may be
utilized is hydrogel materials that include N-alkyl acrylamide
polymers (e.g., N-isopropylacrylamide (NIPAM)). The corresponding
aqueous polyNIPAM hydrogel shows a temperature transition at about
35.degree. C. Above this temperature the hydrogel may collapse. The
mechanism is generally reversible and the gel re-swells to its
original swelling ratio when the temperature reverts to room
temperature. This allows production of nanoparticles by emulsion
polymerization (R. Pelton, Advances in Colloid and Interface
Science, 85, pp. 1-33, (2000)). The swelling characteristics of
poly-NIPAM nanoparticles below the transition temperature have been
reported and are similar to those reported for bulk gel of
polyNIPAM and equivalent to those found for polyacrylamide (i.e.
30-50 g/g) (W. McPhee, Journal of Colloid and Interface Science,
156, pp. 24-30 (1993); and, K. Oh, Journal of Applied Polymer
Science, 69, pp. 109-114 (1997)).
[0566] In some embodiments, the FAP utilized for treatment in
combination with a NHE-inhibitor is a superporous gel that may
delay the emptying of the stomach for the treatment of obesity (J.
Chen, Journal of Controlled Release, 65, pp. 73-82 (2000), or to
deliver proteins. Polyacrylate-based SAP's with a macroporous
structure may also be used. Macroporous SAP and superporous gels
differ in that the porous structure remains almost intact in the
dry state for superporous gels, but disappears upon drying for
macroporous SAP's. The method of preparation is different although
both methods use a foaming agent (e.g., carbonate salt that
generates CO.sub.2 bubbles during polymerization). Typical swelling
ratios, SR, of superporous materials are around 10. Superporous
gels keep a large internal pore volume in the dry state.
[0567] Macroporous hydrogels may also be formed using a method
whereby polymer phase separation in induced by a non-solvent. The
polymer may be poly-NIPAM and the non-solvent utilized may be
glucose (see, e.g., Z. Zhang, J. Org. Chem., 69, 23 (2004)) or NaCl
(see, e.g., Cheng et al., Journal of Biomedical Materials
Research--Part A, Vol. 67, Issue 1, 1 Oct. 2003, Pages 96-103). The
phase separation induced by the presence of NaCl leads to an
increase in swelling ratio. These materials are preferred if the
swelling ratio of the material, SR, is maintained in salt isotonic
solution and if the gels do not collapse under load. The
temperature of "service" should be shifted beyond body temperature,
e.g. by diluting NIPAM in the polymer with monomer devoid of
transition temperature phenomenon.
[0568] In some embodiments, the fluid-absorbing polymer may be
selected from certain naturally-occurring polymers such as those
containing carbohydrate moieties. In a preferred embodiment, such
carbohydrate-containing hydrogels are non-digestible, have a low
fraction of soluble material and a high fraction of gel-forming
materials. In some embodiments, the fluid-absorbing polymer is
selected from xanthan, guar, wellan, hemicelluloses,
alkyl-cellulose, hydro-alkyl-cellulose, carboxy-alkyl-cellulose,
carrageenan, dextran, hyaluronic acid and agarose. In a preferred
embodiment, the gel forming polymer is psyllium. Psyllium (or
"ispaghula") is the common name used for several members of the
plant genus Plantago whose seeds are used commercially for the
production of mucilage. The fluid-absorbing polymer is also in the
gel-forming fraction of psyllium, i.e., a neutral saccharide
copolymer of arabinose (25%) and xylose (75%) as characterized in
(J. Marlett, Proceedings of the Nutrition Society, 62, pp. 2-7-209
(2003); and, M. Fischer, Carbohydrate Research, 339, 2009-2012
(2004)), and further described in U.S. Pat. Nos. 6,287,609;
7,026,303; 5,126,150; 5,445,831; 7,014,862; 4,766,004; 4,999,200,
each of which is incorporated herein for all relevant and
consistent purposes, and over-the-counter psillium-containing
agents such as those marketed under the name Metamucil (The Procter
and Gamble company). A psyllium-containing dosage form is also
suitable for chewing, where the chewing action disintegrates the
tablet into smaller, discrete particles prior to swallowing but
which undergoes minimal gelling in the mouth, and has acceptable
mouthfeel and good aesthetics as perceived by the patient.
[0569] The psyllium-containing dosage form includes physically
discrete unit suitable as a unitary dosage for human subjects and
other mammals, each containing a predetermined quantity of active
material (e.g. the gel-forming polysaccharide) calculated to
produce the desired therapeutic effect. Solid oral dosage forms
that are suitable for the present compositions include tablets,
pills, capsules, lozenges, chewable tablets, troches, cachets,
pellets, wafer and the like.
[0570] In some embodiments, the FAP is a polysaccharide particle
wherein the polysaccharide component includes xylose and arabinose.
The ratio of the xylose to the arabinose may be at least about 3:1
by weight, as described in U.S. Pat. Nos. 6,287,609; 7,026,303 and
7,014,862, each of which is incorporated herein for all relevant
and consistent purposes.
[0571] The fluid-absorbing polymers described herein may be used in
combination with the NHE-inhibiting compound or a pharmaceutical
composition containing it. The NHE-inhibiting compound and the FAP
may also be administered with other agents including those
described under the heading "Combination Therapies" without
departing from the scope of the present disclosure. As described
above, the NHE-inhibiting compound may be administered alone
without use of a fluid-absorbing polymer to resolve symptoms
without eliciting significant diarrhea or fecal fluid secretion
that would require the co-administration of a fluid-absorbing
polymer.
[0572] The fluid-absorbing polymers described herein may be
selected so as to not induce any substantial interaction with the
NHE-inhibiting compound or a pharmaceutical composition containing
it. As used herein, "no substantial interaction" generally means
that the co-administration of the FAP polymer would not
substantially alter (i.e., neither substantially decrease nor
substantially increase) the pharmacological property of the
NHE-inhibiting compounds administered alone. For example, FAPs
containing negatively charged functionality, such as carboxylates,
sulfonates, and the like, may potentially interact ionically with
positively charged NHE-inhibiting compounds, preventing the
inhibitor from reaching its pharmacological target. In addition, it
may be possible that the shape and arrangement of functionality in
a FAP could act as a molecular recognition element, and sequestor
NHE-inhibiting compounds via "host-guest" interactions via the
recognition of specific hydrogen bonds and/or hydrophobic regions
of a given inhibitor. Accordingly, in various embodiments of the
present disclosure, the FAP polymer may be selected, for
co-administration or use with a compound of the present disclosure,
to ensure that (i) it does not ionically interact with or bind with
the compound of the present disclosure (by means of, for example, a
moiety present therein possessing a charge opposite that of a
moiety in the compound itself), and/or (ii) it does not possess a
charge and/or structural conformation (or shape or arrangement)
that enables it to establish a "host-guest" interaction with the
compound of the present disclosure (by means of, for example, a
moiety present therein that may act as a molecular recognition
element and sequester the NHE inhibitor or inhibiting moiety of the
compound).
[0573] D. Dosage
[0574] It is to be noted that, as used herein, an "effective
amount" (or "pharmaceutically effective amount") of a compound
disclosed herein, is a quantity that results in a beneficial
clinical outcome of the condition being treated with the compound
compared with the absence of treatment. The amount of the compound
or compounds administered will depend on the degree, severity, and
type of the disease or condition, the amount of therapy desired,
and the release characteristics of the pharmaceutical formulation.
It will also depend on the subject's health, size, weight, age, sex
and tolerance to drugs. Typically, the compound is administered for
a sufficient period of time to achieve the desired therapeutic
effect.
[0575] In embodiments wherein both an NHE-inhibitor compound and a
fluid-absorbing polymer are used in the treatment protocol, the
NHE-inhibiting compound and FAP may be administered together or in
a "dual-regimen" wherein the two therapeutics are dosed and
administered separately. When the NHE-inhibiting compound and the
fluid-absorbing polymer are dosed separately, the typical dosage
administered to the subject in need of the NHE-inhibiting compound
is typically from about 5 mg per day and about 5000 mg per day and,
in other embodiments, from about 50 mg per day and about 1000 mg
per day. Such dosages may induce fecal excretion of sodium (and its
accompanying anions), from about 10 mmol up to about 250 mmol per
day, from about 20 mmol to about 70 mmol per day or even from about
30 mmol to about 60 mmol per day.
[0576] The typical dose of the fluid-absorbing polymer is a
function of the extent of fecal secretion induced by the
non-absorbable NHE-inhibiting compound. Typically, the dose is
adjusted according to the frequency of bowel movements and
consistency of the stools. More specifically the dose is adjusted
so as to avoid liquid stools and maintain stool consistency as
"soft" or semi-formed, or formed. To achieve the desired stool
consistency and provide abdominal relief to patients, typical
dosage ranges of the fluid-absorbing polymer to be administered in
combination with the NHE-inhibiting compound, are from about 2 g to
about 50 g per day, from about 5 g to about 25 g per day or even
from about 10 g to about 20 g per day. When the NHE-inhibiting
compound and the FAP are administered as a single dosage regimen,
the daily uptake may be from about 2 g to about 50 g per day, from
about 5 g to about 25 g per day, or from about 10 g to about 20 g
per day, with a weight ratio of NHE-inhibiting compound to
fluid-absorbing polymer being from about 1:1000 to 1:10 or even
from about 1:500 to 1:5 or about 1:100 to 1:5.
[0577] A typical dosage of the substantially impermeable or
substantially systemically non-bioavailable, NHE-inhibiting
compound when used alone without a FAP may be between about 0.2 mg
per day and about 2 g per day, or between about 1 mg and about 1 g
per day, or between about 5 mg and about 500 mg, or between about
10 mg and about 250 mg per day, which is administered to a subject
in need of treatment.
[0578] The frequency of administration of therapeutics described
herein may vary from once-a-day (QD) to twice-a-day (BID) or
thrice-a-day (TID), etc., the precise frequency of administration
varying with, for example, the patient's condition, the dosage,
etc. For example, in the case of a dual-regimen, the NHE-inhibiting
compound could be taken once-a-day while the fluid-absorbing
polymer could be taken at each meal (TID). Furthermore, as
disclosed in U.S. Application No. 61/584,753 filed Jan. 9, 2012,
the NHE-inhibiting compound is administered twice-a-day (BID), or
thrice-a-day (TID), and in a more specific embodiment, the
NHE-inhibiting compound is administered in an amount ranging from
2-200 mg per dose BID, or 2-100 mg per dose TID. In more specific
embodiments, the NHE-inhibiting compound is administered in an
amount of about 15 mg per dose, about 30 mg per dose, or about 45
mg per dose, and in a more specific embodiment, in an amount of 15
mg per dose, 30 mg per dose, or 45 mg per dose.
[0579] E. Modes of Administration
[0580] The substantially impermeable or substantially systemically
non-bioavailable NHE-inhibiting compounds of the present disclosure
with or without the fluid-absorbing polymers described herein may
be administered by any suitable route. The compound is
administrated orally (e.g., dietary) in capsules, suspensions,
tablets, pills, dragees, liquids, gels, syrups, slurries, and the
like. Methods for encapsulating compositions (such as in a coating
of hard gelatin or cyclodextran) are known in the art (Baker, et
al., "Controlled Release of Biological Active Agents", John Wiley
and Sons, 1986). The compounds can be administered to the subject
in conjunction with an acceptable pharmaceutical carrier as part of
a pharmaceutical composition. The formulation of the pharmaceutical
composition will vary according to the route of administration
selected. Suitable pharmaceutical carriers may contain inert
ingredients which do not interact with the compound. The carriers
are biocompatible, i.e., non-toxic, non-inflammatory,
non-immunogenic and devoid of other undesired reactions at the
administration site. Examples of pharmaceutically acceptable
carriers include, for example, saline, commercially available inert
gels, or liquids supplemented with albumin, methyl cellulose or a
collagen matrix. Standard pharmaceutical formulation techniques can
be employed, such as those described in Remington's Pharmaceutical
Sciences, Mack Publishing Company, Easton, Pa.
[0581] In other embodiments, the NHE-3 inhibiting compounds may be
systemically administered. In one embodiment, the compounds of the
present invention are administered systemically to inhibit NHE-3 in
the kidney. Without being held to any particular theory, the
impermeable NHE-inhibiting compounds (e.g., NHE-3, -2 and/or -8
inhibitors) of the present disclosure can also be administered
parenterally, by intravenous, subcutaneous or intramuscular
injection or infusion to inhibit NHE3 in the kidney. NHE3 is
expressed at high levels on the apical surface of the proximal
tubule of the kidney and couples luminal Na reabsorption to the
secretion of intracellular protons. Since NHE3 accounts for
approximately 60-80% of sodium reabsorption in the kidney, it is
anticipated that NHE inhibition could permit the removal of
substantial quantities of systemic fluid and sodium to prevent
edema and resolve congestive heart failure symptoms. This effect
could be achieved by NHE inhibition in combination with other
diuretics, specifically loop diuretics, like furosemide, to inhibit
tubuloglomerular feedback. In addition, since sodium reabsorption
via NHE3 in the proximal tubule is responsible for a large
proportion of the energy requirement of the proximal tubule cell,
it is anticipated that NHE inhibition in the kidney could be
beneficial by reducing the energy requirement and protecting the
proximal tubule cell in settings of decreased energy availability
to the proximal tubule, such as those that occur as a result of
kidney hypoxia such as in kidney ischemia reperfusion injury
resulting in acute kidney injury.
[0582] Pharmaceutical preparations for oral use can be obtained by
combining a compound of the present disclosure with a solid
excipient, optionally grinding a resulting mixture, and processing
the mixture of granules, after adding suitable auxiliaries, if
desired, to obtain tablets or dragee cores. Suitable excipients
are, in particular, fillers such as sugars, including lactose,
sucrose, mannitol, or sorbitol; cellulose preparations such as, for
example, maize starch, wheat starch, rice starch, potato starch,
gelatin, gum tragacanth, methyl cellulose,
hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or
polyvinylpyrrolidone (PVP). If desired, disintegrating agents can
be added, such as cross-linked polyvinyl pyrrolidone, agar, or
alginic acid or a salt thereof such as sodium alginate.
[0583] Dragee cores are provided with suitable coatings. For this
purpose, concentrated sugar solutions can be used, which can
optionally contain gum arabic, talc, polyvinyl pyrrolidone,
carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer
solutions, and suitable organic solvents or solvent mixtures.
Dyestuffs or pigments can be added to the tablets or dragee
coatings for identification or to characterize different
combinations of active compound doses.
[0584] Pharmaceutical preparations which can be used orally include
push-fit capsules made of a suitable material, such as gelatin, as
well as soft, sealed capsules made of a suitable material, for
example, gelatin, and a plasticizer, such as glycerol or sorbitol.
The push-fit capsules can contain the active ingredients in
admixture with filler such as lactose, binders such as starches,
and/or lubricants such as talc or magnesium stearate and,
optionally, stabilizers. In soft capsules, the active compounds can
be dissolved or suspended in suitable liquids, such as fatty oils,
liquid paraffin, or liquid polyethylene glycols. In addition,
stabilizers can be added. All formulations for oral administration
should be in dosages suitable for such administration.
[0585] It will be understood that, certain compounds of the
disclosure may be obtained as different stereoisomers (e.g.,
diastereomers and enantiomers) or as isotopes and that the
disclosure includes all isomeric forms, racemic mixtures and
isotopes of the disclosed compounds and a method of treating a
subject with both pure isomers and mixtures thereof, including
racemic mixtures, as well as isotopes. Stereoisomers can be
separated and isolated using any suitable method, such as
chromatography.
[0586] F. Delayed Release
[0587] NHE proteins show considerable diversity in their patterns
of tissue expression, membrane localization and functional roles.
(See, e.g., The sodium-hydrogen exchanger--From molecule To Is Role
In Disease, Karmazyn, M., Avkiran, M., and Fliegel, L., eds.,
Kluwer Academics (2003).)
[0588] In mammals, nine distinct NHE genes (NHE-1 through -9) have
been described. Of these nine, five (NHE-1 through -5) are
principally active at the plasma membrane, whereas NHE-6, -7 and -9
reside predominantly within intracellular compartments.
[0589] NHE-1 is ubiquitously expressed and is chiefly responsible
for restoration of steady state intracellular pH following
cytosolic acidification and for maintenance of cell volume. Recent
findings show that NHE-1 is crucial for organ function and survival
(e.g., NHE-1-null mice exhibit locomotor abnormalities,
epileptic-like seizures and considerable mortality before
weaning).
[0590] In contrast with NHE-1 expressed at the basolateral side of
the nephrons and gut epithelial cells, NHE-2 through -4 are
predominantly expressed on the apical side of epithelia of the
kidney and the gastrointestinal tract. Several lines of evidence
show that NHE-3 is the major contributor of renal bulk Na+ and
fluid re-absorption by the proximal tubule. The associated
secretion of H+ by NHE-3 into the lumen of renal tubules is also
essential for about 2/3 of renal HCO3.sup.- re-absorption. Complete
disruption of NHE-3 function in mice causes a sharp reduction in
HCO3.sup.-, Na.sup.+ and fluid re-absorption in the kidney, which
is consistently associated with hypovolemia and acidosis.
[0591] In one embodiment, the compounds of the disclosure are
intended to target the apical NHE antiporters (e.g. NHE-3, NHE-2
and NHE-8) without substantial permeability across the layer of gut
epithelial cells, and/or without substantial activity towards NHEs
that do not reside predominantly in the GI tract. This invention
provides a method to selectively inhibit GI apical NHE antiporters
and provide the desired effect of salt and fluid absorption
inhibition to correct abnormal fluid homeostasis leading to
constipations states. Because of their absence of systemic
exposure, said compounds do not interfere with other key
physiological roles of NHEs highlighted above. For instance, the
compounds of the disclosure are expected to treat constipation in
patients in need thereof, without eliciting undesired systemic
effects, such as for example salt wasting or bicarbonate loss
leading to hyponatriemia and acidosis among other disorders.
[0592] In another embodiment, the compounds of the disclosure are
delivered to the small bowel with little or no interaction with the
upper GI such as the gastric compartment and the duodenum. The
applicant found that an early release of the compounds in the
stomach or the duodenum can have an untoward effect on gastric
secretion or bicarbonate secretion (also referred to as
"bicarbonate dump"). In this embodiment the compounds are designed
so as to be released in an active form past the duodenum. This can
be accomplished by either a prodrug approach or by specific drug
delivery systems.
[0593] As used herein, "prodrug" is to be understood to refer to a
modified form of the compounds detailed herein that is inactive (or
significantly less active) in the upper GI, but once administered
is metabolised in vivo into an active metabolite after getting
past, for example, the duodenum. Thus, in a prodrug approach, the
activity of the NHE-inhibiting compound can be masked with a
transient protecting group that is liberated after compound passage
through the desired gastric compartment. For example, acylation or
alkylation of the essential guanidinyl functionality of the
NHE-inhibiting compound would render it biochemically inactive;
however, cleavage of these functional groups by intestinal
amidases, esterases, phosphatases, and the like, as well enzymes
present in the colonic flora, would liberate the active parent
compound. Prodrugs can be designed to exploit the relative
expression and localization of such phase I metabolic enzymes by
carefully optimizing the structure of the prodrug for recognition
by specific enzymes. As an example, the anti-inflammatory agent
sulfasalazine is converted to 5-aminosalicylate in the colon by
reduction of the diazo bond by intestinal bacteria.
[0594] In a drug delivery approach the NHE-inhibiting compounds of
the disclosure are formulated in certain pharmaceutical
compositions for oral administration that release the active in the
targeted areas of the GI, i.e., jejunum, ileum or colon, the distal
ileum and colon, or the colon.
[0595] Methods known from the skilled-in-the-art are applicable.
(See, e.g., Kumar, P. and Mishra, B., Colon Targeted Drug Delivery
Systems--An Overview, Curr. Drug Deliv., 2008, 5 (3), 186-198;
Jain, S. K. and Jain, A., Target-specific Drug Release to the
Colon., Expert Opin. Drug Deliv., 2008, 5 (5), 483-498; Yang, L.,
Biorelevant Dissolution Testing of Colon-Specific Delivery Systems
Activated by Colonic Microflora, J. Control Release, 2008, 125 (2),
77-86; Siepmann, F.; Siepmann, J.; Walther, M.; MacRae, R. J.; and
Bodmeier, R., Polymer Blends for Controlled Release Coatings, J.
Control Release 2008, 125 (1), 1-15; Patel, M.; Shah, T.; and Amin,
A., Therapeutic Opportunities in Colon-Specific Drug-Delivery
Systems, Crit. Rev. Ther. Drug Carrier Syst., 2007, 24 (2),
147-202; Jain, A.; Gupta, Y.; Jain, S. K., Perspectives of
Biodegradable Natural Polysaccharides for Site-specific Drug
Delivery to the Colon., J. Pharm. Sci., 2007, 10 (1), 86-128; Van
den, M. G., Colon Drug Delivery, Expert Opin. Drug Deliv., 2006, 3
(1), 111-125; Basit, A. W., Advances in Colonic Drug Delivery,
Drugs 2005, 65 (14), 1991-2007; Chourasia, M. K.; Jain, S. K.,
Polysaccharides for Colon-Targeted Drug Delivery, Drug Deliv. 2004,
11 (2), 129-148; Shareef, M. A.; Khar, R. K.; Ahuja, A.; Ahmad, F.
J.; and Raghava, S., Colonic Drug Delivery: An Updated Review, AAPS
Pharm. Sci. 2003, 5 (2), E17; Chourasia, M. K.; Jain, S. K.,
Pharmaceutical Approaches to Colon Targeted Drug Delivery Systems,
J. Pharm. Sci. 2003, 6 (1), 33-66; and, Sinha, V. R.; Kumria, R.,
Colonic Drug Delivery: Prodrug Approach, Pharm. Res. 2001, 18 (5),
557-564. Typically, the active pharmaceutical ingredient (API) is
contained in a tablet/capsule designed to release said API as a
function of the environment (e.g., pH, enzymatic activity,
temperature, etc.), or as a function of time. One example of this
approach is Eudracol.TM. (Pharma Polymers Business Line of
Degussa's Specialty Acrylics Business Unit), where the
API-containing core tablet is layered with various polymeric
coatings with specific dissolution profiles. The first layer
ensures that the tablet passes through the stomach intact so it can
continue through the small intestine. The change from an acidic
environment in the stomach to an alkaline environment in the small
intestine initiates the release of the protective outer layer. As
it travels through the colon, the next layer is made permeable by
the alkalinity and intestinal fluid. This allows fluid to penetrate
to the interior layer and release the active ingredient, which
diffuses from the core to the outside, where it can be absorbed by
the intestinal wall. Other methods are contemplated without
departing from the scope of the present disclosure.
[0596] In another example, the pharmaceutical compositions of the
invention can be used with drug carriers including pectin and
galactomannan, polysaccharides that are both degradable by colonic
bacterial enzymes. (See, e.g., U.S. Pat. No. 6,413,494, the entire
contents of which are incorporated herein by reference for all
relevant and consistent purposes.) While pectin or galactomannan,
if used alone as a drug carrier, are easily dissolved in simulated
gastric fluid and simulated intestinal fluid, a mixture of these
two polysaccharides prepared at a pH of about 7 or above produces a
strong, elastic, and insoluble gel that is not dissolved or
disintegrated in the simulated gastric and intestinal fluids, thus
protecting drugs coated with the mixture from being released in the
upper GI tract. When the mixture of pectin and galactomannan
arrives in the colon, it is rapidly degraded by the synergic action
of colonic bacterial enzymes. In yet another aspect, the
compositions of the invention may be used with the pharmaceutical
matrix of a complex of gelatin and an anionic polysaccharide (e.g.,
pectinate, pectate, alginate, chondroitin sulfate, polygalacturonic
acid, tragacanth gum, arabic gum, and a mixture thereof), which is
degradable by colonic enzymes (U.S. Pat. No. 6,319,518).
[0597] In yet other embodiments, fluid-absorbing polymers that are
administered in accordance with treatment methods of the present
disclosure are formulated to provide acceptable/pleasant
organoleptic properties such as mouthfeel, taste, and/or to avoid
premature swelling/gelation in the mouth and in the esophagus and
provoke choking or obstruction. The formulation may be designed in
such a way so as to ensure the full hydration and swelling of the
FAP in the GI tract and avoid the formation of lumps. The oral
dosages for the FAP may take various forms including, for example,
powder, granulates, tablets, wafer, cookie and the like, or are
delivered to the small bowel with little or no interaction with the
upper GI such as the gastric compartment and the duodenum.
[0598] The above-described approaches or methods are only some of
the many methods reported to selectively deliver an active in the
lower part of the intestine, and therefore should not be viewed to
restrain or limit the scope of the disclosure.
IV. Preparation of Compounds
[0599] The following Reaction Schemes I-IV illustrate methods for
making compounds of this invention, i.e., compounds of Formula (I).
It is understood that one skilled in the art may be able to make
these compounds by similar methods or by combining other methods
known to one skilled in the art. It is also understood that one
skilled in the art would be able to make, in a similar manner as
described below, other compounds of Formula (I) not specifically
illustrated below by using the appropriate starting components and
modifying the parameters of the synthesis as needed. The compounds
described herein may be made from commercially available starting
materials or synthesized using known organic, inorganic, and/or
enzymatic processes. In general, starting components may be
obtained from sources such as Sigma Aldrich, Lancaster Synthesis,
Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc,
or synthesized according to sources known to those skilled in the
art (see, for example, Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 5th edition (Wiley, December 2000)) or
prepared as described in this invention. The general synthetic
schemes of precursors, intermediates, and final products shown
below are mere illustrations of methods of preparations. The
various radicals (e.g., R.sup.1, R.sup.2, R.sup.1, R.sup.4, etc. .
. . ) affixed on each generic or sub-generic formula in the schemes
below will be understood to represent the corresponding positional
radicals in the compounds of general Formula I and I' described
above. In other words, in the schemes below only the position of
the radical in the structure will matter in the interpretation of
the synthetic scheme rather than its labelling. For example,
radicals R.sup.1, R.sup.2, and R.sup.3 can be used interchangeably
from one scheme to another without necessarily having the same
meaning. Only their position in the generic structure I and I' will
determine their actual substituents for the synthesis.
##STR00028##
[0600] Referring to General Reaction Scheme I, an appropriate
hydrocinnamic acid A, indanone B, or indene C can be obtained
commercially or synthesized according to methods known in the art
and converted to the enantiopure epoxide D via Jacobsen epoxidation
conditions. The chiral compounds obtained (either enantiomer can be
used) are then reacted with an amine HNR2R.sup.3 (where R.sup.2 and
R.sup.3 are as previously defined) to provide the aminoindanol E.
Further reaction with phenol F is facilitated by either formation
of the mesylate or other activated intermediate of E or through
activation using triphenylphosphine and an azodicarboxylate such as
diisopropylazodicarboxylate, diethylaiodicarboxylate,
di-tert-butylazodicarboxylate, or the like, providing the
rearranged aminoindanol G. Oxidation and chlorination are achieved
through use of chlorinating reagents such as N-chlorosuccinimide,
providing the sulfonyl chloride H. There exist multiple methods of
producing the homodimers compounds (1), including reaction of H
with amine dimers J.
##STR00029##
[0601] Compounds of Formula (1) may also be prepared according to
General Reaction Scheme 11. Aminoindanols E as obtained previously
are reacted with phenols K (available commercially or synthetically
via standard procedures, where X'=bromo or iodo) using conditions
described in General Reaction Scheme I furnishing ether product L.
Conversion of the halide to the thioether G is accomplished through
palladium-mediated coupling with benzylmercaptan. Further
elaboration to the compounds of structure (I) is as described in
General Reaction Scheme I.
##STR00030##
[0602] Compounds of Formula (I) are also prepared according to
General Reaction Scheme III. Beginning with the sulfonyl chloride
H, the product sulfonamides N are formed from reaction with an
amine M where Y (with protecting group "PG", in the case where Y is
a primary or secondary amine) is a protected or masked amine
functionality or other functional handle. Subsequent removal of the
protecting group provides the sulfonamide monomer O followed by
dimerization with a bifunctional "X" moiety P generates the
compounds of structure (I).
##STR00031##
[0603] Compounds of Formula (I) can also be prepared according to
the General Reaction Scheme IV. Phenols F are protected to yield
thioethers Q which are then oxidized to the sulfonyl chloride R
using reagents such as N-chlorosuccinimide in acetic acid.
Subsequently these sulfonyl chlorides R can be coupled with amines
M to yield the differentially protected derivatives S. Deprotection
to yield phenol T which is then reacted with E which is activated
by either formation of the mesylate or other activated intermediate
of E or through using triphenylphosphine and an azodicarboxylate
such as diisopropylazodicarboxylate, diethylazodicarboxylate,
di-tert-butylazodicarboxylate, or the like, providing the
rearranged aminoindanol N. The intermediate is deprotected to yield
the monomer O followed by dimer formation with a core P with
leaving groups to yield the compounds of structure (I).
##STR00032##
[0604] Similar to General Reaction Scheme IV, the compounds of
Formula (I) can be prepared through reaction with a fully dimerized
phenolic coupling partner. Reaction of the dimeric amines J with
sulfonyl chlorides R can provide the dimer U under standard
conditions with mild bases such as pyridine or trimethylamine.
Removal of the protecting groups gives the phenol V. Intermediate
of E is activated by either formation of the mesylate or using
triphenylphosphine and an azodicarboxylate such as
diisopropylazodicarboxylate, diethylazodicarboxylate,
di-tert-butylazodicarboxylate, or the like, then reacting with
phenol V providing the rearranged final compounds of structure
(1).
[0605] With regard to General Reaction Schemes I-IV, typical
carboxylate activation reagents include DCC, EDCl, HATU, oxalyl
chloride, thionyl chloride and the like. Typical bases include TEA,
DIEA, pyridine, K.sub.2CO.sub.3, NaH and the like. Typical
acylation catalysts include HOBt, HOAt, 4-dimethylaminopyridine and
the like. Typical catalysts for hydrogenation include palladium on
carbon, rhodium on carbon, platinum on carbon, raney nickel and the
like.
[0606] One skilled in the art will recognize that variations to the
order of the steps and reagents discussed in reference to the
Reaction Schemes are possible. Methodologies for preparation of
compounds of Formula (I) are described in more detail in the
following non-limiting exemplary schemes.
[0607] It will also be appreciated by those skilled in the art that
in the process described herein the functional groups of
intermediate compounds may need to be protected by suitable
protecting groups. Such functional groups include hydroxy, amino,
mercapto and carboxylic acid. Suitable protecting groups for
hydroxy include trialkylsilyl or diarylalkylsilyl (for example,
t-butyldimethylsilyl, f-butyldiphenylsilyl or trimethylsilyl),
tetrahydropyranyl, benzyl, and the like. Suitable protecting groups
for amino, amidino and guanidino include i-butoxycarbonyl,
benzyloxycarbonyl, trifluoroacetyl and the like. Suitable
protecting groups for carboxylic acid include alkyl, aryl or
arylalkyl esters. Protecting groups may be added or removed in
accordance with standard techniques, which are known to one skilled
in the art and as described herein. The use of protecting groups is
described in detail in Green, T. W. and P. G. M. Wutz, Protective
Groups in Organic Synthesis (1999), 3rd Ed., Wiley. As one of skill
in the art would appreciate, the protecting group may also be a
polymer resin such as a Wang resin, Rink resin or a
2-chlorotrityl-chloride resin.
[0608] It will also be appreciated by those skilled in the art,
although such protected derivatives of compounds of this invention
may not possess pharmacological activity as such, they may be
administered to a mammal and thereafter metabolized in the body to
form compounds of the invention which are pharmacologically active.
Such derivatives may therefore be described as "prodrugs". All
prodrugs of compounds of this invention are included within the
scope of the invention.
[0609] The following non-limiting examples are provided to further
illustrate the present disclosure.
EXAMPLES
I General Scheme for Linker Synthesis
##STR00033##
[0611] Step A: To a 250-mL round-bottom flask was added the desired
substituted-bromophenol (1 equiv), acetone (0.45 M), potassium
carbonate (5 equiv), and benzyl bromide (2.5 equiv). The resulting
solution was stirred for 4 h at room temperature. The resulting
solution was diluted with 30 mL of H.sub.2O. The resulting mixture
was concentrated under vacuum and extracted with of ethyl acetate.
The organic layers were combined and washed with 3.times.H.sub.2O
and 1.times. brine. The mixture was dried over anhydrous sodium
sulfate, filtered, and the resulting mixture concentrated under
vacuum. The residue was applied onto a silica gel column with
petroleum ether providing the desired benzylethers INT-L1.
[0612] Step B: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added benzylether INT-L1 (1
equiv), 1,4-dioxane (0.16 M), N,N-diisopropylethylamine (2 equiv),
benzylmercaptan (2 equiv), Pd.sub.2(dba).sub.3.CHCl.sub.3 (0.05
equiv), and Xantphos (0.10 equiv). The resulting solution was
stirred overnight at 100.degree. C. The resulting slurry was
concentrated under vacuum and diluted with of H.sub.2O. The
resulting solution was extracted with of ethyl acetate and the
organic layers combined and washed with 3.times.H.sub.2O and
1.times. brine. The mixture was dried over anhydrous sodium
sulfate, filtered, and the resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with
petroleum ether providing the desired thioethers INT-L2.
[0613] Step C: To a round-bottom flask was added thioether INT-L2
(1 equiv), acetic acid (0.25 M), and water (3 equiv). This was
followed by the addition of N-chlorosuccinimide (NCS, 5 equiv) in
several batches at 0.degree. C. The resulting solution was stirred
for 1 h at room temperature. The resulting slurry was concentrated
under vacuum and diluted with H.sub.2O. The resulting solution was
extracted with of ethyl acetate and the organic layers combined and
washed with 3.times.H.sub.2O and 1.times. brine. The mixture was
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue was applied onto a silica gel column with
petroleum ether providing the sulfonyl chloride INT-L3.
[0614] Step D: To a round-bottom flask was added sulfonyl chloride
INT-L3 (1 equiv), CH.sub.2Cl.sub.2 (0.2 M), triethylamine (5
equiv), and
N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2,2,2-trifluoroacetamide
(INT-L4, 2 equiv). The resulting solution was stirred overnight at
room temperature. The resulting mixture was concentrated under
vacuum and diluted with of H.sub.2O. The resulting slurry was
extracted with CH.sub.2C.sub.12 and the organic layers combined and
washed with 3.times.H.sub.2O and 1.times. brine. The mixture was
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (30:1) providing the sulfonamide
INT-L5.
[0615] Step E: To a round-bottom flask purged and maintained with
an inert atmosphere of H.sub.2, was added sulfonamide INT-L5 (1
equiv), methanol (0.1 M), and palladium on carbon (.about.10-20%).
The resulting slurry was stirred for 1 h at room temperature. The
solids were filtered out and the resulting mixture was concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:1) providing the desired phenol
INT-L6.
[0616] The following intermediates were made by applying the above
procedures to the appropriate phenol:
##STR00034## ##STR00035##
General Scheme for Indane Epoxide Synthesis
##STR00036##
[0618] Step A: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added the desired
R.sup.4-substituted bromide/iodide (1 equiv), CH.sub.3CN (0.25 M),
tert-butyl prop-2-enoate (equiv), diisopropylethylamine (3 equiv),
P(o-tol).sub.3 (0.20 equiv), and Pd(OAc).sub.2 (0.10 equiv). The
resulting solution was stirred overnight at 95.degree. C. The
solids were removed by filtration and the filtrate was concentrated
under vacuum. The resulting slurry was diluted with water and
extracted with 3.times.CH.sub.2Cl.sub.2. The organic layers were
combined and dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:500) providing the cinnamate
INT-I1.
[0619] Step B: To a round-bottom flask was cinnamate INT-I1 (1
equiv), ethyl acetate (0.1 M), and Raney Ni. The flask was purged
and filled with H.sub.2(g), cycling three times, leaving a positive
H.sub.2 atmosphere. The resulting solution was stirred for 2 h at
room temperature. The solids were filtered out and the resulting
mixture was concentrated under vacuum providing the hydrocinnamate
INT-I2.
[0620] Step C: To a round-bottom flask was added hydrocinnamate
INT-I2 (1 equiv) and 2:1 CH.sub.2Cl.sub.2:TFA (0.4 M). The
resulting slurry was stirred for 1 h at room temperature. The
resulting mixture was concentrated under vacuum and the residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(0-10%). The collected fractions were combined and concentrated
under vacuum providing the hydrocinnamic acid INT-I3.
[0621] Step D: To a 3-necked round-bottom flask was added
hydrocinnamic acid INT-I3 (1 equiv) and CH.sub.2Cl.sub.2 (0.4 M).
The reaction slurry was cooled to 0.degree. C. and treated with
(COCl).sub.2 (2 equiv) dropwise. The resulting solution was stirred
for 2 h at room temperature. The resulting solution was
concentrated under vacuum. To a 3-necked round-bottom flask was
added AlICl.sub.3 (2 equiv) and CH.sub.2Cl.sub.2 (0.4 M). The
product of the first step dissolved in CH.sub.2Cl.sub.2 and added
dropwise to this AICI3 slurry. The resulting solution was stirred
for 2 h at 40.degree. C. in an oil bath. The reaction was then
quenched by the addition of 2N HCl.sub.(aq). The resulting solution
was extracted with 3.times.CH.sub.2Cl.sub.2 and the organic layers
combined and concentrated under vacuum. The residue was applied
onto a silica gel column with ethyl acetate/petroleum ether
(0-1:10). The collected fractions were combined and concentrated
under vacuum providing the indanone INT-I4.
[0622] Step E: To a round-bottom flask was indanone INT-I4 (1
equiv), methanol (0.7 M), and NaBH.sub.4 (2 equiv). The resulting
solution was stirred for 1 h at room temperature. The reaction was
then quenched by the addition of 20 mL of water and extracted with
3.times.CH.sub.2Cl.sub.2. The organic layers were combined and
washed with 3.times. brine. The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum
providing indanol INT-I5.
[0623] Step F: To a round-bottom flask was added indanol INT-I5 (1
equiv), methanol (0.5 M), and HCl (half volume of methanol). The
resulting solution was stirred for 1 h at room temperature. The
resulting mixture was quenched with methanol and concentrated under
vacuum. The resulting slurry was extracted with 3.times.n-hexane
and the organic layers combined. The residue was applied onto a
silica gel column with n-hexane providing indene INT-I6.
[0624] Step G: To a 3-necked round-bottom flask was added indene
INT-I6 (1 equiv), CH.sub.2Cl.sub.2 (0.08M, dried over magnesium
sulfate), pyridine N-oxide (5 equiv in CH.sub.2Cl.sub.2 solution
dried over magnesium sulfate), and (S,S)-Jacobsen's catalyst (0.05
equiv). The resulting solution was stirred for 10 min at 0.degree.
C. followed by the addition of m-CPBA (2 equiv) in portions at
0.degree. C. The resulting slurry was stirred for an additional 1 h
at 0.degree. C. The reaction was then quenched by the addition of
sodium hydroxide (3 M.sub.(aq), approx. 13 equiv). The resulting
slurry was washed with 1.times.H.sub.2O and 1.times. brine. The
mixture was dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:30-1:15) providing the epoxide
INT-I7.
[0625] The following intermediates were made by applying the above
procedures to the appropriate starting aryl compounds (starting
materials are available commercially at different stages of this
sequence):
##STR00037##
General Scheme for Aminoindanol Synthesis
##STR00038##
[0627] To a round-bottom flask was added epoxide INT-I7 (1 equiv),
the desired amine R.sup.2R.sup.3NH (2 equiv), and CH.sub.3CN (0.16
M). The resulting solution was heated to reflux for 16 h. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1:3-1:2) providing the aminoindanol INT-I8.
[0628] The following intermediates are made by applying the above
procedures to the appropriate starting epoxides and amines:
##STR00039## ##STR00040##
Subsequent Substitutions of Aminoindanols
##STR00041##
[0630] To a round-bottom flask purged and maintained with an inert
atmosphere of nitrogen was added INT-I8 bromide (1 equiv),
CH.sub.3B(OH).sub.2 (1.5 equiv), PPh.sub.3 (0.10 equiv),
K.sub.3PO.sub.4 (4 equiv), tetrahydrofuran (0.3 M), and
Pd(OAc).sub.2 (0.05 equiv). The resulting solution was stirred for
2 h at 80.degree. C. The reaction was then quenched by the addition
of H.sub.2O and extracted with 3.times. ethyl acetate. The organic
layers were combined, dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was applied
onto a silica gel column with CH.sub.2C.sub.12/methanol (10:1). The
collected fractions were combined and concentrated under vacuum
providing the 4-methyl substituted aminoindanols INT-I9.
[0631] The following intermediates are made by applying the above
procedures to the appropriate starting 4-bromo aminoindanols:
##STR00042##
##STR00043##
[0632] To a round-bottom flask purged and maintained with an inert
atmosphere of nitrogen was added 4-bromoaminoindanol INT-I8 (1
equiv), Zn(CN).sub.2 (0.60 equiv), Pd(PPh.sub.3).sub.4 (0.10
equiv), and NMP (DMF on the scheme) (0.4 M). The resulting slurry
was stirred overnight at 95.degree. C. The reaction slurry was
cooled and extracted with 3.times. ethyl acetate. The combined
organic layers were washed with 3.times. brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was applied onto a silica gel column with ethyl acetate/petroleum
ether (1:1) providing the 4-cyano substituted aminoindanols
INT-I10.
[0633] The following intermediates are made by applying the above
procedures to the appropriate starting 4-bromo aminoindanols:
##STR00044##
##STR00045##
[0634] Step A: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added 4-bromoaminoindanol
INT-I8B (or INT-I8H) (1 equiv), CH.sub.2Cl.sub.2 (0.25 M), and
imidazole (3 equiv). This was followed by the addition of TBSCl
(1.5 equiv) in several batches at 0.degree. C. The resulting slurry
was stirred overnight at room temperature. The reaction was
quenched by the addition of H.sub.2O and extracted with 3.times.
ethyl acetate. The organic layers were combined, washed with
1.times. brine, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1/10) providing the
TBS-protected intermediates.
[0635] Step B: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added the TBS-protected
aminoindanol (1 equiv), Cs.sub.2CO.sub.3 (3 equiv), and methanol (8
equiv). A solution of 3rd Generation BrettPhos precatalyst (0.05
equiv) in dioxane (0.5 M) was added. The resulting slurry was
stirred for 2 h at 60.degree. C. in an oil bath. The reaction was
quenched by the addition of H.sub.2O and extracted with 3.times.
ethyl acetate. The organic layers were combined, washed with
1.times. brine, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1/5) providing the
4-methoxy substituted aminoindanol TBS-ethers.
[0636] Step C: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added 4-methoxy substituted
aminoindanol TBS-ether (1 equiv) and tetrahydrofuran (0.5 M). TBAF
(1.5 equiv, 1M THF solution) was added and the resulting solution
stirred for 1 h at room temperature. The reaction slurry was
diluted with 1:1 EtOAc:Et.sub.2O and washed with 3.times.H.sub.2O.
The mixture was dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1/1) providing
4-methoxy substituted aminoindanols INT-I11A and B.
General Scheme for Monomer Synthesis:
##STR00046##
[0638] Step A: To a round-bottom flask was added aminoindanol
INT-I8 (1 equiv) and tetrahydrofuran (0.2 M), followed by the
addition of phenol linker INT-L6 (1.1 equiv) and heating to
40.degree. C. To this slurry was added PPh.sub.3 (2 equiv) and DIAD
(1.5 equiv). The resulting solution was stirred for 1.5 h at
40.degree. C. The resulting mixture was concentrated under vacuum
and diluted with CH.sub.2Cl.sub.2. The residue was applied onto a
silica gel column with ethyl acetate/petroleum ether (1:1)
providing indane monomer INT-M1.
[0639] Step B: To a round-bottom flask was added indane monomer
INT-M1 (1 equiv), methanol (0.1 M), and sodium hydroxide (3
M.sub.(aq), 3 equiv). The resulting solution was stirred for 1.5 h
at 60.degree. C. The resulting mixture was concentrated under
vacuum and diluted with CH.sub.2Cl.sub.2. The residue was applied
onto a silica gel column with ethyl acetate (100%) providing indane
amine monomer INT-M2.
[0640] The following intermediates are made by applying the above
procedures to the appropriate starting aminoindanols INT-I8 and
linkers INT-L6:
##STR00047## ##STR00048## ##STR00049## ##STR00050##
General Scheme for Dimer Formation (Non-Protected Analogs):
##STR00051##
[0642] To a round-bottom flask was added INT-M2 (1 equiv),
N,N-dimethylformamide (DMF, 0.12 M), and 1,4-diisocyanatobutane
(0.40 equiv). The resulting solution was stirred for 2 h at
60.degree. C. The resulting mixture was concentrated under vacuum
and diluted with CH.sub.2Cl.sub.2. The residue was applied onto a
silica gel column with chloroform/methanol (10:1) providing the
desired dimer Product 1. Final products were purified by
Preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm; mobile phase, water (0.05% TFA)
and CH.sub.3CN (10.0% CH.sub.3CN up to 70.0% in 8 min); Detector,
UV 254 nm. The final products were generally isolated as the TFA
salts or exchanged to the hydrochloride salts.
General Scheme for Deprotection of Dimers:
##STR00052##
[0644] To a round-bottom flask was added Boc-protected dimers (1
equiv) and 3:1 CH.sub.2Cl.sub.2:TFA (.about.0.05 M). The resulting
solution was stirred for 2 h at room temperature. The resulting
mixture was concentrated under vacuum. The crude product was
purified by Preparative HPLC with the following conditions: Column,
XBridge C18 OBD Preparative Column, 19*250 mm; mobile phase, water
(0.05% TFA) and CH.sub.3CN (10.0% CH.sub.3CN up to 70.0% in 8 min);
Detector, UV 254 nm. The final dimer Products 1 were generally
isolated as the TFA salts or exchanged to the hydrochloride
salts.
General Scheme for Linker Synthesis
##STR00053##
[0646] Step A: To a 250-mL round-bottom flask was added the desired
substituted-bromophenol (1 equiv), acetone (0.45 M), potassium
carbonate (5 equiv), and benzyl bromide (2.5 equiv). The resulting
solution was stirred for 4 h at room temperature. The resulting
solution was diluted with 30 mL of H.sub.2O. The resulting mixture
was concentrated under vacuum and extracted with of ethyl acetate.
The organic layers were combined and washed with 3.times.H.sub.2O
and 1.times. brine. The mixture was dried over anhydrous sodium
sulfate, filtered, and the resulting mixture concentrated under
vacuum. The residue was applied onto a silica gel column with
petroleum ether providing the desired benzylethers INT-L1.
[0647] Step B: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added benzylether INT-L1 (1
equiv), 1,4-dioxane (0.16 M), N,N-diisopropylethylamine (2 equiv),
benzylmercaptan (2 equiv), Pd.sub.2(dba).sub.3-CHCl.sub.3 (0.05
equiv), and Xantphos (0.10 equiv). The resulting solution was
stirred overnight at 100.degree. C. The resulting slurry was
concentrated under vacuum and diluted with of H.sub.2O. The
resulting solution was extracted with of ethyl acetate and the
organic layers combined and washed with 3.times.H.sub.2O and
1.times. brine. The mixture was dried over anhydrous sodium
sulfate, filtered, and the resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with
petroleum ether providing the desired thioethers INT-L2.
[0648] Step C: To a round-bottom flask was added thioether INT-L2
(1 equiv), acetic acid (0.25 M), and water (3 equiv). This was
followed by the addition of N-chlorosuccinimide (NCS, 5 equiv) in
several batches at 0.degree. C. The resulting solution was stirred
for 1 h at room temperature. The resulting slurry was concentrated
under vacuum and diluted with H.sub.2O. The resulting solution was
extracted with of ethyl acetate and the organic layers combined and
washed with 3.times.H.sub.2O and 1.times. brine. The mixture was
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue was applied onto a silica gel column with
petroleum ether providing the sulfonyl chloride INT-L3.
[0649] Step D: To a round-bottom flask was added sulfonyl chloride
INT-L3 (1 equiv), CH.sub.2Cl.sub.2 (0.2 M), triethylamine (5
equiv), and
N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-2,2,2-trifluoroacetamide
(INT-L4, 2 equiv). The resulting solution was stirred overnight at
room temperature. The resulting mixture was concentrated under
vacuum and diluted with of H.sub.2O. The resulting slurry was
extracted with CH.sub.2Cl.sub.2 and the organic layers combined and
washed with 3.times.H.sub.2O and 1.times. brine. The mixture was
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue was applied onto a silica gel column with
CH.sub.22C/methanol (30:1) providing the sulfonamide INT-L5.
[0650] Step E: To a round-bottom flask purged and maintained with
an inert atmosphere of 112, was added sulfonamide INT-L5 (1 equiv),
methanol (0.1 M), and palladium on carbon (.about.10-20%). The
resulting slurry was stirred for 1 h at room temperature. The
solids were filtered out and the resulting mixture was concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1: I) providing the desired phenol
INT-L6.
[0651] The following intermediates were made by applying the above
procedures to the appropriate phenol:
##STR00054## ##STR00055##
General Scheme for Indane Epoxide Synthesis
##STR00056##
[0653] Step A: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added the desired
R.sup.4-substituted bromide/iodide (1 equiv), CH.sub.3CN (0.25 M),
tert-butyl prop-2-enoate (equiv), diisopropylethylamine (3 equiv),
P(o-tol).sub.3 (0.20 equiv), and Pd(OAc).sub.2 (0.10 equiv). The
resulting solution was stirred overnight at 95.degree. C. The
solids were removed by filtration and the filtrate was concentrated
under vacuum. The resulting slurry was diluted with water and
extracted with 3.times.CH.sub.2Cl.sub.2. The organic layers were
combined and dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:500) providing the cinnamate
INT-I1.
[0654] Step B: To a round-bottom flask was cinnamate INT-I1 (1
equiv), ethyl acetate (0.1 M), and Raney Ni. The flask was purged
and filled with H.sub.2(g), cycling three times, leaving a positive
H.sub.2 atmosphere. The resulting solution was stirred for 2 h at
room temperature. The solids were filtered out and the resulting
mixture was concentrated under vacuum providing the hydrocinnamate
INT-I2.
[0655] Step C: To a round-bottom flask was added hydrocinnamate
INT-I2 (1 equiv) and 2:1 CH.sub.2Cl.sub.2:TFA (0.4 M). The
resulting slurry was stirred for 1 h at room temperature. The
resulting mixture was concentrated under vacuum and the residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(0-10%). The collected fractions were combined and concentrated
under vacuum providing the hydrocinnamic acid INT-I3.
[0656] Step D: To a 3-necked round-bottom flask was added
hydrocinnamic acid INT-I3 (I equiv) and CH.sub.2Cl.sub.2 (0.4 M).
The reaction slurry was cooled to 0.degree. C. and treated with
(COCI).sub.2 (2 equiv) dropwise. The resulting solution was stirred
for 2 h at room temperature. The resulting solution was
concentrated under vacuum. To a 3-necked round-bottom flask was
added AlCl.sub.3 (2 equiv) and CH.sub.2Ch (0.4 M). The product of
the first step dissolved in CH.sub.2Cl.sub.2 and added dropwise to
this AlCl.sub.3 slurry. The resulting solution was stirred for 2 h
at 40.degree. C. in an oil bath. The reaction was then quenched by
the addition of 2N HCl.sub.(aq). The resulting solution was
extracted with 3.times.CH.sub.2Cl.sub.2 and the organic layers
combined and concentrated under vacuum. The residue was applied
onto a silica gel column with ethyl acetate/petroleum ether
(0-1:10). The collected fractions were combined and concentrated
under vacuum providing the indanone INT-I4.
[0657] Step E: To a round-bottom flask was indanone INT-I4 (1
equiv), methanol (0.7 M), and NaBH.sub.4 (2 equiv). The resulting
solution was stirred for 1 h at room temperature. The reaction was
then quenched by the addition of 20 mL, of water and extracted with
3.times.CH.sub.2Cl.sub.2. The organic layers were combined and
washed with 3.times. brine. The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum
providing indanol INT-I5.
[0658] Step F: To a round-bottom flask was added indanol INT-I5 (1
equiv), methanol (0.5 M), and HCl (half volume of methanol). The
resulting solution was stirred for 1 h at room temperature. The
resulting mixture was quenched with methanol and concentrated under
vacuum. The resulting slurry was extracted with 3.times.n-hexane
and the organic layers combined. The residue was applied onto a
silica gel column with n-hexane providing indene INT-I6.
[0659] Step G: To a 3-necked round-bottom flask was added indene
INT-I6 (1 equiv), CH.sub.2Cl.sub.2 (0.08M, dried over magnesium
sulfate), pyridine N-oxide (5 equiv in CH.sub.2Cl.sub.2 solution
dried over magnesium sulfate), and (S,S)-Jacobsen's catalyst (0.05
equiv). The resulting solution was stirred for 10 min at 0.degree.
C. followed by the addition of m-CPBA (2 equiv) in portions at
0.degree. C. The resulting slurry was stirred for an additional 1 h
at 0.degree. C. The reaction was then quenched by the addition of
sodium hydroxide (3 M.sub.(aq), approx. 13 equiv). The resulting
slurry was washed with 1.times.H.sub.2O and 1.times. brine. The
mixture was dried over anhydrous sodium sulfate, filtered, and
concentrated. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (1:30-1:15) providing the epoxide
INT-I7.
[0660] The following intermediates were made by applying the above
procedures to the appropriate starting aryl compounds (starting
materials are available commercially at different stages of this
sequence):
##STR00057##
General Scheme for Aminoindanol Synthesis
##STR00058##
[0662] To a round-bottom flask was added epoxide INT-I7 (1 equiv),
the desired amine R.sup.2R.sup.3NH (2 equiv), and CH.sub.3CN (0.16
M). The resulting solution was heated to reflux for 16 h. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1:3-1:2) providing the aminoindanol INT-I8.
[0663] The following intermediates are made by applying the above
procedures to the appropriate starting epoxides and amines:
##STR00059## ##STR00060##
Subsequent Substitutions of Aminoindanols
##STR00061##
[0665] To a round-bottom flask purged and maintained with an inert
atmosphere of nitrogen was added INT-I8 bromide (1 equiv),
CH.sub.3B(OH).sub.2 (1.5 equiv), PPh3 (0.10 equiv), K3P04 (4
equiv), tetrahydrofuran (0.3 M), and Pd(OAc).sub.2 (0.05 equiv).
The resulting solution was stirred for 2 h at 80.degree. C. The
reaction was then quenched by the addition of H.sub.2O and
extracted with 3.times. ethyl acetate. The organic layers were
combined, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with CH.sub.2Cl.sub.2/methanol (10:1). The collected
fractions were combined and concentrated under vacuum providing the
4-methyl substituted aminoindanols INT-I9.
[0666] The following intermediates are made by applying the above
procedures to the appropriate starting 4-bromo aminoindanols:
##STR00062##
##STR00063##
[0667] To a round-bottom flask purged and maintained with an inert
atmosphere of nitrogen was added 4-bromoaminoindanol INT-I8 (1
equiv), Zn(CN).sub.2 (0.60 equiv), Pd(PPh.sub.3).sub.4 (0.10
equiv), and NMP (DMF on the scheme) (0.4 M). The resulting slurry
was stirred overnight at 95.degree. C. The reaction slurry was
cooled and extracted with 3.times. ethyl acetate. The combined
organic layers were washed with 3.times. brine, dried over
anhydrous sodium sulfate, filtered, and concentrated. The residue
was applied onto a silica gel column with ethyl acetate/petroleum
ether (1:1) providing the 4-cyano substituted aminoindanols
INT-I10.
[0668] The following intermediates are made by applying the above
procedures to the appropriate starting 4-bromo aminoindanols:
##STR00064##
##STR00065##
[0669] Step A: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added 4-bromoaminoindanol
INT-I8B (or INT-18H) (1 equiv), CH.sub.2Cl.sub.2 (0.25 M), and
imidazole (3 equiv). This was followed by the addition of TBSCl
(1.5 equiv) in several batches at 0.degree. C. The resulting slurry
was stirred overnight at room temperature. The reaction was
quenched by the addition of H.sub.2O and extracted with 3.times.
ethyl acetate. The organic layers were combined, washed with
1.times. brine, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1/10) providing the
TBS-protected intermediates.
[0670] Step B: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added the TBS-protected
aminoindanol (1 equiv), Cs.sub.2CO.sub.3 (3 equiv), and methanol (8
equiv). A solution of 3rd Generation BrettPhos precatalyst (0.05
equiv) in dioxane (0.5 M) was added. The resulting slurry was
stirred for 2 h at 60.degree. C. in an oil bath. The reaction was
quenched by the addition of H.sub.2O and extracted with 3.times.
ethyl acetate. The organic layers were combined, washed with
1.times. brine, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1/5) providing the
4-methoxy substituted aminoindanol TBS-ethers.
[0671] Step C: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added 4-methoxy substituted
aminoindanol TBS-ether (1 equiv) and tetrahydrofuran (0.5 M). TBAF
(1.5 equiv, 1M THF solution) was added and the resulting solution
stirred for 1 h at room temperature. The reaction slurry was
diluted with 1:1 EtOAc:Et.sub.2O and washed with 3.times.H.sub.2O.
The mixture was dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1/1) providing
4-methoxy substituted aminoindanols INT-IIIA and B.
General Scheme for Monomer Synthesis:
##STR00066##
[0673] Step A: To a round-bottom flask was added aminoindanol
INT-I8 (1 equiv) and tetrahydrofuran (0.2 M), followed by the
addition of phenol linker INT-L6 (1.1 equiv) and heating to
40.degree. C. To this slurry was added PPh.sub.3 (2 equiv) and DIAD
(1.5 equiv). The resulting solution was stirred for 1.5 h at
40.degree. C. The resulting mixture was concentrated under vacuum
and diluted with CH.sub.2Cl.sub.2. The residue was applied onto a
silica gel column with ethyl acetate/petroleum ether (1:1)
providing indane monomer INT-M1.
[0674] Step B: To a round-bottom flask was added indane monomer
INT-M1 (1 equiv), methanol (0.1 M), and sodium hydroxide (3
M.sub.(aq), 3 equiv). The resulting solution was stirred for 1.5 h
at 60.degree. C. The resulting mixture was concentrated under
vacuum and diluted with CH.sub.2Cl.sub.2. The residue was applied
onto a silica gel column with ethyl acetate (100%) providing indane
amine monomer INT-M2.
[0675] The following intermediates are made by applying the above
procedures to the appropriate starting amninoindanols INT-I8 and
linkers INT-L6:
##STR00067## ##STR00068## ##STR00069## ##STR00070##
General Scheme for Dimer Formation (Non-Protected Analogs):
##STR00071##
[0677] To a round-bottom flask was added INT-M2 (1 equiv),
N,N-dimethylformamide (DMF, 0.12 M), and 1,4-diisocyanatobutane
(0.40 equiv). The resulting solution was stirred for 2 h at
60.degree. C. The resulting mixture was concentrated under vacuum
and diluted with CH.sub.2Cl.sub.2. The residue was applied onto a
silica gel column with chloroform/methanol (10:1) providing the
desired dimer Product 1. Final products were purified by
Preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm; mobile phase, water (0.05% TFA)
and CH.sub.3CN (10.0% CH.sub.3CN up to 70.0% in 8 min); Detector,
UV 254 nm. The final products were generally isolated as the TFA
salts or exchanged to the hydrochloride salts.
General Scheme for Deprotection of Dimers:
##STR00072##
[0679] To a round-bottom flask was added Boc-protected dimers (1
equiv) and 3:1 CH.sub.2CL.sub.2:TFA (.about.0.05 M). The resulting
solution was stirred for 2 h at room temperature. The resulting
mixture was concentrated under vacuum. The crude product was
purified by Preparative HPLC with the following conditions: Column,
XBridge C18 OBD Preparative Column, 19*250 mm; mobile phase, water
(0.05% TFA) and CH.sub.3CN (10.0% CH.sub.3CN up to 70.0% in 8 min);
Detector, UV 254 nm. The final dimer Products 1 were generally
isolated as the TFA salts or exchanged to the hydrochloride
salts.
Example 1:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dic-
hloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]et-
hoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin
-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfon-
amido]ethoxy)ethoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00073##
[0681] Prepared according to the General Scheme above from INT-M2A.
Purification by preparative HPLC with the following conditions:
Column, XBridge Shield RP18 OBD Column, 19*250 mm, 10 um; mobile
phase, water (0.05% HCl) and CH.sub.3CN (26.0% CH.sub.3CN up to
47.0% in 8 min); Detector, UV 254 nm. This resulted in 695.3 mg
(38%) of the title compound as a light yellow solid. MS (m/z):
1343.4 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.74
(s, 2H), 7.82 (d, J=8.4 Hz, 2H), 7.49 (t, J=8.4 Hz, 4H), 7.12 (s,
2H), 6.31 (s, 2H), 4.01 (s, 2H), 3.68-3.42 (m, 20H), 3.33-3.29 (m,
6H), 3.28-3.00 (m, 12H), 2.85 (s, 4H), 2.26 (s, 6H), 2.01 (s, 4H),
1.82 (s, 2H), 1.67 (d, J=9.6 Hz, 2H), 1.50 (s, 2H).
Example 2:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dic-
hloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]et-
hoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,1S)-2-[(3R)-3-aminopiperidin-1-yl]-4-
,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]eth-
oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea, bis(trifluoroacetic
acid)
##STR00074##
[0683] Prepared according to the General Scheme above from INT-M2B
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XSelect CSH
Preparative C18 OBD Column, 19* 150 mm, 5 um; mobile phase, water
(0.05% TFA) and CH.sub.3CN (15% CH.sub.3CN up to 45% in 8 min);
Detector, UV 254 nm. This resulted in 192.6 mg (56%) of the title
compound as a white solid. MS (m/z): 1351 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 8.50 (s, 2H), 7.76-7.56 (m, 6H),
7.45 (d, J=1.7 Hz, 2H), 7.20 (d, J=1.7 Hz, 2H), 6.01 (d, J=5.2 Hz,
2H), 3.71 (td, J=7.1, 5.1 Hz, 2H), 3.62-3.46 (m, 16H), 3.31-3.17
(m, 6H), 3.09 (dd, J=6.2, 4.3 Hz, 8H), 2.99 (dd, J=16.8, 6.8 Hz,
2H), 2.88 (d, J=11.4 Hz, 2H), 2.65 (s, 2H), 2.60-2.48 (m, 4H),
1.97-1.87 (m, 2H), 1.87-1.77 (m, 2H), 1.68-1.42 (m, 8H).
Example 3:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chlor-
o-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy-
)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chl-
oro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]etho-
xy)ethyl]carbamoyl]amino)butyl]urea
##STR00075##
[0685] Prepared according to the General Scheme above from INT-M2C
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (10.0% CH.sub.3CN up to 70.0% in 8 min);
Detector, UV 254 nm. This resulted in 42.3 mg (26%) of the title
compound as a white solid. MS (m/z): 1273 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.91-7.83 (m, 4H), 7.32-7.25 (m,
4H), 7.18 (d, J=1.7 Hz, 2H), 7.00 (d, J=1.7 Hz, 2H), 6.00 (s, 2H),
3.68 (s, 2H), 3.61-3.46 (m, 16H), 3.38 (s, 1H), 3.27 (d, J==5.4 Hz,
3H), 3.19 (d, J=17.9 Hz, 4H), 3.09 (d, J=5.2 Hz, 8H), 2.93 (s, 4H),
2.78 (s, 2H), 2.63 (s, 4H), 2.30 (s, 6H), 1.92 (s, 3H), 1.86 (s,
1H), 1.69 (s, 3H), 1.59 (d, J=10.3 Hz, 2H), 1.50-1.42 (m, 4H).
Example 4:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chlor-
o-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)-
ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlo-
ro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethy]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00076##
[0687] Prepared according to the General Scheme above from INT-M2D
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (25.0% CH.sub.3CN up to 45.0% in 8 min);
Detector, UV 254 nm. This resulted in 143.9 mg (71%) of the title
compound as a white solid. MS (m/z): .sup.1H NMR (Methanol-d4, 400
MHz) .delta. 7.85 (d, J=8.6 Hz, 4H), 7.75 (d, J=1.9 Hz, 2H), 7.47
(d, J=1.8 Hz, 2H), 7.29 (d, J=8.7 Hz, 4H), 6.02 (d, J=5.5 Hz, 2H),
3.72 (d, J=6.5 Hz, 2H), 3.59-3.42 (m, 16H), 3.41-3.29 (m, 1H), 3.24
(d, J=5.4 Hz, 3H), 3.20-2.99 (m, 11H), 2.89 (d, J=11.5 Hz, 2H),
2.66-2.52 (m, 7H), 1.87 (s, 4H), 1.44 (s, 4H).
Example 5:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chlor-
o-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethox-
y)ethyl]-1[-4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-ch-
loro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]et-
hoxy)ethyl]carbamoyl]amino)butyl]urea; bis(trifluoroacetic
acid)
##STR00077##
[0689] Prepared according to the General Scheme above from INT-M2E
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (18.0% CH.sub.3CN up to 32.0% in 8 min);
Detector, UV 254 nm. This resulted in 227.2 mg (74%) of the title
compound as a white solid. MS (m/z): 135 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.88 (d, J=8.3 Hz, 4H), 7.34-7.26
(m, 4H), 6.96 (s, 2H), 6.77 (s, 2H), 6.09 (d, J=19.2 Hz, 2H), 3.86
(s, 6H), 3.61-3.46 (m, 17H), 3.42 (s, 2H), 3.28 (t, J=5.4 Hz, 4H),
3.13-3.04 (m, 8H), 2.72 (s, 6H), 1.96 (s, 4H), 1.74 (s, 2H), 1.61
(s, 2H), 1.50-1.42 (m, 4H).
Example 6:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chlor-
o-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]etho-
xy]ethoxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1--
yl]-6-chloro-4-fluoro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfo-
namido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00078##
[0691] Prepared according to the General Scheme above from INT-M2F
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm; mobile phase, water (0.05% HCl)
and CH.sub.3CN (34% CH.sub.3CN up to 54% in 8 min); Detector, UV
254 nm. This resulted in 168.1 mg (51%) of the titled compound as a
light yellow solid. MS (m/z): 1311.45 M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.85 (d, J=2.4 Hz, 2H), 7.82 (s,
2H), 7.55 (d, J=8.8 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 6.91 (s, 2H),
6.77 (d, J=6.4 Hz, 2H), 4.54 (d, J=6.8 Hz, 2H), 3.89-3.70 (m, 8H),
3.57-3.49 (m, 17H), 3.31-3.23 (m, 10H), 3.18-3.08 (m, 9H), 2.30 (s,
6H), 2.19-2.07 (m, 6H), 1.75 (s, 2H), 1.48 (s, 4H).
Example 7:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chlor-
o-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]
ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperid-
in-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)-
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00079##
[0693] Prepared according to the General Scheme above from INT-M2G
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XSelect CSH
Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase, water
(0.05% TFA) and CH.sub.3CN (16.0% CH.sub.3CN up to 40.0% in 8 min);
Detector, UV 254 nm. This resulted in 157 mg (52%) of the title
compound as a white solid. MS (m/z): 1301 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) 7.77 (d, J=9.0 Hz, 2H), 7.70 (s, 2H), 7.44
(d, J=8.5 Hz, 2H), 7.18 (s, 2H), 6.97 (d, J=6.5 Hz, 2H), 3.28 (t,
J=5.4 Hz, 6H), 3.08 (dt, J=10.9, 5.5 Hz, 10H), 2.94 (s, 4H), 2.73
(s, 5H), 3.61-3.46 (m, 16H), 2.27 (d, J=22.7 Hz, 13H), 1.95 (s,
5H), 1.67 (d, =49.5 Hz, 5H), 1.50-1.42 (m, 4H).
Example 8:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlor-
o-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethox-
y]ethoxy)ethyl]-1H-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-
-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00080##
[0695] Prepared according to the General Scheme above from INT-M2H
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (24.0% CH.sub.3CN up to 41.0% in 7 min):
Detector, UV 254 nm. This resulted in 30.1 mg (25%) of the title
compound as a white solid. MS (m/z): 661.7 [M/2+H].sup.+. .sup.1H
NMR (Methanol-d4, 400 MHz) .delta. 7.81-7.68 (m, 6H), 7.50-7.42 (m,
4H), 6.08 (d, J=6.6 Hz, 2H), 3.78 (d, J=8.2 Hz, 2H), 3.53 (dtd,
J=22.6, 5.4, 2.5 Hz, 16H), 3.45-3.33 (m, 6H), 3.27 (d, J=5.5 Hz,
3H), 3.18 (d, J=7.6 Hz, 2H), 3.13-3.02 (m, 8H), 2.92 (s, 2H), 2.66
(d, J=27.7 Hz, 6H), 2.25 (s, 6H), 1.83 (s, 4H), 1.69-1.55 (m, 4H),
1.46 (p, J=3.2 Hz, 4H).
Example 9:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chlor-
o-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]eth-
oxy]ethoxy)ethyl]-1[-4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-
-yl]-6-chloro-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sul-
fonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00081##
[0697] Prepared according to the General Scheme above from INT-M2J
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (30.0% CH.sub.3CN up to 38.0% in 12 min);
Detector, UV 254 nm. This resulted in 19.5 mg (13%) of the title
compound as a white solid. MS (m/z): 1334 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.81-7.73 (m, 2H), 7.70 (dd, J=2.4,
1.0 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 6.94 (d, J=1.6 Hz, 2H), 6.75
(d, J=1.5 Hz, 2H), 6.03 (d, J=5.4 Hz, 2H), 3.86 (s, 6H), 3.75-3.67
(m, 2H), 3.61-3.46 (m, 15H), 3.38 (dd, J=7.9, 4.4 Hz, 2H),
3.32-3.16 (m, 5H), 3.08 (dt, J=11.0, 5.7 Hz, 8H), 2.98 (d, J=11.5
Hz, 2H), 2.92-2.78 (m, 4H), 2.71-2.62 (m, 4H), 2.24 (s, 6H), 1.93
(s, 4H), 1.86 (s, 2H), 1.70 (s, 2H), 1.59 (s, 2H), 1.50-1.42 (m,
4H).
Example 10:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2--
[(3R)-3-aminopiperidin-1-yl]-6-chloro-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]-
urea; bis(trifluoroacetic acid)
##STR00082##
[0699] Prepared according to the General Scheme above from INT-M2K
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (29.0% CH.sub.3CN up to 33.0% in 10 min);
Detector, UV 254 nm. This resulted in 302.6 mg (59%) of the title
compound as a white solid. MS (m/z): 1309 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.77-7.55 (m, 6H), 7.21 (d, J=1.8
Hz, 2H), 7.00 (d, J=1.8 Hz, 2H), 6.15 (s, 2H), 4.89 (s, 2H), 3.89
(s, 2H), 3.62-3.46 (m, 15H), 3.41 (s, 3H), 3.28 (t, J=5.4 Hz, 4H),
3.10 (q, J=5.4 Hz, 8H), 3.03-2.94 (m, 3H), 2.73 (s, 4H), 2.31 (s,
5H), 1.98 (s, 2H), 1.92 (s, 1H), 1.74 (s, 2H), 1.60 (d, J=10.8 Hz,
2H), 1.50-1.42 (m, 4H).
Example 11:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro--
1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)
ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carb-
amoyl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00083##
[0701] Prepared according to the General Scheme above from INT-M2L
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XSelect CSH Preparative C18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (25.0% CH.sub.3CN up to 32.0% in 12 min); Detector, UV
254 nm. This resulted in 278.8 mg (21%) of the title compound as a
white solid. MS (m/z): 1163.45) [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.96-7.88 (m, 4H), 7.39-7.30 (m,
4H), 7.26 (s, 2H), 6.98 (s, 2H), 6.39 (d, J=6.7 Hz, 2H), 4.35 (q,
J=8.1 Hz, 2H), 3.62-3.45 (m, 18H), 3.27 (t, J=5.4 Hz, 4H),
3.18-3.01 (m, 22H), 2.33 (s, 6H), 1.45 (p, J=3.4 Hz, 41).
Example 12:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-[[(2-[2-[(4-
-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]ox-
y]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00084##
[0703] Prepared according to the General Scheme above from INT-M2M
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(25% CH.sub.3CN up to 45% in 9 min); Detector, UV 254 nm. This
resulted in 165.8 mg (41%) of the title compound as a white solid.
MS (m/z): 1185 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.98-7.86 (m, 6H), 7.45 (s, 2H), 7.43-7.34 (m, 4H), 6.48
(s, 1H), 4.50 (q, J=8.0 Hz, 2H), 3.79 (dd, J=16.6, 8.4 Hz, 2H),
3.61-3.37 (m, 18H), 3.27 (t, J=5.4 Hz, 3H), 3.07 (d, J=12.7 Hz,
20H), 1.50-1.42 (m, 4H).
Example 13:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carba-
moyl]amino)butyl]urea
##STR00085##
[0705] Prepared according to the General Scheme above from INT-M2N
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm; mobile phase, water (10 mmol/L NH.sub.4HCO.sub.3) and
CH.sub.3CN (80.0% CH.sub.3CN up to 90.0% in 10 min); Detector, UV
254 nm. This resulted in 41.6 mg (7%) of the title compound as a
white solid. MS (m/z): 1371.2 [M+100].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 8.01 (s, 2H), 7.91-7.88 (m, 4H),
7.38-7.33 (m, 6H), 5.97 (d, J=5.6 Hz, 2H), 3.71 (q, J=8.0 Hz, 2H),
3.60-3.50 (m, 19H), 3.33-3.26 (m, 5H), 3.12-3.08 (m, 8H), 2.37 (s,
12H), 1.50-1.31 (m, 5H).
Example 14:
1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[-
4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoromethyl)--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)carbamoyl]-
amino)butyl]urea
##STR00086##
[0707] Prepared according to the General Scheme above from INT-M2O
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (10 mmol/L NH.sub.4HCO.sub.3)
and CH.sub.3CN (80.0% CH.sub.3CN up to 90.0% in 10 min); Detector,
UV 254 nm. This resulted in 26.5 mg (13%) of the title compound as
a white solid. MS (m/z): 1403.15 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.87 (d, J=8.8 Hz, 4H), 7.61 (s,
2H), 7.32 (d, J=8.8 Hz, 4H), 7.19 (s, 2H), 5.97 (d, J=6.0 Hz, 2H),
3.93 (q, J=8.1 Hz, 2H), 3.57-3.47 (m, 19H), 3.30 (s, 6H), 3.15-3.05
(m, 9H), 2.34 (s, 12H), 1.47 (s, 4H). .sup.19F NMR (Methanol-d4,
376 MHz) .delta.: 76.92 (s, 6F).
Example 15:
3-[2-(2-[2-[(4-[[(1S,1S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-
-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[-
2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-1H-inden--
1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]ure-
a; bis(trifluoroacetic acid)
##STR00087##
[0709] Prepared according to the General Scheme above from INT-M2P
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XSelect CSH Preparative C18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (24.0% CH.sub.3CN up to 33.0% in 10 min); Detector, UV
254 nm. This resulted in 159.1 mg (34%) of the title compound as a
white solid. MS (m/z): 1195 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
400 MHz) .delta. 7.96-7.88 (m, 4H), 7.38-7.31 (m, 4H), 7.04 (d,
J==1.5 Hz, 2H), 6.76 (s, 2H), 6.36 (d, 6.6 Hz, 2H), 4.91 (d, J=10.0
Hz, 4H), 4.42-4.31 (m, 2H), 3.89 (s, 6H), 3.61-3.46 (m, 17H), 3.28
(t, J=5.4 Hz, 4H), 3.13-3.00 (m, 21H), 1.45 (s, 5H).
Example 16:
3-[2-(2-[2-[(4-[[1S,2S)-6-Chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-fluoro-2,3-dihydro-1H--
inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]-
amino) butyl]urea
##STR00088##
[0711] Prepared according to the General Scheme above from INT-M2Q
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge Preparative OBD C18 Column,
19*250 mm, 5 um; mobile phase, water (0.05% HCl) and CH.sub.3CN
(20.0% CH.sub.3CN up to 50.0% in 8 min); Detector, UV 254 nm. This
resulted in 255 mg (29%) of the title compound as a white solid. MS
(m/z): 1201.35 [M.+-.H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.84 (q, J=3.6 Hz, 2H), 7.77 (d, J=1.6 Hz, 2H), 7.52 (d,
J=8.8 Hz, 2H), 7.30 (q, J=3.2 Hz, 2H), 6.99 (s, 2H), 6.59 (d, J=6.8
Hz, 2H), 4.54-4.48 (m, 2H), 3.73 (q, J=8.4 Hz, 2H), 3.62-3.51 (m,
16H), 3.51-3.35 (m, 4H), 3.34-3.33 (m, 2H), 3.30 (s, 4H), 3.17-2.92
(m, 16H), 2.36-2.33 (m, 6H), 1.53 (s, 1H).
Example 17:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methyl
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6--
chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylb-
enzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00089##
[0713] Prepared according to the General Scheme above from INT-M2R
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge Preparative C18 OBD Column,
19*150 mm, 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (5.0% CH.sub.3CN up to 70.0% in 1 min, up to 77.0% in 6
min); Detector, UV 254/220 nm. This resulted in 109.9 mg (12%) of
the title compound as a white solid. MS (in/z): 1191 [M+H].sup.+.
.sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.80-7.67 (m, 4H), 7.40
(d, J=8.7 Hz, 2H), 7.17-7.12 (m, 2H), 6.93 (d, J=1.8 Hz, 2H), 5.91
(d, J=6.1 Hz, 2H), 3.61-3.37 (m, 19H), 3.32-3.15 (m, 6H), 3.08 (dt,
J=14.5, 5.7 Hz, 8H), 2.79 (dd, J=15.9, 7.9 Hz, 2H), 2.45-2.13 (m,
25H), 1.47 (p, J=3.3 Hz, 4H).
Example 18:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-i-
nden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy) ethyl]
carbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00090##
[0715] Prepared according to the General Scheme above from INT-M2S
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XSelect CSH Preparative C18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (22.0% CH.sub.3CN up to 38.0% in 8 min); Detector, UV
254 nm. This resulted in 75.8 mg (24%) of the title compound as a
white solid. MS (m/z): 1213 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
300 MHz) .delta. 7.94-7.75 (m, 6H), 7.56-7.39 (m, 4H), 6.54 (d,
J=6.7 Hz, 2H), 4.64-4.49 (m, 2H), 3.84 (dd, J=16.7, 8.5 Fir, 2H),
3.65-3.39 (m, 18H), 3.29 (d, J=5.4 Hz, 3H), 3.16-3.05 (m, 21H),
2.34 (s, 6H), 1.54-1.43 (m, 4H).
Example 19:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethyl)-2-
,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)et-
hyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluoro-
methyl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]-
ethoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00091##
[0717] Prepared according to the General Scheme above from INT-M2T
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge Preparative C18 OBD Column,
19*150 mm, 5 um; mobile phase, water (10 mmol/L NH.sub.4HCO.sub.3)
and CH.sub.3CN (75% CH.sub.3CN up to 80% in 8 min); Detector, UV
220 nm. This resulted in 42.5 mg (16%) of the title compound as a
white solid. MS (m/z): 1399.36 [M+100].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 8.00 (d, J=1.6 Hz, 2H), 7.80 (d,
J=2.0 Hz, 2H), 7.78 (d, J=2.0 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.34
(s, 2H), 5.98 (d, J=5.6 Hz, 2H), 3.75 (q, 8.0 Hz, 2H), 3.59-3.50
(m, 18H), 3.33-3.26 (m, 8H), 3.12-3.07 (m, 8H), 2.38 (s, 12H), 1.49
(s, 4H), 1.31 (s, 1H). .sup.19F NMR (Methanol-d4, 400 MHz) .delta.:
-76.94 (s, 6F).
Example 20:
1-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-(trifluoromethoxy)--
2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-(trifluor-
omethoxy)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethox-
y]ethoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00092##
[0719] Prepared according to the General Scheme above from INT-M2U
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (10 mmol/L NH.sub.4HCO.sub.3)
and CN3CN (hold 90.0% CH.sub.3CN in 10 min); Detector, UV 254 nm.
This resulted in 64.5 mg (39%) of the title compound as a white
solid. MS (m/z): 1431.30]M+100].sup.+. .sup.1H NMR (Methanol-d4,
400 MHz) .delta. 7.80 (d, J=2.4 Hz, 2H), 7.78 (s, 2H), 7.63 (s,
2H), 7.48 (d, J=8.8 Hz, 2H), 7.19 (s, 2H), 6.01 (d, J=6.0 Hz, 2H),
3.63-3.60 (m, 4H), 3.59-3.50 (m, 14H), 3.38-3.33 (m, 4H), 3.32-3.30
(m, 4H), 3.19-3.12 (m, 4H), 3.10-3.07 (m, 4H), 2.97 (q, J=7.8 Hz,
2H), 2.37 (s, 12H), 2.28 (s, 6H), 1.49 (s, 4H).
[0720] .sup.19F NMR (Methanol-d4, 376 MHz) .delta.: -75.47 (s,
6F).
Example 21:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methoxy-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]
ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylam-
ino)-4-methoxy-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-
ethoxy]ethyl)ethyl]carbamoyl]amino)butyl]urea; bis(trifluoroacetic
acid)
##STR00093##
[0722] Prepared according to the General Scheme above from INT-M2V
by dimer formation. Purification by preparative HPLC with the
following conditions Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(15% CH.sub.3CN up to 33% in 8 min); Detector, UV 254 nm. This
resulted in 69.6 mg (16%) of the title compound as a white solid.
MS (m/z): 1225 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.81-7.68 (m, 4H), 7.41 (d, J=8.7 Hz, 2H), 6.94 (d, J=1.6
Hz, 2H), 6.70 (d, J=1.3 Hz, 2H), 6.01 (d, J=6.2 Hz, 2H), 4.61 (s,
7H), 3.86 (s, 6H), 3.66-3.45 (m, 18H), 3.27 (d, J=5.7 Hz, 3H), 3.08
(dt, J=10.8, 5.0 Hz, 9H), 2.80 (dd, J=16.2, 8.0 Hz, 2H), 2.49 (s,
12H), 2.26 (s, 6H), 1.51-1.43 (m, 4H).
Example 22:
3-[2-(2-[2-[(4-[[1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-ind-
en-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-
-[[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-y-
l]oxy]-3-methyl
benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea
dihydrochloride
##STR00094##
[0724] Prepared according to the General Scheme above from INT-M2W
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C.sub.18 OBD Preparative
Column, 19*250 mm, 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (80.0% CH.sub.3CN up to 90.0% in 8 min); Detector, UV
220 nm. The product was treated with hydrogen chloride and
lyophilized. This resulted in 566 mg (62%) of the title compound as
a white solid. MS (m/z): 1233.53 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.87-7.75 (m, 4H), 7.53 (t, 3.6 Hz,
4H), 7.11 (s, 2H), 6.64 (d, J=6.8 Hz, 2H), 4.51 (td, J=8.4, 6.7 Hz,
2H), 3.72 (dd, J=16.4, 8.4 Hz, 2H), 3.65-3.48 (m, 16H), 3.41-3.31
(m, 6H), 3.16 (s, 4H), 3.10 (t, J=12.4 Hz, 10H), 3.01 (s, 6H), 2.33
(s, 6H), 1.53 (dt, J=6.4, 3.6 Hz, 4H).
Example 23:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethoxy]-1-[4-([[2--
(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1--
yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)bu-
tyl]urea; bis(trifluoroacetic acid)
##STR00095##
[0726] Prepared according to the General Scheme above from INT-M2X
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XSelect CSH Preparative C18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (73% CH.sub.3CN up to 87% in 8 min); Detector, UV 254
nm. This resulted in 122.2 mg (23%) of the title compound as a
white solid. MS (m/z): 1241.5 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.75-7.58 (m, 6H), 7.43 (d, J=1.7
Hz, 2H), 7.18-7.12 (m, 2H), 5.97 (d, J=5.8 Hz, 2H), 3.61-3.46 (m,
17H), 3.35-3.20 (m, 7H), 3.13-3.05 (m, 7H), 2.91 (dd, J=16.7, 7.4
Hz, 2H), 2.33 (s, 12H), 1.51-1.43 (m, 4H).
Example 24:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-(dimethylamino)-4-methyl-2,3-dihydro--
1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-(dimethylamino)-4-methyl-2,3-dihydro-1H-
-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea
##STR00096##
[0728] Prepared according to the General Scheme above from INT-M2Y
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 .mu.m; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (50.0% CH.sub.3CN up to 67.0% in 8 min); Detector, UV
254 nm. This resulted in 132.5 mg (12%) of as a white solid. MS
(m/z): 1200 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.75-7.55 (m, 6H), 7.19-7.14 (m, 2H), 7.01-6.95 (m, 2H), 5.95-5.89
(d, J=5.7 Hz, 2H), 3.61-3.43 (m, 19H), 3.31-3.24 (d, J=5.4 Hz, 3H),
3.24-3.05 (m, 11H), 2.86-2.75 (dd, J=16.2, 7.4 Hz, 2H), 2.36-2.27
(d, J=18.7 Hz, 18H), 1.51-1.43 (m, 4H).
Example 25:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin--
1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethy-
l]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylamino)pip-
eridin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]etho-
xy)ethyl]carbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00097##
[0730] Prepared according to the General Scheme above from INT-M2Z
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(30.0% CH.sub.3CN up to 62.0% in 8 min); Detector, UV 254 nm. This
resulted in 203.4 mg (58%) of the title compound as yellow oil. MS
(m/z): 1371 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.93-7.85 (m, 4H), 7.46 (t, J=2.1 Hz, 2H), 7.34 (d, J=8.6 Hz, 4H),
7.16-7.10 (m, 2H), 6.29 (dd, 15.1, 6.7 Hz, 2H), 4.00 (q J=7.6 Hz,
2H), 3.62-3.24 (m, 23H), 3.20-2.99 (m, 1H), 2.92 (s, 5), 2.83 (s,
8), 2.73 (s, 1H), 2.11 (s, 2H), 1.96 (d, J=12.8 Hz, 2H), 1.79 (dd,
J=10.9, 9.1 Hz, 4H), 1.41-1.51 (m, 4H).
Example 26:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin--
1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]et-
hoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethyl-
amino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfo-
namido]ethoxy]ethoxy)ethoxy]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00098##
[0732] Prepared according to the General Scheme above from INT-M2AA
by dimer formation. Purification by preparative HPLC with the
following conditions (Column, XBridge Shield RP18 OBD Column,
19*150 mm, 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (isocratic 61.0% CH.sub.3CN in 10 min); Detector, UV
254/220 nm. This resulted in 90.6 mg (13%) of the title compound as
a white solid. MS (m/z): 1398.9 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.80-7.67 (m, 4H), 7.50-7.38 (m,
4H), 7.16-7.10 (m, 2H), 5.99 (d, J=6.0 Hz, 2H), 3.62-3.46 (m. 18H),
3.32-3.23 (m, 6H), 3.07 (dt, J=29.7, 5.8 Hz, 10H), 2.91 (dd,
J=16.4, 8.0 Hz, 4H), 2.27 (s, 8H), 2.14 (s, 16H), 1.95 (d, J=12.6
Hz, 2H), 1.84-1.75 (m, 2H), 1.64-1.52 (m, 2H), 1.52-1.44 (m, 4H),
1.28-1.15 (m, 2H).
Example 27:
3-[2-(2-[2-[(4[[1S,2S)-4,6-Dichloro-2-[(3R)-3-(dimethylamino)piperidin-1--
yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]etho-
xy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-(dimethylam-
ino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00099##
[0734] Prepared according to the General Scheme above from INT-M2AB
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(29.0% CH.sub.3CN up to 33.0% in 10 min); Detector, UV 254 nm. This
resulted in 267 mg (65%) of the title compound as colorless oil. MS
(m/z): 1407 [M+].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.76-7.57 (m, 6H), 7.45 (d, 1=1.8 Hz, 2H), 7.22-7.17 (m, 2H), 6.11
(d, 1=5.7 Hz, 2H), 3.86 (td, J=7.7, 5.8 Hz, 2H), 3.54 (dtd, J=21.8,
5.5, 2.6 Hz, 17H), 3.31-3.21 (m, 5H), 3.17-2.99 (m, 13H), 2.87 (s,
16H), 2.52 (t, J=9.8 Hz, 2H), 2.03 (s, 2H), 1.88 (dd, J=11.2, 6.6
Hz, 2H), 1.78-1.61 (m, 4H), 1.51-1.41 (m, 4H).
Example 28:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy-
)ethyl]-1-[4-(1-[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethylamino)-
piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido-
]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]area;
bis(trifluoroacetic acid)
##STR00100##
[0736] Prepared according to the General Scheme above from INT-M2AC
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(30.0% CH.sub.3CN up to 34.0% in 9 min); Detector, UV 254 nm. This
resulted in 210.2 mg (18%) of the title compound as a white solid.
MS (m/z): 1331.7 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.94-7.85 (m, 4H), 7.38-7.30 (m, 4H), 7.24-7.19 (m, 2H),
6.97 (d, J=1.8 Hz, 2H), 6.36 (d, J=6.1 Hz, 2H), 4.15 (q, J=7.6 Hz,
2H), 3.66-3.33 (m, 24H), 3.32-3.20 (m, 6H), 3.16-3.04 (m, 10H),
2.82 (s, 14H), 2.31 (s, 6H), 2.18 (d, J=11.9 Hz, 2H), 2.13-2.03 (m,
2H), 1.94-1.73 (m, 4H), 1.47 (h, J=3.0 Hz, 4H).
Example 29:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]etho-
xy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethy-
lamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylben-
zene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00101##
[0738] Prepared according to the General Scheme above from INT-M2AD
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(31.0% CH.sub.3CN up to 36.0% in 10 min); Detector, UV 254 nm. This
resulted in 163.7 mg (52%) of the title compound as a white solid.
MS (m/z): 1359.75 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz)
.delta. 7.80-7.65 (m, 4H), 7.43 (d, J=8.6 Hz, 2H), 7.21-7.14 (m,
2H), 6.92 (d, J=1.3 Hz, 2H), 6.23 (d, J=5.7 Hz, 2H), 4.00 (q, J=7.2
Hz, 2H), 3.50 (dt, J=16.7, 4.6 Hz, 19H), 3.41-3.29 (m, 4H), 3.24
(d, J=5.4 Hz, 3H), 3.16 (s, 2H), 3.03 (tt, J=12.2, 6.5 Hz, 15H),
2.80 (s, 14H), 2.26 (d, J=14.0 Hz, 12H), 2.10 (s, 2H), 1.96 (s,
2H), 1.77 (s, 4H), 1.49-1.38 (m, 4H).
Example 30:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-2-[(3R)-3-(dimethylamino)piperidin-1-yl-
]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]etho-
xy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-2-[(3R)-3-(dimethy-
lamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoroben-
zene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00102##
[0740] Prepared according to the General Scheme above from INT-M2AE
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(31.0% CH.sub.3CN up to 36.0% in 10 min); Detector, UV 254 nm. This
resulted in 161.2 mg (61%) of the title compound as a white solid.
MS (m/z): 1368 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz)
.delta. 7.65 (dt, J=19.4, 8.6 Hz, 6H), 7.23-7.16 (m, 2H), 6.98 (d,
J=1.9 Hz, 2H), 6.22 (s, 2H), 4.02 (s, 2H), 3.60-3.20 (m, 23H), 3.07
(t, J=5.5 Hz, 12H), 2.84 (s, 12H), 2.71 (s, 2H), 2.29 (s, 6H), 2.09
(s, 2H), 1.95 (s, 2H), 1.75 (s, 5H), 1.44 (dd, J=4.1, 2.7 Hz,
4H).
Example 31:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-
-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy]b-
enzene)sulfonamido]ethoxy)ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00103##
[0742] Prepared according to the General Scheme above from INT-M2AF
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (30.0% CH.sub.3CN up to 52.0% in 8 min);
Detector, UV 254 nm. This resulted in 122.7 mg (40%) of the title
compound as a white solid. MS (m/z): 1287 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.95-7.84 (m, 4H), 7.46 (d, 1.8 Hz,
2H), 7.39-7.29 (m, 4H), 7.21-7.13 (m, 2H), 6.09 (d, J=6.0 Hz, 2H),
3.77-3.48 (m, 19H), 3.28 (dd, J=11.7, 6.7 Hz, 6H), 3.14-2.86 (m,
10H), 1.55-1.44 (m, 4H).
Example 32:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2--
(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)b-
utyl]urea; bis(trifluoroacetic acid)
##STR00104##
[0744] Prepared according to the General Scheme above from INT-M2AG
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (35.0% CH.sub.3CN up to 55.0% in 8 min);
Detector, UV 254 nm. This resulted in 183.2 mg (60%) of title
compound as a white solid. MS (m/z): 1316.2 [M+H].sup.+. .sup.1H
NMR (Methanol-d4, 400 MHz) .delta. 7.82-7.70 (m, 4H), 7.54-7.43 (m,
5H), 7.17-7.12 (m, 2H), 6.09 (d, J=6.1 Hz, 2H), 3.72 (td, J=7.9,
6.0 Hz, 2H), 3.64-3.49 (m, 16H), 3.28 (dt, J=17.6, 5.2 Hz, 13H),
3.16-2.79 (m, 19H), 2.29 (s, 6H), 1.49 (p, J=3.4 Hz, 4H).
Example 33:
3-[2-(2-[2-[4-[[(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(piperazin-1
yl)-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfanamido]ethoxy]eth-
oxy)ethyl]carbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00105##
[0746] Prepared according to the General Scheme above from INT-M2AH
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm; mobile phase, water (0.05% TFA)
and CH.sub.3CN (22.0% CH.sub.3CN up to 42.0% in 11 min); Detector,
UV 254 nm. This resulted in 419.2 mg (69%) of the title compound as
a white solid. MS (m/z): 1323 [M+H]. .sup.1H NMR (Methanol-d4, 300
MHz) .delta. 7.75-7.52 (m, 6H), 7.42 (d, J=1.7 Hz, 2H), 7.20-7.12
(m, 2H), 6.04 (d, J=5.9 Hz, 2H), 3.72 (td, J=7.7, 5.8 Hz, 2H),
3.60-3.43 (m, 16H), 3.29-3.12 (m, 13H), 3.13-2.72 (m, 19H), 1.44
(p, J=3.3 Hz, 4H).
Example 34:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[-
2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden--
1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]ure-
a; bis(trifluoroacetic acid)
##STR00106##
[0748] Prepared according to the General Scheme above from INT-M2AI
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (20% CH.sub.3CN up to 38% in 8 min); Detector,
UV 254 nm. This resulted in 288.6 mg (64%) of the title compound as
a white solid. MS (m/z): 1245 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.91-7.82 (m, 4H), 7.34-7.25 (m,
4H), 7.20-7.14 (m, 2H), 6.98 (d, J=1.9 Hz, 2H), 6.00 (d, J=5.8 Hz,
2H), 3.69-3.46 (m, 18H), 3.32-3.03 (m, 22H), 2.97-2.79 (m, 10H),
2.29 (s, 6H), 1.47 (p, J=3.3 Hz, 4H).
Example 35:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4--
([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamo-
yl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00107##
[0750] Prepared according to the General Scheme above from INT-M2AJ
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (22% CH.sub.3CN up to 38% in 10 min); Detector,
UV 254 nm. This resulted in 303.9 mg (66%) of the title compound as
a white solid. MS (m/z): 638.15 [M/2+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.80-7.67 (m, 4H), 7.43 (d, J=8.7
Hz, 2H), 7.20-7.14 (m, 2H), 6.96 (d, J=1.8 Hz, 2H), 6.02 (d, J=5.9
Hz, 2H), 3.71-3.61 (m, 2H), 3.61-3.46 (m, 16H), 3.32-3.15 (m, 14H),
3.08 (dt, J=15.4, 5.7 Hz, 8H), 2.89 (ddt, J=22.8, 13.6, 6.0 Hz,
10H), 2.28 (d, J=16.7 Hz, 12H), 1.47 (p, J=3.2 Hz, 4H).
Example 36:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-methyl-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4--
([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-methyl-2-(piperazin-1-yl]-2,3-dihydro--
1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamo-
yl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00108##
[0752] Prepared according to the General Scheme above from INT-M2AK
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following condition: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (30.0% CH.sub.3CN up to 38.0% in 11 min);
Detector, UV 254 nm. This resulted in 358.1 mg (59%) of the title
compound as a white solid. MS (in/z): 1281 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.74-7.51 (m, 6H), 7.20-7.13 (m,
2H), 6.99 (d, J=1.8 Hz, 2H), 6.01 (d, J=5.6 Hz, 2H), 3.69 (td,
J=7.6, 5.6 Hz, 2H), 3.60-3.42 (m, 16H), 3.29-3.01 (m, 22H), 2.88
(tq, J=11.5, 6.9, 5.7 Hz, 10H), 2.27 (s, 6H), 1.50-1.39 (m,
4H).
Alternate Route to Monomer Synthesis
##STR00109##
[0754] Step A: To a round-bottom flask was added bromoaminoindanol
INT-18 (1 equiv), phenol INT-L6 (1.2 equiv), tetrahydrofuran (0.43
M), and PPh3 (1.5 equiv). The flask was heated to 40-45.degree. C.
followed by the addition of DIAD (1.5 equiv) dropwise over 15-20
min. The resulting slurry was stirred for 1 h at 40.degree. C. in
an oil bath. The resulting mixture was concentrated under vacuum
and diluted with CH.sub.2Cl.sub.2. The residue was applied onto a
silica gel column with ethyl acetate/petroleum ether (0-80%)
providing the sulfonamide INT-M3.
[0755] Step B: To a round-bottom flask was added INT-M3 (I equiv),
NMP (0.1 M), Pd(PPh3).sub.4 (0.1 equiv), and Zn(CN).sub.2 (0.6
equiv). The resulting solution was stirred overnight at 100.degree.
C. in an oil bath. The resulting solution was extracted with
3.times. ethyl acetate. The organic layers were combined, washed
with 3.times. brine, dried over anhydrous sodium sulfate, filtered,
and concentrated under vacuum. The residue was applied onto a
silica gel column with ethyl acetate/petroleum ether (0-80%)
providing the 4-cyano aminoindanols INT-M4.
[0756] Step C: To a round-bottom flask was added aminoindanol
INT-M4 (1 equiv), tetrahydrofuran (0.066 M), and sodium hydroxide
(3 M, 7.5 equiv). The resulting slurry was stirred for 1 h at room
temperature. The resulting solution was extracted with 4.times.
ethyl acetate. The organic layers were combined, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (5:1) providing the amine monomer
INT-M5.
[0757] The following intermediates are made by applying the above
procedures to the appropriate starting aminoindanols INT-I8 and
linkers INT-L6:
##STR00110##
[0758] General Procedure for Dimer Product Synthesis: Conversion of
monomers INT-M5 proceeded via the same sequence as the conversion
of INT-M2 to the desired dimer Products 1 (with or without the
follow-on Boc-deprotection as necessary).
Example 37:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-M-
-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[-
2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]am-
ino)butyl]urea
##STR00111##
[0760] Prepared according to the General Scheme above from INT-M5A
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge Preparative C18 OBD Column,
19*150 mm 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (55.0% CH.sub.3CN up to 59.0% in 7 min); Detector, UV
254/220 nm. This resulted in 64.8 mg (6%) of the title compound as
a white solid. MS (m/z): 1223.6 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.77 (d, J=1.8 Hz, 2H), 7.75-7.62
(m, 6H), 7.53-7.47 (m, 2H), 6.00 (d, J=5.8 Hz, 2H), 3.65 (q, J=7.3
Hz, 2H), 3.60-3.52 (m, 8H), 3.50 (td, J=5.5, 2.1 Hz, 8H), 3.31 (m,
4H), 3.28 (d, 5.4 Hz, 3H), 3.15-3.04 (m, 10H), 2.36 (s, 12H), 1.47
(p, J=3.2 Hz, 4H).
Example 38:
3-[2-(2-[2-[(4-[[(1S,2S)-21(3R)-3-Aminopiperidin-1-yl]-6-chloro-4-methyl--
2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)e-
thyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-6-chlor-
o-4-methyl-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]etho-
xy]ethoxy)ethyl]carbamoyl]amino)butyl]urea; bis(trifluoroacetic
acid)
##STR00112##
[0762] Prepared according to the General Scheme above from INT-M5B
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (29.0% CH.sub.3CN up to 33.0% in 10 min);
Detector, UV 254 nm. This resulted in 302.6 mg (59%) of the title
compound as a white solid. MS (m/z): 1331 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.80 (d, J=1.9 Hz, 2H), 7.77-7.58
(m, 7H), 7.54 (d, J=2.3 Hz, 2H), 6.14-6.04 (m, 2H), 3.84 (d, J=16.5
Hz, 2H), 3.54 (dtd, J=23.1, 5.3, 3.1 Hz, 17H), 3.38 (dd, J=18.7,
7.4 Hz, 5H), 3.19 (dt, J=75.2, 5.4 Hz, 15H), 2.98 (s, 3H), 2.76 (s,
2H), 2.61 (s, 5H), 1.93 (s, 3H), 1.85 (s, 2H), 1.65 (s, 2H), 1.56
(s, 3H), 1.47 (p, J=3.3 Hz, 4H).
Example 39:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperi-
din-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethox-
y]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenze-
ne)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00113##
[0764] Prepared according to the General Scheme above from INT-M5C
by dimer formation. Purification by preparative HPLC with the
following conditions (Column, XBridge Shield RP18 OBD Column,
19*150 mm, 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (47.0% CH.sub.3CN up to 48.0% in 15 min); Detector, UV
254/220 nm. This resulted in 52.9 mg (10%) of the title compound as
a white solid. MS (m/z): 1381.85 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.80-7.67 (m, 6H), 7.53-7.44 (m,
4H), 6.02 (d, J=6.0 Hz, 2H), 3.69-3.46 (m, 20H), 3.39 (dd, J=16.7,
8.0 Hz, 2H), 3.28 (d, J=5.4 Hz, 2H), 3.15-2.99 (m, 12H), 2.92 (d,
J=11.1 Hz, 2H), 2.28 (s, 8H), 2.15 (s, 16H), 1.95 (d, J=12.9 Hz,
2H), 1.80 (dt, J=13.8, 3.4 Hz, 2H), 1.65-1.43 (m, 6H), 1.23 (ddt,
J=20.4, 12.3, 6.6 Hz, 2H).
Example 40:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperi-
din-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethox-
y]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluorobenze-
ne)sulfon amido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00114##
[0766] Prepared according to the General Scheme above from INT-M5D
by dimer formation. Purification by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(30.0% CH.sub.3CN up to 40.0% in 8 min); Detector, UV 254 nm. This
resulted in 334 mg (73%) of the title compound as a white solid. MS
(m/z): 1387 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.80 (d, J=1.9 Hz, 2H), 7.77-7.59 (m, 6H), 7.54 (dd, J=1.8, 0.8 Hz,
2H), 6.16 (d, J=6.0 Hz, 2H), 3.97 (q, J=7.6 Hz, 2H), 3.54 (dtd,
J=22.5, 5.4, 2.9 Hz, 17H), 3.46-3.17 (m, 13H), 3.14-3.05 (in, 8H),
2.87 (s, 16H), 2.55 (t, J=9.8 Hz, 2H), 2.06 (t, J=11.1 Hz, 2H),
1.90 (dd, J=10.2, 5.1 Hz, 2H), 1.69 (q, J=10.9, 10.0 Hz, 4H),
1.53-1.41 (m, 4H).
Example 41:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-
-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1--
yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00115##
[0768] Prepared according to the General Scheme above from INT-M5E
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge
Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase, water
(0.05% TFA) and CH.sub.3CN (28.0% CH.sub.3CN up to 29.0% in 7 min);
Detector, UV 254/220 nm. This resulted in 326.1 mg (53%) of the
title compound as a white solid. MS (m/z): 1267 [M+H].sup.+.
.sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.92-7.89 (m, 4H), 7.77
(d, J=1.9 Hz, 2H), 7.47 (dd, J=1.8, 0.9 Hz, 2H), 7.37-7.28 (m, 4H),
6.09 (d, J=6.1 Hz, 2H), 3.76 (td, J=7.9, 6.0 Hz, 2H), 3.62-3.46 (m,
16H), 3.38 (dd, J=16.8, 8.0 Hz, 2H), 3.26 (dt, J=14.7, 5.2 Hz,
11H), 3.20-3.03 (m, 10H), 2.88 (qt, J=12.8, 4.5 Hz, 8H), 1.51-1.43
(m, 4H).
Example 42:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy]ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00116##
[0770] Prepared according to the General Scheme above from INT-M5F
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XSelect CSH
Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase, water
(0.05% TFA) and CH.sub.3CN (20.0% CH.sub.3CN up to 40.0% in 10
min); Detector, UV 254 nm. This resulted in 361.4 mg (59%) of the
title compound as a white solid. MS (m/z): 1297.70 [M+H].sup.+.
.sup.1H NMR (Methanol-d4, 300 MHz) .delta. 7.79-7.64 (m, 6H),
7.48-7.39 (m, 4H), 6.08 (d, J=6.1 Hz, 2H), 3.76 (td, J=7.9, 6.0 Hz,
2H), 3.60-3.30 (m, 19H), 3.29-2.75 (m, 29H), 2.24 (s, 6H),
1.50-1.39 (m, 4H).
Example 43:
3-[2-(2-[2-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy]-3-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00117##
[0772] Prepared according to the General Scheme above from INT-M5G
by dimer formation and Boc-deprotection. Purification by
preparative HPLC with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (20.0% CH.sub.3CN up to 42.0% in 8 min);
Detector, UV 254 nm. This resulted in 355.1 mg (81%) of the title
compound as a white solid. MS (m/z): 1303 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.80-7.47 (m, 10H), 6.06 (d, J=6.1
Hz, 2H), 3.80 (td, J=7.9, 6.0 Hz, 2H), 3.51 (dtd, J=17.3, 5.2, 2.4
Hz, 16H), 3.42-3.01 (m, 24H), 2.86 (tq, J=13.2, 7.8, 6.3 Hz, 8H),
1.50-1.39 (m, 4H).
Scheme for Hydroxymethylpyrrolidine Linker Synthesis:
##STR00118##
[0774] Step A: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added tert-butyl (3,
S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (500 mg, 2.48 mmol, 1
equiv), CH.sub.2Cl.sub.2 (5 mL), and trifluoroacetic acid (1 ml).
The resulting solution was stirred for 1 h at room temperature in
an oil bath. The resulting mixture was concentrated under vacuum.
This resulted in 250 mg (99%) of (3S)-pyrrolidin-3-ylmethanol
trifluoroacetic acid salt as brown oil which was used directly in
Step B.
[0775] Step B: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added
(3S)-pyrrolidin-3-ylmethanol (125 mg, 1.24 mmol, 1 equiv),
CH.sub.2Cl.sub.2 (5 mL), and trimethylamine (0.5 mL, 3 equiv). This
was followed by the dropwise addition of a solution of
4-(benzyloxy)-3-methylbenzene-1-sulfonyl chloride (INT-L3 where
R.sup.1=m-methyl, 360 mg, 1.21 mmol, 0.98 equiv) in
CH.sub.2Cl.sub.2 (5 mL). The resulting solution was stirred for 1 h
at room temperature. The resulting slurry was extracted with
3.times.20 mL of ethyl acetate. The organic layers were combined,
washed with 1.times.20 mL of brine, dried over anhydrous sodium
sulfate, filtered, and concentrated under vacuum. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1/10) providing 400 mg (90%) of
[(3S)-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidin-3-yl]methanol
as a yellow oil.
[0776] Step C: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added sodium hydride (763
mg, 31.79 mmol, 3 equiv), N,N-dimethylformamide (60 mL), INT-SM2
(2.3 g, 6.36 mmol, 1 equiv), 15-crown-5 (3.8 mL, 3 equiv), and
1-[2-(2-azidoethoxy)ethoxy]sulfonyl-4-methylbenzene (2.7 g, 9.46
mmol, 1.5 equiv). The resulting solution was stirred overnight at
room temperature. The reaction was then quenched by the addition of
water and extracted with 3.times.50 mL of ethyl acetate. The
organic layers combined, washed with 4.times.100 mL of brine, dried
over anhydrous sodium sulfate, filtered, and concentrated under
vacuum. The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1/3) providing 1.2 g (40%) of
(3S)-3-[[2-(2-azidoethoxy)ethoxy]methyl]-1-[[4-(benzyloxy)-3-methylbenzen-
e]sulfonyl]pyrrolidine (INT-SM3) as a yellow oil.
[0777] Step D: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of hydrogen was added azide INT-SM3 (1.2
g, 2.53 mmol, 1 equiv), ethyl acetate (6 mL), methanol (6 mL), and
palladium on carbon (500 mg). The resulting slurry was stirred for
2 h at room temperature. The resulting mixture filtered to remove
palladium and the filtrate concentrated under vacuum. This resulted
in 740 mg (82%) of
4-[(3S)-3-[[2-(2-aminoethoxy)ethoxy]methyl]pyrrolidine-1-sulfonyl]-2-meth-
ylphenol (INT-SM4) as a yellow oil.
[0778] Step E: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added amine INT-SM4 (740
mg, 2.06 mmol, 1 equiv), methanol (8 mL), triethylamine (41.7 mg,
0.41 mmol, 0.20 equiv), and ethyl 2,2,2-trifluoroacetate (0.75 mL,
3 equiv). The resulting solution was stirred for 2 h at room
temperature. The resulting slurry was concentrated under vacuum.
The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1/1) providing 800 mg (85%) of
2,2,2-trifluoro-N-[2-(2-[[(3S)-1-[(4-hydroxy-3-methylbenzene)sulfonyl]pyr-
rolidin-3-yl]methoxy]ethoxy)ethyl]acetamide (INT-SM5) as a yellow
oil.
[0779] The R-enantiomer of INT-SM5 was generated from the analogous
procedure beginning with tert-butyl
(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate. This provided
INT-RM5:
##STR00119##
Scheme for Hydroxymethylpyrrolidine Dimer Product Synthesis:
##STR00120##
[0781] Step A: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added phenol INT-SM5 (300
mg, 0.66 mmol, 1 equiv), aminoindanol INT-18C (162.47 mg, 0.66
mmol, 1 equiv), and tetrahydrofuran (1.5 mL). This was followed by
the addition of PPh.sub.3 (260 mg, 0.99 mmol, 1.5 equiv) at
40.degree. C. followed by the dropwise addition of DIAD (0.195 mL,
1.5 equiv) with stirring at 40.degree. C. The resulting solution
was stirred for 1 h at 40.degree. C. in an oil bath. The resulting
slurry was concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether (2/1)
providing 400 mg (89%) of
N-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethox-
y)ethyl]-2,2,2-trifluoroacetamide (INT-SMG) as a yellow oil.
[0782] Step B: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen, was added INT-SMG (400 mg,
0.59 mmol, 1 equiv) and methanol (4 mL) followed by the addition of
sodium hydroxide (3 M, 1 mL). The resulting slurry was stirred for
1 h at GO .degree. C. in an oil bath. The resulting solution was
extracted with 3.times.20 mL of ethyl acetate. The organic layers
combined, washed with 1.times.20 mL of brine, dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The
residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (5/1) providing 300 mg (87%) of
(1S,2S)-1-[4-[(3S)-3-[[2-(2-aminoethoxy)ethoxy]methyl]pyrrolidine-1-sulfo-
nyl]-2-methylphenoxy]-4,6-dichloro-N,N-dimethyl-2,3-dihydro-1H-inden-2-ami-
ne (INT-SM7) as a yellow oil.
[0783] Step C: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added amine INT-SM7 (300
mg, 0.51 mmol, 1 equiv), N,N-dimethylformamide (3.4 mL), and
1,4-diisocyanatobutane (0.029 mL, 0.45 equiv). The resulting
solution was stirred for 1 h at 60.degree. C. in an oil bath. The
resulting mixture was concentrated under vacuum. The crude product
was purified by preparative HPLC with the following conditions:
Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5 um; mobile
phase, water (0.05% TFA) and CH.sub.3CN (35.0% CH.sub.3CN up to
48.0% in 8 min); Detector, UV 254 nm.
Example 44:
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethox-
y)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino-
)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]-
methoxy]ethoxy)ethyl]carbamoyl]amino) butyl]urea;
bis(trifluoroacetic acid)
[0784] Steps A-C provided 221.4 mg (28%) of the title compound as a
white solid. MS (m/z): 1313 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
400 MHz) .delta. 7.82-7.70 (m, 4H), 7.57-7.47 (m, 4H), 7.10-7.04
(m, 2H), 6.49 (d, J=6.7 Hz, 2H), 4.50 (td, J=8.4, 6.6 Hz, 2H), 3.70
(dd, J=16.5, 8.6 Hz, 2H), 3.57-3.53 (m, 4H), 3.53-3.44 (m, 8H),
3.40-3.31 (m, 6H), 3.29-3.16 (m, 10H), 3.12-3.07 (m, 6H), 3.05 (s,
12H), 2.38 (p, J=6.7 Hz, 2H), 2.32 (s, 6H), 1.92 (td, J=12.8, 7.4
Hz, 2H), 1.65-1.51 (m, 2H), 1.50-1.42 (m, 4H).
Example 45:
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]ethox-
y)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino-
)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]-
methoxy]ethoxy]ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00121##
[0786] Beginning with R-enantiomer INT-RM5 and INT-18C, Steps A-C
provided 306 mg (67%) of the title compound as a white solid. MS
(m/z): 1314 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.82-7.70 (m, 4H), 7.56-7.48 (m, 4H), 7.10-7.04 (m, 2H), 6.51 (d,
J=6.7 Hz, 2H), 4.49 (td, J=8.5, 6.6 Hz, 2H), 3.70 (dd, J=16.5, 8.6
Hz, 2H), 3.59-3.44 (m, 12H), 3.41-3.03 (m, 33H), 2.32 (s, 8H),
1.99-1.86 (m, 2H), 1.58 (dq, J=14.5, 7.4 Hz, 2H), 1.49-1.41 (m,
4H).
Scheme for Cyano-containing Hydroxymethylpyrrolidine Dimer Product
Synthesis:
Example 46:
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]e-
thoxy)ethyl]-1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimet-
hylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolid-
in-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00122##
[0788] Step A: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen, was added phenol INT-SM5 (500
mg, 1.1 mmol, 1 equiv), aminoindanol INT-I8B (320 mg, 1.1 mmol, 1
equiv), tetrahydrofuran (2.5 mL), and PPh.sub.3 (433 mg, 1.65 mmol,
1.5 equiv). Heating at 40.degree. C. in an oil bath DIAD (0.33 mL,
1.5 equiv) was added dropwise with stirring. The resulting solution
was stirred for 1 h. The resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (2/1) providing 700 mg (88%) of
N-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-4-bromo-6-chloro-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]e-
thoxy)ethyl]-2,2,2-trifluoroacetamide (INT-SM8) as a yellow
oil.
[0789] Step B: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added bromoaminoindanol
INT-SM8 (640 mg, 0.88 mmol, 1.00 equiv), NMP (7 mL), Zn(CN).sub.2
(62 mg, 0.60 equiv), and Pd(PPh.sub.3).sub.4 (102 mg, 0.09 mmol,
0.10 equiv). The resulting solution was stirred overnight at
100.degree. C. in an oil bath. The resulting slurry was diluted
with water and extracted with 3.times.20 mL of ethyl acetate. The
organic layers were combined, washed with 3.times.20 mL of brine,
and dried in an oven under reduced pressure. The residue was
applied onto a silica gel column with ethyl acetate/petroleum ether
(1/5) providing 550 mg (93%) of
N-[2-(2-[[(3S)-1-[[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-di-
hydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]-
ethoxy)ethyl]-2,2,2-trifluoroacetamide (INT-SM9) as a yellow
oil.
[0790] Step C: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added INT-SM9 (550 mg,
0.82 mmol, 1 equiv) and methanol 7 mL) followed by the addition of
sodium hydroxide (3 M.sub.(aq), 1 mL). The resulting solution was
stirred for 5 h at room temperature. The reaction was then quenched
by the addition of water and extracted with 3.times.20 mL of ethyl
acetate. The organic layers were combined, washed with 1.times.20
mL of brine, filtered, and concentrated to a solid under vacuum.
The solid was dried in an oven under reduced pressure. The residue
was applied onto a silica gel column with CH.sub.2Cl.sub.2/methanol
(5/1) providing 460 mg (98%) of
(1S,2S)-1-[4-[(3S)-3-[[2-(2-aminoethoxy)ethoxy]methyl]pyrrolidine-1-sulfo-
nyl]-2-methylphenoxy]-6-chloro-2-(dimethylamino)-2,3-dihydro-1
ii-indene-4-carbonitrile (INT-SM10) as a yellow oil.
[0791] Step D: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added amine INT-SM10 (460
mg, 0.80 mmol, 1 equiv), N,N-dimethyl formamide (5.5 mL), and
1,4-diisocyanatobutane (52.4 mg, 0.37 mmol, 0.47 equiv). The
resulting solution was stirred for 1 h at 60.degree. C. in an oil
bath. The resulting mixture was concentrated under vacuum. The
crude product was purified by Preparative HPLC with the following
conditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm,
5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN (32.0%
CH.sub.3CN up to 54.0% in 8 min); Detector, UV 254 nm.
Example 46:
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]e-
thoxy)ethyl]-1[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimeth-
ylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidi-
n-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
[0792] Steps A-D provided 130.6 mg (11%) of the title compound as a
white solid. MS (m/z): 1295 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
400 MHz) .delta. 7.89 (d, J=1.9 Hz, 2H), 7.85-7.70 (m, 4H), 7.54
(d, J=8.7 Hz, 2H), 7.44-7.37 (m, 2H), 6.56 (d, J=6.6 Hz, 2H),
4.63-4.49 (m, 2H), 3.83 (dd, J=16.7, 8.5 Hz, 2H), 3.61-3.04 (m,
46H), 2.33 (s, 8H), 1.94 (dt, J=13.5, 6.8 Hz, 2H), 1.59 (dd,
J=13.1, 7.2 Hz, 2H), 1.47 (dd, J=3.7, 3.0 Hz, 4H).
Example 47:
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]e-
thoxy)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimet-
hylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolid-
in-3-yl]methoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00123##
[0794] Beginning with R-enantiomer INT-RM5 and INT-18B, Steps A-D
provided 248 mg (27%) of the title compound as a white solid. MS
(m/z): 1293 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) a
7.78-7.65 (m, 6H), 7.51 (d, J=8.7 Hz, 2H), 7.45-7.40 (m, 2H), 6.00
(d, J-6.1 Hz, 2H), 3.64-3.45 (m, 14H), 3.44-3.14 (m, 14H),
3.14-3.02 (m, 8H), 2.35 (s, 12H), 2.27 (s, 6H), 1.91 (dtd, J=12.8,
7.5, 5.4 Hz, 2H), 1.57 (dq, J=14.3, 7.3 Hz, 2H), 1.47 (p, J=3.3 Hz,
4H).
Scheme for Pyridinyl Linker Synthesis:
##STR00124##
[0796] Step A: To a 50-mL round-bottom flask was added
N,N-dimethylformamide (12 mL), sodium hydride (331.2 mg, 13.8 mmol,
5 equiv), 4-chloropyridine-2-carbonitrile (574.1 mg, 4.14 mmol, 1.5
equiv), sulfonamide INT-SM2 (1.0 g, 2.77 mmol, 1 equiv). The
resulting solution was stirred for 1.5 h at room temperature. The
reaction was then quenched by the addition of 20 mL of NR.sub.4Cl
and extracted with 3.times.100 mL of ethyl acetate. The organic
layers were combined, washed with 1.times.100 mL of brine, dried
over anhydrous sodium sulfate, filtered, and concentrated under
vacuum. The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:1) providing 570 mg (44%) of
4-[[(3S)-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidin-3-yl]metho-
xy]pyridine-2-carbonitrile (INT-SP1) as a white solid.
[0797] Step B: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of H.sub.2 was added INT-SP1 (660 mg, 1.42
mmol, 1 equiv), ethanol (20 mL), and Raney Ni (660 mg). The
resulting solution was stirred for overnight at room temperature.
The resulting mixture was filtered and concentrated under vacuum
providing 520 mg (78%) of
(4-[[(3S)-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidin-3-yl]meth-
oxy]pyridin-2-yl)methanamine (INT-SP2) as a brown solid.
[0798] Step C: To a 100-mL round-bottom flask was added amine
INT-SP2 (520 mg, 1.11 mmol, 1 equiv), 1:1 tetrahydrofuran:H.sub.2O
(20 mL), and sodium carbonate (588.3 mg, 5.55 mmol, 5 equiv). This
was followed by the addition of a solution of Boc.sub.2O (485 mg,
2.22 mmol, 2 equiv) in tetrahydrofuran (5 mL) dropwise with
stirring at 5-10.degree. C. in 5 min. The resulting solution was
stirred for 2 h at room temperature. The resulting slurry was
extracted with 3.times.100 mL of ethyl acetate. The organic layers
were combined, washed with 1.times.100 mL of brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (5:1) providing 520 mg (82%) of
tert-butyl
N-[(4-[[(3S)-1-[[4-(benzyloxy)-3-methylbenzene]sulfonyl]pyrrolidin-3-yl]m-
ethoxy]pyridin-2-yl)methyl]carbamate (INT-SP3) as a white
solid.
[0799] Step D: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of hydrogen was added a solution of
INT-SP3 (520 mg, 0.92 mmol, 1 equiv), ethyl acetate (10 mL), and
10% Pd/C (520 mg). The resulting slurry was stirred for 1 h at room
temperature. The solids were filtered out and the filtrate
concentrated under vacuum providing 420 mg (96%) of tert-butyl
N-[(4-[[(3,
S)-1-[(4-hydroxy-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-
-2-yl)methyl]carbamate (INT-SP4) as a white solid.
[0800] The R-enantiomer of INT-SP4 was generated from the analogous
procedure beginning with tert-butyl
(3R)-3-(hydroxymethyl)pyrrolidine-1-carboxylate. This provided
INT-RP4:
##STR00125##
Scheme for Pyridinyl Dimer Product Synthesis:
Example 48:
3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-
-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylam-
ino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3--
yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea
##STR00126##
[0802] Step A: To a 7-mL round-bottom flask was added phenol
INT-SP4 (170 mg, 0.36 mmol, 1 equiv), aminoindanol INT-I8C (96.4
mg, 0.39 mmol, 1.1 equiv), tetrahydrofuran (0.83 mL), and PPh.sub.3
(140.1 mg, 0.53 mmol, 1.50 equiv). Heating at 40.degree. C. in an
oil bath DIAD (0.11 mL) was added dropwise with stirring over 15
min. The resulting solution was stirred for 1 h at 40-45.degree. C.
in an oil bath. The residue was applied onto a silica gel column
with ethyl acetate/petroleum ether (100%) providing 200 mg (80%) of
tert-butyl
N-[(4-[[(3S)-1-[1(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridi-
n-2-yl)methyl]carbamate (INT-SP5) as a yellow oil.
[0803] Step B: To a 100-mL round-bottom flask was added INT-SP5
(200 mg, 0.28 mmol, 1 equiv), CH.sub.2Cl.sub.2 (15 mL), and
trifluoroacetic acid (5 mL). The resulting solution was stirred for
1 h at room temperature. The pH value of the solution was adjusted
to 9.0-10.0 with sodium bicarbonate (100%) and the slurry extracted
with 3.times.100 mL of ethyl acetate. The organic layers were
combined, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with CH.sub.2Cl.sub.2/methanol (5:1) providing 153 mg
(89%) of
(1S,2S)-1-[4-[(3S)-([[2-(aminomethyl)pyridin-4-yl]oxy]methyl)pyrrolidine--
1-sulfonyl]-2-methylphenoxy]-4,6-dichloro-N,N-dimethyl-2,3-dihydro-1H-inde-
n-2-amine (INT-SP6) as a white solid.
[0804] Step C: To a 25-mL round-bottom flask was added amine
INT-SP6 (153 mg, 0.25 mmol, 2.08 equiv), 1,4-diisocyanatobutane (17
mg, 0.12 mmol, 1 equiv), and N,N-dimethylformamide (1.7 mL). The
resulting solution was stirred for 1 h at 60.degree. C. in an oil
bath. The solids were filtered out. The crude product was purified
by Preparative HPLC with the following conditions: Column, XBridge
C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water
(0.05% NH.sub.4OH) and CH.sub.3CN (85% CH.sub.3CN up to 90% in 8
min); Detector, UV 254 nm.
Example 48:
3-[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-
-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylam-
ino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3--
yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea
[0805] Steps A-C provided 62.3 mg (38%) of the title compound as a
white solid. MS (m/z): 1351 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
300 MHz) .delta. 8.15 (d, J=5.9 Hz, 2H), 7.77-7.60 (m, 4H),
7.49-7.34 (m, 4H), 7.06 (d, J=1.1 Hz, 2H), 6.82 (d, J=2.5 Hz, 2H),
6.67 (dd, J=5.9, 2.5 Hz, 2H), 5.93 (d, J=6.2 Hz, 2H), 4.29 (s, 4H),
4.00 (s, 2H), 3.88 (dd, J=9.4, 6.0 Hz, 2H), 3.73 (t, J=8.7 Hz, 2H),
3.50-3.29 (m, 10H), 3.28-3.10 (m, 6H), 2.87 (dd, J=16.4, 7.7 Hz,
1H), 2.58 (s, 4H), 2.29 (s, 11H), 2.16 (s, 6H), 1.49 (s, 4H).
##STR00127##
Example 49:
3-[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1-
H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyridin-
-2-yl)methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylam-
ino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3--
yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea.
Beginning with R-enantiomer INT-RP4 and INT-18B
[0806] Steps A-C provided 54.3 mg (31%) of the title compound as a
white solid. MS (m/z): 1351 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
300 MHz) .delta. 8.18 (d, J=5.9 Hz, 1H), 7.77-7.61 (m, 2H),
7.49-7.33 (m, 2H), 7.04 (d, J=1.1 Hz, 1H), 6.83 (d, J=2.4 Hz, 1H),
6.71 (dd, J=5.9, 2.5 Hz, 1H), 5.92 (d, J=5.8 Hz, 1H), 4.56 (s, 5H),
4.30 (s, 2H), 3.96-3.73 (m, 2H), 3.51-3.32 (m, 3H) 3.27-3.08 (m,
5H), 2.87 (dd, J=16.6, 7.7 Hz, 1H), 2.30 (s, 7H), 2.63-2.52 (m,
1H), 2.19 (s, 4H), 2.00 (d, J=7.9 Hz, 2H), 1.67 (dd, J=13.2, 71 Hz,
1H), 1.50 (s, 4H), 1.30 (d, J=25.9 Hz, 6H), 0.86 (d, J=6.2 Hz,
2H).
Scheme for Cyano-containing Pyridinyl Dimer Product Synthesis:
Example 50:
3-[4-[[(3S)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydr-
o-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyri-
din-2-yl)methyl]-1-[4-([[4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dime-
thylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrroli-
din-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea
##STR00128##
[0808] Step A: To a 7-mL round-bottom flask was added phenol
INT-SP4 (250 mg, 0.52 mmol, 1 equiv), aminoindanol INT-18B (167.36
mg, 0.58 mmol, 1.1 equiv), tetrahydrofuran (1.22 mL), and PPh.sub.3
(206.2 mg, 0.79 mmol, 1.50 equiv). Heating at 40.degree. C. in an
oil bath DIAD (0.16 mL) was added dropwise with stirring. The
resulting solution was stirred for 1 h at 40-45.degree. C. in an
oil bath. The resulting mixture was concentrated under vacuum. The
residue was applied onto a silica gel column with
dichloromethane/methanol (5:1) providing 300 mg (76%) of tert-butyl
N-[(4-[[3S)-1-[(4-[[(1S,2S)-4-bromo-6-chloro-2-(dimethylamino)-2,3-dihydr-
o-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyri-
din-2-yl)methyl]carbamate (INT-SP7) as a white solid.
[0809] Step B: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added bromoaminoindanol
INT-SP7 (300 mg, 0.40 mmol, 1 equiv), Zn(CN).sub.2 (28.16 mg, 0.24
mmol, 0.60 equiv), NMP (5 mL), and Pd(PPh3).sub.4 (46.22 mg, 0.04
mmol, 0.10 equiv). The resulting solution was stirred for overnight
at 100.degree. C. in an oil bath. The resulting solution was
extracted with 3.times.100 mL of ethyl acetate. The organic layers
were combined, washed with 3.times.100 mL of brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was applied onto a silica gel column with
dichloromethane/methanol (10:1) providing 300 mg (crude) of
tort-butyl
N-[(4-([[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]py-
ridin-2-yl)methyl]carbamate (INT-SP8) as a white solid, used
without further purification in Step C.
[0810] Step C: To a 100-mL round-bottom flask was added INT-SP8
(220 mg, 0.32 mmol, 1 equiv) and 3:1 CH.sub.2Cl.sub.2:TFA (20 mL).
The resulting solution was stirred for 1 h at room temperature. The
pH value of the solution was adjusted to 9.0-10.0 with sodium
bicarbonate and extracted with 3.times.100 mL of ethyl acetate. The
organic layers were combined, dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (5:1)
providing 187 mg (crude) of
(1S,2S)-1-[4-[(3S)-3-([[2-(aminomethyl)pyridin-4-yl]oxy]methyl)pyrrolidin-
e-1-sulfonyl]-2-methylphenoxy]-6-chloro-2-(dimethylamino)-2,3-dihydro-1H-i-
ndene-4-carbonitrile (INT-SP9) as a white solid.
[0811] Step D: To a 7-mL round-bottom flask was added amine INT-SP9
(187 mg, 0.31 mmol, 2.22 equiv), N,N-dimethylformamide (2.1 mL),
and 1,4-diisocyanatobutane (19.8 mg, 0.14 mmol, 1 equiv). The
resulting solution was stirred for 1 h at 60.degree. C. in an oil
bath. The solids were filtered out. The crude product was purified
by preparative HPLC with the following conditions: Column, X Bridge
C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water
(0.05% NH.sub.4OH) and CH.sub.3CN (55% CH.sub.3CN up to 57% in 8
min); Detector, UV 254 nm.
Example 50:
3-[(4-[[(3S)-1[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihydr-
o-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyri-
din-2-yl)methyl]-1-[4-([[(4-[[(3S)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dim-
ethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrol-
idin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea
[0812] Steps A-D provided 64.5 mg (34%) of the title compound as a
white solid. MS (m/z): 1333 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
300 MHz) .delta. 8.16 (d, J=5.7 Hz, 2H), 7.77-7.61 (m, 6H),
7.52-7.36 (m, 4H), 6.82 (d, J=2.3 Hz, 2H), 6.73-6.64 (m, 2H), 5.95
(d, J=6.0 Hz, 2H), 4.29 (s, 4H), 3.88 (dd, J=9.5, 6.0 Hz, 2H), 3.74
(dd, J=9.5, 7.7 Hz, 2H), 3.61-3.28 (m, 7H), 3.28-2.97 (m, 11H),
2.57 (dt J=14.1, 7.0 Hz, 2H), 2.30 (s, 12H), 2.18 (s, 6H),
2.10-1.92 (m, 2H), 1.68 (dq, J=14.0, 7.2 Hz, 2H), 1.55-1.44 (m,
4H).
Example 51:
3-[(4-[[(3R)-1-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihyd-
ro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrrolidin-3-yl]methoxy]pyr-
idin-2-yl]methyl]-1-[4-([[(4-[[(3R)-1-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(di-
methylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonyl]pyrro-
lidin-3-yl]methoxy]pyridin-2-yl)methyl]carbamoyl]amino)butyl]urea
##STR00129##
[0814] Beginning with R-enantiomer INT-RP4 and INT-18B, Steps A-D
provided 39.6 mg (37%) of the title compound as a white solid. MS
(m/z): 1333 [M+H].sup.+. .sup.1H NMR (DMSO-d6, 400 MHz) .delta.
8.23 (d, J=5.6 Hz, 2H), 7.99 (d, J=1.9 Hz, 2H), 7.70-7.60 (m, 4H),
7.58-7.49 (m, 4H), 6.76-6.66 (m, 4H), 6.32 (t, J=5.8 Hz, 2H), 6.09
(t, J=5.6 Hz, 2H), 5.93 (d, J=5.4 Hz, 2H), 4.18 (d, J=5.7 Hz, 4H),
3.80 (ddd, J=32.6, 9.6, 6.8 Hz, 4H), 3.52 (dd, J=7.7, 5.8 Hz, 2H),
3.36-2.93 (m, 16H), 2.49 (s, 210, 2.16 (d, J=11.9 Hz, 18H), 1.91
(dt, J=13.1, 6.6 Hz, 2H), 1.58 (4 J=14.2, 7.4 Hz, 2H), 1.38-1.29
(m, 4H).
Scheme for Hydroxyethylpyrrolidine Linker Synthesis:
##STR00130##
[0816] Step A: To a 100-mL round-bottom flask was added tert-butyl
(3S)-3-aminopyrrolidine-1-carboxylate (2.5 g, 13.42 mmol, 1 equiv),
CH.sub.2Cl.sub.2 (20 mL), and sulfonyl chloride INT-L3 (where
R.sup.1=m-methyl, 4.72 g, 15.90 mmol, 3 equiv). The resulting
solution was stirred overnight at room temperature. The resulting
mixture was concentrated under vacuum. The residue was applied onto
a silica gel column with ethyl acetate/petroleum ether
(1/100-100/1) providing 3.0 g (50%) of tert-butyl
(3S)-3-[[4-(benzyloxy)-3-methylbenzene]sulfonamido]pyrrolidine-1-carboxyl-
ate (INT-SE1) as a yellow oil.
[0817] Step B: To a 100-mL round-bottom flask was added sulfonamide
INT-SE1 (3.0 g, 6.72 mmol, 1 equiv), CH.sub.2Cl.sub.2 (15 mL), and
trifluoroacetic acid (5 mL). The resulting solution was stirred for
1.5 h at room temperature. The pH value of the solution was
adjusted to 9-10 with saturated aqueous sodium bicarbonate and
extracted with 3.times.100 mL of ethyl acetate. The organic layers
were combined and concentrated under vacuum. The residue was
applied onto a silica gel column with CH.sub.2Cl.sub.2/methanol
(10:1) providing 2.1 g (90%) of
4-(benzyloxy)-3-methyl-N-[(3S)-pyrrolidin-3-yl]benzene-1-sulfonamide
(INT-SE2) as an off-white solid.
[0818] Step C: To a 100-mL round-bottom flask was added amine
INT-SE2 (2.41 g, 6.96 mmol, 1 equiv), CH.sub.3CN (20 mL), potassium
carbonate (2.5 g, 18.09 mmol, 3 equiv), and
1-[2-(2-azidoethoxy)ethoxy]sulfonyl-4-methylbenzene (1.9 g, 6.66
mmol, 1.1 equiv). The resulting slurry was stirred overnight at
60.degree. C. The resulting solution was diluted with water and
extracted with 3.times.100 mL of ethyl acetate. The organic layers
were combined, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:100-100:1)
providing 2.4 g (75%) of
N-[(3S)-1-[2-(2-azidoethoxy)ethyl]pyrrolidin-3-yl]-4-(benzyloxy)-3-methyl-
benzene-1-sulfonamide (INT-SE3) as a yellow oil.
[0819] Step D: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of hydrogen was added azide INT-SE3 (1.0
g, 2.18 mmol, 1 equiv), ethyl acetate (5 mL), methanol (5 mL), and
10% palladium on carbon (500 mg). The resulting slurry was stirred
for 2 h at room temperature. The solids were filtered out. The
residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (8:1) providing 420 mg (56%) of
N-[(3S)-1-[2-(2-aminoethoxy)ethyl]pyrrolidin-3-yl]-4-hydroxy-3-m-
ethylbenzene-1-sulfonamide (INT-SE4) as an off-white solid.
[0820] Step E: To a 25-mL round-bottom flask was added amine
INT-SE4 (400 mg, 1.16 mmol, 1 equiv), methanol (5 mL),
triethylamine (24 mg, 0.24 mmol, 0.20 equiv), and ethyl 2,2,2-tri
fluoroacetate (653 mg, 4.60 mmol, 4 equiv). The resulting solution
was stirred for 1.5 h at room temperature. The resulting slurry was
diluted with water and extracted with 3.times.100 mL of ethyl
acetate. The organic layers were combined, dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The
residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (10:1) providing 400 mg (78%) of
2,2,2-trifluoro-N-(2-[2-[(3S)-3-[(4-hydroxy-3-methylbenzene)sulfonamido]p-
yrrolidin-1-yl]ethoxy]ethyl)acetamide (INT-SE5) as a yellow
oil.
[0821] The R-enantiomer of INT-SE5 was generated from the analogous
procedure beginning with tert-butyl
(3R)-3-aminopyrrolidine-1-carboxylate. This provided INT-RES:
##STR00131##
Scheme for Hydroxyethylpyrrolidine Dimer Product Synthesis:
Example 52:
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethy-
l)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimtethylamino)-2,3--
dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]eth-
oxy]ethyl)carbamoyl]amino]butyl)urea
##STR00132##
[0823] Step A: To a 7-mL round-bottom flask was added aminoindanol
INT-18C (92.4 mg, 0.38 mmol, 1.1 equiv), tetrahydrofuran (I mL),
phenol INT-SE5 (150 mg, 0.34 mmol, 1 equiv), and PPh3 (178.9 mg,
0.68 mmol, 2 equiv). Heating at 40.degree. C. in an oil bath DIAD
(103.4 mg, 0.51 mmol, 1.5 equiv) was added dropwise with stirring
over 15 min. The resulting slurry was stirred for 1 h at
40-45.degree. C. in an oil bath. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/methanol (10:1) providing
200 mg (88%) of
N-(2-[2-[(3S)-3-[[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-
-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]eth-
yl)-2,2,2-trifluoroacetamide (INT-SE6) as a yellow oil.
[0824] Step B: To a 25-mL round-bottom flask was added INT-SE6 (200
mg, 0.30 mmol, 1 equiv), methanol (5 mL), and sodium hydroxide
(3M.sub.(aq), 1 mL). The resulting solution was stirred for 1.5 h
at 60.degree. C. The resulting solution was cooled to room
temperature and extracted with 3.times.50 mL of ethyl acetate. The
organic layers were combined, dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (8:1)
providing 100 mg (58%) of
N-[(3S)-1-[2-(2-aminoethoxy)ethyl]pyrrolidin-3-yl]-4-[[(1S,2S)-4,6-dichlo-
ro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene-1-sulf-
onamide (INT-SE7) as a yellow oil.
[0825] Step C: To a 25-mL round-bottom flask was added amine
INT-SE7 (100 mg, 0.17 mmol, 1 equiv), N,N-dimethylformamide (1 mL),
and 1,4-diisocyanatobutane (0.0945 mL, 0.45 equiv). The resulting
solution was stirred for 1.5 h at 60.degree. C. The crude product
was purified by preparative HPLC with the following conditions:
Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5 um; mobile
phase, water (0.05% TEA) and CH.sub.3CN (24.0% CH.sub.3CN up to
40.0% in 8 min); Detector, UV 220 nm.
Example 52:
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,-
2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methyl-
benzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)
carbamoyl]amino]butyl)urea
[0826] Steps A-C provided 42.1 mg (19%) of the title compound as a
colorless viscous oil. MS (m/z): 1283.7 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.88-7.82 (m, 2H), 7.79 (s, 2H),
7.56-7.48 (m, 4H), 7.06 (d, J=1.3 Hz, 2H), 6.55 (d, J=6.7 Hz, 2H),
4.48 (q, J=8.2 Hz, 2H), 4.09-3.59 (m, 13H), 3.54 (t, J=5.3 Hz, 4H),
3.50-3.35 (m, 8H), 3.33 (s, 3H), 3.13 (m, 6H), 3.04 (s, 12H), 2.32
(m, 8H), 2.09-1.88 (m, 2H), 1.50 (s, 4H).
Example 53:
3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]ethy-
l)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-d-
ihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]etho-
xy]ethyl]carbamoyl]amino]butyl)urea
##STR00133##
[0828] Beginning with R-enantiomer INT-RES and INT-I8C, Steps A-C
provided 19.4 mg (21%) of the title compound as a white solid. MS
(m/z): 1283.6 [M+H].sup.+. .sup.1H NMR (DMSO-d6, 300 MHz) .delta.
7.68-7.45 (m, 10H), 7.12 (d, J=1.8 Hz, 2H), 5.98-5.81 (m, 4H), 5.73
(t, J=5.6 Hz, 2H), 3.54 (s, 2H), 3.48-3.21 (m, 10H), 3.16-2.99 (m,
6H), 2.94-2.74 (m, 6H), 2.56 (s, 2H), 2.39 (s, 5H), 2.16 (d, J=6.0
Hz, 19H), 1.80 (s, 2H), 1.40 (d, J=7.8 Hz, 2H), 1.29-1.15 (m,
8H).
Scheme for Cyano-Containing Hydroxyethylpyrrolidine Dimer Product
Synthesis:
Example 54:
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamin-
o)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-
-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea
##STR00134##
[0830] Step A: To a 8-mL round-bottom flask was added aminoindanol
INT-18B (181.84 mg, 0.63 mmol, 1.1 equiv), tetrahydrofuran (I mL),
phenol INT-SE5 (250 mg, 0.57 mmol, 1 equiv), and PPh3 (298.1 mg,
1.14 mmol, 2 equiv). Heating at 40.degree. C. in an oil bath DIAD
(172.4 mg, 0.85 mmol, 1.5 equiv) was added dropwise with stirring
over 15 min. The resulting solution was stirred for 1 h at
40-45.degree. C. in an oil bath. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/methanol (10:1) providing
200 mg (49%) of
N-(2-[2-[(3S)-3-[(4-[[(1S,1S)-4-bromo-6-chloro-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]-
ethyl)-2,2,2-trifluoroacetamide (INT-SE8) as an off-white
solid.
[0831] Step B: To a 25-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added bromoaminoindanol
INT-SE8 (200 mg, 0.28 mmol, 1 equiv), NMP (2 mL), Zn(CN).sub.2
(19.72 mg, 0.60 equiv), and Pd(PPh.sub.3).sub.4 (32.5 mg, 0.03
mmol, 0.10 equiv). The resulting solution was stirred overnight at
95.degree. C. The resulting slurry was cooled to room temperature,
diluted with water, and extracted with 3.times.50 mL of ethyl
acetate. The organic layers were combined, dried over anhydrous
sodium sulfate, filtered, and concentrated. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (25:1)
providing 150 mg (81%) of
N-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]pyrrolidin-1-yl]ethoxy]ethyl)-2,2,2-trifluoroacetamide
(INT-SE9) as a yellow oil.
[0832] Step C: To a 50-mL round-bottom flask was added INT-SE9 (150
mg, 0.23 mmol, 1 equiv), methanol (5 mL), and sodium hydroxide (3M
aqueous, 1 mL). The resulting solution was stirred for 1.5 h at
room temperature. The resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with ethyl
acetate (100%) providing 60 mg (47%) of
N-[(3S)-1-[2-(2-aminoethoxy)ethyl]pyrrolidin-3-yl]-4-[[(1S,2S)-6-chloro-4-
-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene-1--
sulfonamide (INT-SE10) as a yellow oil.
[0833] Step D: To a 25-mL round-bottom flask was added amine
INT-SE10 (60 mg, 0.11 mmol, 1 equiv), N,N-dimethylformamide (1 mL),
and 1,4-diisocyanatobutane (0.00672 mL). The resulting solution was
stirred for 1 h at 60.degree. C. The crude product was purified by
preparative HPLC with the following conditions: Column, XBridge
Preparative C18 OBD Column, 19*150 mm, 5 um; mobile phase, water
(0.05% NH.sub.4OH) and CH.sub.3CN (40.0% CH.sub.3CN up to 77.0% in
7 min); Detector, UV 254/220 nm.
Example 54:
3-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamin-
o)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-
-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea
[0834] Steps A-D provided 9.8 mg (7%) of the title compound as a
white solid. MS (m/z): 1265.4 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.79-7.74 (m, 4H), 7.72-7.68 (m,
2H), 7.48 (d, J=8.7 Hz, 2H), 7.41 (d, J=1.2 Hz, 2H), 6.00 (d, J=6.1
Hz, 2H), 4.60 (s, 5H), 3.76 (s, 2H), 3.66-3.49 (m, 6H), 3.49-3.39
(m, 5H), 3.37 (d, J=8.0 Hz, 1H), 3.32-3.21 (m, 4H), 3.15-3.03 (m,
6H), 2.83-2.74 (m, 2H), 2.63 (t, J=16.1 Hz, 8H), 2.41 (m, 2H), 2.35
(s, 12H), 2.26 (s, 6H), 2.11-1.96 (m, 21-), 1.58 (m, 2H), 1.52-1.44
(m, 4H).
Example 55:
3-(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]pyrrolidin-1-yl]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(3R)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(di
methylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamitio]-
pyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea
##STR00135##
[0836] Beginning with R-enantiomer INT-RES and INT-I8B, Steps A-D
provided 30.3 mg (27%) of the title compound as a white solid. MS
(m/z): 1263[M+H].sup.+. .sup.1H NMR (DMSO-d6, 400 MHz) .delta. 8.00
(d, J=1.9 Hz, 2H), 7.69-7.58 (m, 6H), 7.57-7.47 (m, 4H), 5.92 (dd,
J=29.5, 5.7 Hz, 4H), 5.76 (t, J=5.6 Hz, 2H), 3.58-3.45 (m, 5H),
3.38 (t, J=6.2 Hz, 4H), 3.31-3.18 (m, 8H), 3.12-2.87 (m, 13H), 2.59
(s, 2H), 2.42 (s, 5H), 2.18 (d, J=10.9 Hz, 18H), 1.83 (t, J=10.5
Hz, 2H), 1.43 (s, 2H), 1.32-1.19 (m, 5H).
Scheme for Synthesis of Triazole-Type Linker Compounds
##STR00136## ##STR00137##
[0838] Step A: To a 250-mL round-bottom flask was added
2-[2-(2-aminoethoxy)ethoxy]ethan-1-ol (5.3 g, 35.53 mmol, 2 equiv),
CH.sub.2Cl.sub.2 (50 mL), triethylamine (5.37 g, 53.07 mmol, 3
equiv), and INT-L3 (R.sup.1.dbd.H, 5 g, 17.7 mmol, 1 equiv). The
resulting solution was stirred overnight. The reaction was then
quenched by the addition of 50 mL of water and extracted with
3.times.50 mL of ethyl acetate. The organic layers were combined,
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (0-55%) providing 6.4 g (92%) of
2-[2-(2-[[4-(benzyloxy)benzene]sulfonamido]ethoxy)ethoxy]ethan-1-ol
(INT-T1) as a white solid.
[0839] Step B: To a 250-mL round-bottom flask was added INT-T1 (6.4
g, 16.2 mmol, 1 equiv), CH.sub.2Cl.sub.2 (50 mL), triethylamine
(3.3 g, 32.6 mmol, 2 equiv), and p-TsCl (4.6 g, 24.13 mmol, 1.5
equiv). The resulting solution was stirred overnight. The reaction
was quenched by the addition of 50 mL of water and extracted with
3.times.50 mL of CH.sub.2Cl.sub.2. The organic layers were
combined, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with petroleum ether/ethyl acetate (0-50%) providing 8.3
g (93%) of
2-[2-(2-[[4-(benzyloxy)benzene]sulfonamido]ethoxy)ethoxy]ethyl
4-methylbenzene-1-sulfonate (INT-T2) as a white solid.
[0840] Step C: To a 250-mL round-bottom flask was added INT-T2 (8.3
g, 15.1 mmol, 1 equiv), N,N-dimethylformamide (20 mL), and
NaN.sub.3 (1.47 g, 22.6 mmol, 1.5 equiv). The resulting slurry was
stirred for 5 h at 90.degree. C. The reaction was then quenched by
the addition of 50 mL of water and extracted with 3.times.50 mL of
ethyl acetate. The organic layers were combined, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was applied onto a silica gel column with petroleum
ether/ethyl acetate (0-50%) providing 6 g (94%) of
2-[12-(2-azidoethoxy)ethoxy]-S-[4-(benzyloxy)phenyl]ethane-1-sulfonamido
(INT-T3) as a white solid.
[0841] Step D: To a 100-mL round-bottom flask was added INT-T3 (6.6
g, 15.70 mmol, 1 equiv) and CH.sub.2Cl.sub.2 (20 mL), followed by
the addition of BBr.sub.3 (11.8 g, 47.1 mmol 3 equiv) dropwise with
stirring at -60.degree. C. The resulting solution was stirred for
30 min at -60.degree. C. The reaction was then carefully quenched
by the addition of 50 mL of watertice. The resulting solution was
extracted with 3.times.50 mL of ethyl acetate. The organic layers
were combined, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with petroleum ether/ethyl acetate (0-50%) providing 5 g
(crude) of
2-[2-(2-azidoethoxy)ethoxy]-S-(4-hydroxyphenyl)ethane-1-sulfonamido
(INT-T4) as a yellow oil.
[0842] Step E: To a 7-mL round-bottom flask was added INT-T4 (100
mg, 0.30 mmol, 1 equiv), NA-dimethylformamide (2 mL),
2,2,2-trifluoro-N-(prop-2-yn-1-yl)acetamide (55 mg, 0.36 mmol, 1.2
equiv), sodium ascorbate (11.97 mg), and CuSO.sub.4.5H.sub.2O (7.54
mg). The resulting slurry was stirred for 3 h at room temperature.
The resulting solution was diluted with 20 mL of ethyl acetate and
quenched by the addition of 20 mL of water. The resulting solution
was extracted with 3.times.20 mL of ethyl acetate. The organic
layers were combined, washed with 3.times.50 mL of brine, dried
over anhydrous sodium sulfate, filtered, and concentrated under
vacuum. The residue was applied onto a silica gel column with
petroleum ether/ethyl acetate (100%) providing 80 mg (55%) of
2,2,2-trifluoro-N-([1-[2-(2-[2-[(4-hydroxybenzene)sulfonamido]ethoxy]etho-
xy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)acetamide (INT-T5) as a
colorless oil.
[0843] Step F: To a 25-mL round-bottom flask was added aminoindanol
INT-18E (693 mg, 1.73 mmol, 1 equiv), phenol INT-T5 (1.0 g, 2.08
mmol, 1.2 equiv), PPh3 (682 mg, 2.60 mmol, 1.51 equiv), and THE (4
mL). Heating at 40.degree. C. in an oil bath DIAD (526 mg, 2.60
mmol, 1.51 equiv) was added in portions over 20 min. The resulting
solution was stirred for 1 h at 40.degree. C. in an oil bath. The
resulting slurry was concentrated under vacuum. The residue was
applied onto a silica gel column with petroleum ether/ethyl acetate
(100%) providing 2.0 g (crude) of tert-butyl
N-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-([2-[2-(2-[4-[(trifluoroacetamido)
methyl]-1H-1,2,3-triazol-1-yl]ethoxy)ethoxy]ethyl]sulfamoyl)phenoxy]-2,3--
dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate (INT-T6) as a yellow
oil.
[0844] Step G: To a 100-mL round-bottom flask was added INT-T6 (2.0
g, 2.31 mmol, 1 equiv), methanol (25 mL), and sodium hydroxide (3M
(aq), 3 mL). The resulting slurry was stirred for 2 h at 60.degree.
C. in an oil bath. The resulting mixture was concentrated under
vacuum. The resulting solution was extracted with 3.times.100 ml,
of ethyl acetate. The organic layers were combined, washed with
1.times.100 mL of brine, dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (10:1)
providing 1.06 g (60%) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-(4-[[2-(2-[2-[4-(aminomethyl)-1H-1,2,3-triazol-1-yl]-
ethoxy]ethoxy)ethyl]sulfamoyl]phenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-
-yl]piperidin-3-yl]carbamate as an off-white solid.
Scheme for the Synthesis of Triazole-Type Dimer Products:
Example 56:
1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[([(-
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-d-
ihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-
-triazol-4-yl]methyl)carbamoyl]amino]butyl)urea
##STR00138##
[0846] Step A: To a 7-mL round-bottom flask was added amine INT-T7
(400 mg, 0.52 mmol, 1 equiv), DMF (3 mL), and
1,4-diisocyanatobutane (29 mg, 0.21 mmol, 0.4 equiv). The resulting
solution was stirred for 2 h at 60.degree. C. in an oil bath. The
resulting solution was diluted with 50 mL of water. The resulting
solution was extracted with 3.times.50 mL of ethyl acetate. The
organic layers were combined, washed with 3.times.50 mL of brine,
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (10:1) providing 320 mg (37%) of
tert-butyl
N-[(3R)-1-[(1S,2S)-1-(4-[[2-(2-[2-[4-([[(4-[[(1-([2-(2-[2-([4-[[(1S,2S)-2-
-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3--
triazol-4-yl]methyl)carbamoyl]amino]
butyl)carbamoyl]amino]methyl)-1H-1,2,3-triazol-1-yl]ethoxy]ethoxy)ethyl]s-
ulfamoyl]phenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]ca-
rbamate (INT-T8) as a brown solid.
[0847] Step B: To a 25-mL round-bottom flask was added INT-T8 (320
mg, 0.19 mmol, 1 equiv) and 20% TFA in CH.sub.2Cl.sub.2 (10 mL).
The resulting solution was stirred for 1 h at room temperature. The
resulting solution was diluted with 20 mL of CH.sub.2Cl.sub.2. The
pH value of the solution was adjusted to 9-10 with saturated sodium
bicarbonate and extracted with 3.times.100 mL of ethyl acetate. The
organic layers were combined, washed with 1.times.100 mL of brine,
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The crude product was purified by preparative HPLC
with the following conditions: Column, XBridge C18 OBD Preparative
Column, 19*250 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (28.0% CH.sub.3CN up to 52.0% in 8 min); Detector, UV
254 nm.
Example 56:
1-([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-3-(4-[[(1--
[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dih-
ydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-t-
riazol-4-yl]methyl)carbamoyl]amino]butyl)urea
[0848] Steps A and B provided 137.6 mg (49%) of the title compound
as an off-white solid. MS (m/z): 1477 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.90-7.79 (m, 6H), 7.44 (d, J=1.7
Hz, 2H), 7.31-7.21 (m, 4H), 7.11-7.04 (m, 2H), 6.31 (d, J=6.0 Hz,
2H), 4.51 (t, J=4.9 Hz, 4H), 4.31 (s, 4H), 4.03 (d, 6.8 Hz, 2H),
3.83 (t, J=5.0 Hz, 4H), 3.59-3.36 (m, 18H), 3.22-2.98 (m, 12H),
2.87 (dt, J=20.0, 10.8 Hz, 4H), 2.00 (s, 2H), 1.83 (s, 1H), 1.63
(d, J=10.2 Hz, 2H), 1.43 (s, 4H).
Scheme for Synthesis of Protected Galactaric Acid
##STR00139##
[0850] Step A: To a 1-L round-bottom flask was added
(2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexanedioic acid (galactaric
acid, 20 g, 95.2 mmol, 1 equiv), methanol (386 mL), and sulfuric
acid (5.08 mL, 1 equiv). The resulting solution was stirred for 96
h at 70.degree. C. The resulting solution was allowed to react,
with stirring, for an additional 36 h at room temperature. The
solids were collected by filtration. The resulting mixture was
concentrated under vacuum. This resulted in 20.3 g (90%) of
1,6-dimethyl (2R,3S,4R,5S)-2,3,4,5-tetrahydroxyhexanedioate as a
white solid.
[0851] Step B: To a 250-mL round-bottom flask was added
1,6-dimethyl (2R,3S,4R,5S)-2,3,4,5-tetrahydroxy hexanedioate (5.0
g, 21 mmol, 1 equiv), 2,2-dimethoxypropane (26 mL, 0.01 equiv),
acetone (50 mL), and
[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl]methanesulfonic
acid (camphorsulfonic acid, 1.105 g, 4.76 mmol, 0.2 equiv). The
mixture was stirred for 1 h at 65.degree. C. The reaction was then
quenched by the addition of K.sub.2CO.sub.3 (3M.sub.(aq)) and
concentrated under vacuum. The resulting slurry was extracted with
3.times.100 mL of CH.sub.2Cl.sub.2. The organic layers were
combined, washed with 1.times.100 mL of brine, dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The crude
product was purified by re-crystallization from methanol. The
solids were collected by filtration providing 2.9 g (43%) of methyl
(4R,
5S)-5-[(4R,5S)-5-(methoxycarbonyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-di-
methyl-1,3-dioxolane-4-carboxylate as a white solid.
[0852] Step C: To a 100-mL round-bottom flask was added methyl
(4R,5S)-5-[(4R,5S)-5-(methoxycarbonyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,-
2-dimethyl-1,3-dioxolane-4-carboxylate (2.5 g, 7.85 mmol, 1 equiv),
water (30 mg), and sodium hydroxide (785 mg, 19.63 mmol, 5 equiv).
The resulting solution was stirred overnight at 60.degree. C. The
reaction was then quenched by the addition of 50 mL of hydrogen
chloride (1M.sub.(aq) in ice. The resulting solution was extracted
with 3.times.100 ml, of ethyl acetate. The organic layers were
combined, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum providing 2.0 g (80%) of
(4R,4'S,5S,5'R)-2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolane)]-5,5'-dicar-
boxylic acid as a white solid.
Scheme for Synthesis of Triazole-Type Dimer Products with
Galactaric Acid Core:
Example 57:
(2R,3S,4R,5S)--N.sup.1,N.sup.6-Bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-am-
inopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulf-
onamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahy-
droxyhexanediamide
##STR00140##
[0854] Step A: To a 25-mL round-bottom flask was added amine INT-T7
(300 mg, 0.39 mmol, 2.2 equiv),
(4R,5S)-5-[(4R,5S)-5-carboxy-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-
-1,3-dioxolane-4-carboxylic acid (51.54 mg, 0.18 mmol, 1 equiv),
DMF (8 mL), diisopropylethylamine (115 mg, 0.89 mmol, 5 equiv), and
HATU (202.92 mg, 0.53 mmol, 3 equiv). The resulting solution was
stirred for 2 h at room temperature. The reaction was quenched by
the addition of 20 mL of water and the resulting solution was
extracted with 3.times.50 mL of ethyl acetate. The organic layers
were combined, washed with 3.times.100 mL of brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (10:1) providing 340 mg (crude) of INT-T9
as a white solid.
[0855] Step B: To a 25-mL round-bottom flask was added INT-T9 (450
mg, 0.25 mmol, 1 equiv) and TFA/H.sub.2O (7/0.35 mL). The resulting
solution was stirred for 3 h at room temperature. The resulting
mixture was concentrated under vacuum. The crude product was
purified by preparative HPLC with the following conditions: Column,
XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase,
water (0.05% TFA) and CH.sub.3CN (28.0% CH.sub.3CN up to 45.0% in
12 min); Detector, UV 254 nm.
Example 57:
(2R,3S,4R,5S)--N.sup.1,N.sup.6-Bis([1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-am-
inopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulf-
onamido]ethoxy]ethoxy)ethyl]-1H-1,2,3-triazol-4-yl]methyl)-2,3,4,5-tetrahy-
droxyhexanediamide
[0856] Steps A and B provided 72.3 mg (19%) of the title compound
as a white solid. MS (m/z): 1511 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.94-7.79 (m, 6H), 7.42 (s, 2H),
7.26 (d, J=8.6 Hz, 4H), 7.08 (s, 2H), 6.21 (t, J=6.3 Hz, 2H),
4.56-4.44 (m, 8H), 4.39 (d, J=1.1 Hz, 2H), 4.00 (s, 2H), 3.93-3.78
(m, 6H), 3.59-3.27 (m, 17H), 3.03 (t, J=5.4 Hz, 10H), 2.85-2.71 (m,
4H), 1.92 (d, J=18.5 Hz, 3H), 1.76 (s, 2H), 1.59 (d J=9.8 Hz,
2H).
Scheme for Synthesis of Aliphatic Triazole-Type Intermediates:
##STR00141## ##STR00142##
[0858] Step A: To a 250-mL round-bottom flask, was added
aminoindanol INT-18F (2.0 g, 5 mmol, 1 equiv), 4-bromophenol (1.3
g, 7.5 mmol, 1.5 equiv), PPh3 (2.62 g, 10 mmol, 2 equiv), and
tetrahydrofuran (100 mL). Heating at 40.degree. C. in an oil bath
DIAD (2.02 g, 10 mmol, 1.5 equiv) was added dropwise with stirring
over 20 min. The resulting solution was stirred for 3 h at
40.degree. C. The resulting mixture was concentrated under vacuum.
The residue was applied onto a silica gel column with petroleum
ether/ethyl acetate (10:1-8:1) providing 2.5 g (90%) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-(4-bromophenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-
-yl]piperidin-3-yl]carbamate (INT-T10) as a light yellow solid.
[0859] Step B: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added bromide INT-T10 (2.5
g, 4.14 mmol, 1 equiv), 1,4-dioxane (100 mL), benzyl mercaptan
(1.12 g, 9 mmol, 2 equiv), Xantphos (260 mg, 0.45 mmol, 0.10
equiv), and diisopropylethylamine (1.46 g, 11.3 mmol, 2.73 equiv).
This was followed by the addition of Pd.sub.2(dba).sub.3.CHCl.sub.3
(240 mg, 0.23 mmol, 0.05 equiv) in portions at room temperature.
The resulting solution was stirred for 14 h at 100.degree. C. The
resulting mixture was concentrated under vacuum and the residue was
dissolved in 150 mL of ethyl acetate. The resulting mixture was
washed with 3.times.80 mL of water and 1.times.80 mL of saturated
aqueous sodium chloride. The organic layers were combined, dried
over anhydrous sodium sulfate, filtered, and concentrated under
vacuum. The residue was applied onto a silica gel column with
petroleum ether/ethyl acetate (10:1-3:1) providing 2.5 g (93%) of
tert-butyl
N-[(3R)-1-[(1S,2S)-1-[4-(benzylsulfanyl)phenoxy]-4,6-dichloro-2,3-dihydro-
-1H-inden-2-yl]piperidin-3-yl]carbamate (INT-T11) as a brown
solid.
[0860] Step C: To a 100-mL round-bottom flask was added thioether
INT-T11 (2.5 g, 4.17 mmol, 1 equiv), acetic acid (24 mL), and water
(8 mL). This was followed by the addition of NCS (1.93 g, 14.45
mmol, 3.5 equiv) in portions at 0.degree. C. The resulting solution
was stirred for 4 h at room temperature. The resulting slurry was
diluted with 30 mL of water. The pH value of the solution adjusted
to 8 with saturated aqueous sodium bicarbonate and extracted with
3.times.80 mL of ethyl acetate. The organic layers were combined
and washed with 1.times.100 mL of water and 1.times.100 mL of
brine. The mixture was dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. This resulted in 2.0 g
(83%) of crude tert-butyl
N-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[14-(chlorosulfonyl)phenoxy]-2,3-dihydr-
o-1H-inden-2-yl]piperidin-3-yl]carbamate as a brown solid.
[0861] Step D: To a 250-mL round-bottom flask was added sulfonyl
chloride INT-T12 (2.0 g, 3.47 mmol, 1 equiv), CH.sub.2Cl.sub.2 (50
mL), triethylamine (1.4 mL, 3 equiv), and 4-aminobutan-1-ol (0.64
mL, 2 equiv). The resulting solution was stirred overnight at room
temperature. The resulting slurry was diluted with water and
extracted with 3.times.150 mL of CH.sub.2Cl.sub.2. The organic
layers were combined and washed with 1.times.100 mL of water and
1.times.100 mL of brine. The mixture was dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The
residue was applied onto a silica gel column with petroleum
ether/ethyl acetate (1:2) providing 1.47 g (67%) of tart-butyl
N-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-[(4-hydroxybutyl)sulfamoyl]phenoxy]--
2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate (INT-T13) as a
yellow oil.
[0862] Step E: To a 250-mL round-bottom flask was added alcohol
INT-T13 (1.47 g, 2.34 mmol, 1 equiv), CH.sub.2Cl.sub.2 (30 mL),
triethylamine (1.3 mL, 4 equiv), and p-toluenesulfonyl chloride
(1.34 g, 7.03 mmol, 3 equiv). The resulting solution was stirred
overnight at room temperature. The resulting slurry was diluted
with water and extracted with 3.times.150 mL of CH.sub.2Cl.sub.2.
The organic layers were combined and washed with 1.times.100 mL of
water and 1.times.100 mL of brine. The mixture was dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was applied onto a silica gel column with petroleum
ether/ethyl acetate (1:1) providing 1.46 g (80%) of tert-butyl
N-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-[(4-[[(4-methylbenzene)sulfonyl]oxy]-
butyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamat-
e (INT-T14) as a yellow solid.
[0863] Step F: To a 100-mL round-bottom flask was added tosylate
INT-T14 (1.46 g, 1.87 mmol, 1 equiv), DMF (10 mL), and sodium azide
(182 mg, 2.80 mmol, 1.5 equiv). The resulting solution was stirred
overnight at 90.degree. C. The resulting slurry was diluted with
water and extracted with 3.times.150 mL of ethyl acetate. The
organic layers were combined and washed with 1.times.100 mL of
water and 1.times.100 mL of brine. The mixture was dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was applied onto a silica gel column with petroleum
ether/ethyl acetate (1:1) providing 1.06 g (87%) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-[4-[(4-azidobutyl)sulfamoyl]phenoxy]-4,6-dichloro-2,-
3-dihydro-1H-inden-2-yl]piperidin-3-yl](carbamate (INT-T15) as a
yellow oil.
[0864] Step G: To a 50-mL round-bottom flask was azide INT-T15 (500
mg, 0.76 mmol, 1 equiv),
2,2,2-trifluoro-N-(prop-2-yn-1-yl)acetamide (280 mg, 1.85 mmol, 2.4
equiv), 2-methylpropan-2-ol (12 mL), water (5 mL), sodium ascorbate
(30 mg, 0.15 mmol, 0.2 equiv), and CuSO.sub.4.5H.sub.2O (20 mg,
0.08 mmol, 0.1 equiv). The resulting solution was stirred overnight
at room temperature. The resulting mixture was concentrated under
vacuum. The resulting solution was diluted with water and extracted
with 3.times.100 mL of CH.sub.2Cl.sub.2. The organic layers were
combined and washed with 1.times.100 mL of water and 1.times.100 mL
of brine. The mixture was dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was applied
onto a silica gel column with petroleum ether/ethyl acetate (1:1)
providing 480 mg (78%) of tert-butyl
N-[(3R)-[[(1S,2S)-4,6-dichloro-1-[4-[(4-[4-1(trifluoroacetamido)methyl]-1-
H-1,2,3-triazol-1-yl]butyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]pi-
peridin-3-yl]carbamate (INT-T16) as a white solid.
[0865] Step H: To a 100-mL round-bottom flask was added INT-T16
(432 mg, 0.54 mmol, 1 equiv), methanol (20 mL), and sodium
hydroxide (3M.sub.(aq), 0.4 mL). The resulting solution was stirred
for 1 h at 60.degree. C. The resulting solution was extracted with
3.times.100 mL of CH.sub.2Cl.sub.2. The organic layers were
combined and washed with 1.times.50 mL of water and 1.times.50 mL
of brine. The mixture was dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (10:1)
providing 356 mg (94%) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-[4-([4-[4-(aminomethyl)-1H-1,2,3-triazol-1-yl]butyl]-
sulfamoyl)phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]c-
arbamate (INT-T17) as a white solid.
The 6-carbon intermediate was generated from the analogous
procedure beginning with 6-aminohexan-1-ol. This provided
INT-T18:
##STR00143##
General Scheme for Aliphatic Triazole-Type Dimer Products:
Example 58:
3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)m-
ethyl]-1-[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dich-
loro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-tri-
azol-4-yl)methyl]carbamoyl]amino)butyl]urea
##STR00144##
[0867] Step A: To a 50-mL round-bottom flask was added amine
INT-T17 (394 mg, 0.56 mmol, 1 equiv), DMF (4.7 mL), and
1,4-diisocyanatobutane (39 mg, 0.28 mmol, 0.5 equiv). The resulting
solution was stirred for 1 h at 60.degree. C. The resulting mixture
was concentrated under vacuum. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/methanol (10:1) providing
455 mg (crude) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-[4-[(4-[4-[([[4-([[(1-[4-[(4-[[(1S,2S)-2-[(3R)-
3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3-dihydro--
1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)methyl]-
carbamoyl]amino)butyl]carbamoyl]
amino)methyl]-1H-1,2,3-triazol-1-yl]butyl)sulfamoyl]phenoxy]-4,6-dichloro-
-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate (INT-T19) as a
yellow oil.
[0868] Step B: To a 50-mL round-bottom flask was added dimer
INT-T19 (455 mg, 0.29 mmol, 1 equiv), CH.sub.2Cl.sub.2 (10 mL), and
trifluoroacetic acid (1.5 mL). The resulting solution was stirred
for 1 h at room temperature. The pH value of the solution was
adjusted to 8 with saturated aqueous potassium carbonate and
extracted with 3.times.150 mL of CH.sub.2Cl.sub.2. The organic
layers were combined and washed with 1.times.100 mL of water and
1.times.100 mL of brine. The mixture was dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The crude
product was purified by preparative-HPLC with the following
conditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm,
5 um; mobile phase, water (10 mmol/L NH.sub.4HCO.sub.3) and
CH.sub.3CN (50.0% CH.sub.3CN up to 65.0% in 8 min); Detector, UV
254 nm.
Example 58:
3-[(1-[4-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl)m-
ethyl]-1-[4-([[1-([4-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dich-
loro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-tri-
azol-4-yl)methyl]carbamoyl]amino)butyl]urea
[0869] Steps A and B provided 94 mg (24%) of the title compound as
a white solid. MS (m/z): 1357.05 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.80 (t, J=3.6 Hz, 6H), 7.40-7.15
(m, 8H), 5.95 (d, J=5.2 Hz, 2H), 4.35 (t, 7.0 Hz, 8H), 3.59 (q,
J=6.6 Hz, 2H), 3.22-3.10 (m, 6H), 3.04-2.92 (m, 2H), 2.85 (q, J=6.6
Hz, 8H), 2.72 (d, J=11.2 Hz, 2H), 2.25 (t, J=8.0 Hz, 2H), 2.15 (t,
J=8.4 Hz, 2H), 1.95-1.79 (m, 6H), 1.79-1.70 (m, 2H), 1.60-1.50 (m,
2H), 1.49-1.40 (m, 8H), 1.29 (d, J=18.4 Hz, 3H), 1.18 (q, J=5.4 Hz,
2H).
##STR00145##
Example 59:
3-[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]benzene)sulfonamino]hexyl]-1H-1,2,3-triazol-4-yl)m-
ethyl]-1-[4-([[(1-[6-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dich-
loro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]hexyl]-1H-1,2,3-tri-
azol-4-yl)methyl]carbamoyl]amino)butyl]urea. Beginning with
INT-T18
[0870] Steps A and B provided 221 mg (55%) of the title compound as
a white solid. MS (m/z): 1413 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.96-7.87 (m, 6H), 7.54 (d, J=1.7
Hz, 2H), 7.45-7.37 (m, 4H), 7.08-7.02 (m, 2H), 6.74 (d, 1=6.5 Hz,
2H), 4.52-4.36 (m, 10H), 3.79 (s, 2H), 3.70 (q, J=7.8 Hz, 6H), 3.42
(dd, J=16.3, 8.4 Hz, 2H), 3.30-3.09 (m, 8H), 2.89 (t, J=6.8 Hz,
4H), 2.18 (d, J=15.1 Hz, 4H), 2.08 (d, J=14.3 lit, 2H), 1.88 (p,
J=7.2 Hz, 4H), 1.81-1.68 (m, 2H), 1.57-1.42 (m, 8H), 1.39-1.19 (m,
10H).
General Scheme for Synthesis of Aliphatic Triazole-Type Dimer
Products with Galactaric Acid Core:
##STR00146##
[0871] Step A: To a 25-mL round-bottom flask was added amine
INT-T17 (300 mg, 0.42 mmol, 2.2 equiv),
(4R,5S)-5-[(4R,5S)-5-carboxy-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-
-1,3-dioxolane-4-carboxylic acid (55.9 mg, 0.19 mmol, 1 equiv), DMF
(8 mL), diisopropylethylamine (124.5 mg, 0.96 mmol, 5 equiv), and
HATU (220.02 mg, 0.58 mmol, 3 equiv). The resulting solution was
stirred for 2 h at room temperature. The reaction was quenched by
the addition of 20 mL of water and extracted with 3.times.50 mL of
ethyl acetate. The organic layers were combined, washed with
3.times.100 mL of brine, dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (10:1)
providing 350 mg (crude) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-[4-([4-[4-([[(4S,4aR,8R,8aS)-8-[[(1-[4-[(4-[[(1S,2S)-
-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]butyl]-1H-1,2,3-triazol-4-yl-
)methyl]carbamoyl]-2,2,6,6-tetramethyl-hexahydro-[1,3]dioxino[5,4-d][1,3]d-
ioxin-4-yl]formamido]methyl)-1H-1,2,3-triazol-1-yl]butyl]sulfamoyl)phenoxy-
]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate
(INT-T20) as a white solid.
[0872] Step B: To a 25-mL round-bottom flask was added dimer
INT-T20 (480 mg, 0.29 mmol, 1 equiv), and TFA/H.sub.2O (7/0.35 mL).
The resulting solution was stirred for 3 h at room temperature. The
resulting mixture was concentrated under vacuum. The crude product
was purified by preparative HPLC with the following conditions:
Column, XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobile
phase, water (0.05% TFA) and CH.sub.3CN (28.0% CH.sub.3CN up to
43.0% in 8 min); Detector, UV 254 nm.
Example 60:
(4R,4aS,8S,8aR)--N.sup.4,N.sup.8-Bis([1-(4-[4-((1S,2S)-2-[(3R)-3-aminopip-
eridin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenyl
sulfonamide]butyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetr-
ahydro-[1,3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide
[0873] Steps A and B provided 190.0 mg (48%) of the title compound
as a white solid. MS (m/z): 1389 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.85-7.76 (m, 6H), 7.45-7.38 (m,
2H), 7.27 (d, J=8.7 Hz, 4H), 7.13-7.06 (m, 2H), 6.13 (d, J=5.7 Hz,
2H), 4.61-4.26 (m, 10H), 4.00 (s, 2H), 3.82 (s, 2H), 3.37 (d,
J=18.5 Hz, 4H), 3.03 (dd, J=16.6, 7.7 Hz, 4H), 2.86 (dt, J=7.2, 3.6
Hz, 6H), 2.68 (s, 4H), 1.88 (dd, J=14.5, 7.1 Hz, 8H), 1.72 (s, 2H),
1.57 (d, J=10.9 Hz, 2H), 1.40 (t, J=7.5 Hz, 4H).
Example 61:
(4R,4aS,8S,8aR)--N.sup.4,N.sup.8-Bis([1-(6-[4-((1S,2S)-2-[(3R)-3-amino
piperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yloxy)phenylsulfonami-
do]hexyl)-1H-1,2,3-triazol-4-yl]methyl)-2,2,6,6-tetramethyl-tetrahydro-[1,-
3]dioxino[5,4-d][1,3]dioxine-4,8-dicarboxamide
##STR00147##
[0875] Beginning with INT-T18, Steps A and B provided 130.8 mg
(52%) of the title compound as a white solid. MS (m/z): 1445
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.84 (dd,
J=6.9, 1.9 Hz, 6H), 7.44 (d, J=1.8 Hz, 2H), 7.34-7.26 (m, 4H),
7.15-7.09 (m, 2H), 6.08 (d, J=5.5 Hz, 2H), 4.61-4.39 (m, 5H), 4.34
(t, J=7.0 Hz, 4H), 4.02 (s, 2H), 3.74 (q, J=7.1 Hz, 2H), 3.42-3.35
(m, 2H), 3.31-3.22 (m, 2H), 3.08-2.93 (m, 4H), 2.85 (t, J=6.8 Hz,
4H), 2.76 (s, 2H), 2.70-2.60 (m, 4H), 1.87 (tt, J=14.4, 8.2 Hz,
8H), 1.69 (s, 2H), 1.58 (s, 2H), 1.48-1.20 (m, 13H).
General Scheme for Synthesis of Alkyl Linker Monomers:
##STR00148##
[0877] Step A: To a 250-mL round-bottom flask, was added tert-butyl
N-(8-aminooctyl)carbamate (2 g, 8.18 mmol, 1.1 equiv),
CH.sub.2Cl.sub.2 (30 mL), and triethylamine (3 mL, 3 equiv). This
was followed by the addition of 4-(benzyloxy)benzene-1-sulfonyl
chloride (INT-L3 where R.sup.1.dbd.H, 2.1 g, 7.43 mmol, 1 equiv) in
several portions. The resulting solution was stirred overnight at
room temperature. The resulting solution was diluted with water and
extracted with 3.times.100 mL of CH.sub.2Cl.sub.2. The organic
layers were combined and washed with 2.times.150 mL of brine. The
mixture was dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with petroleum ether/ethyl acetate (2:1) providing 3.3 g
(91%) of tert-butyl
N-(8-[[4-(benzyloxy)benzene]sulfonamido]octyl)carbamate (INT-C1) as
a white solid.
[0878] Step B: To a 250-mL round-bottom flask was added sulfonamide
INT-C1 (2.7 g, 5.50 mmol, 1 equiv), CH.sub.2Cl.sub.2 (30 mL), and
trifluoroacetic acid (4 mL). The resulting solution was stirred for
1 h at room temperature. The pH value of the solution was adjusted
to 9 with saturated aqueous NaHCO.sub.3. The solids were collected
by filtration. This resulted in 1.8 g (84%) of
N-(8-aminooctyl)-4-(benzyloxy)benzene-1-sulfonamide (INT-C2) as a
white solid.
[0879] Step C: To a 250-mL round-bottom flask was added amine
INT-C2 (1.68 g, 4.30 mmol, 1 equiv), methanol (20 mL), and
triethylamine (2.3 mL, 4 equiv). This was followed by the addition
of ethyl trifluoroacetate (1.2 mL, 2 equiv) dropwise with stirring
at room temperature. The resulting solution was stirred for 1 h at
room temperature. The resulting solution was diluted with water and
extracted with 100 mL of ethyl acetate. The organic layers were
combined and washed with 2.times.150 mL of brine. The mixture was
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue was applied onto a silica gel column with
petroleum ether/ethyl acetate (2:1) providing 2 g (96%) of
N-(8-[[4-(benzyloxy)benzene]sulfonamido]octyl)-2,2,2-trifluoroacetamide
(INT-C3) as a white solid.
[0880] Step D: To a 250-mL round-bottom flask was added benzyl
ether INT-C3 (2 g, 4.11 mmol, 1 equiv), methanol (20 mL), and 10%
palladium on carbon (1 g). To the above H.sub.2(g) was introduced
in and the resulting slurry was stirred for 1 h at room
temperature. The solids were filtered out and the resulting mixture
concentrated under vacuum. The residue was applied onto a silica
gel column with petroleum ether/ethyl acetate (1:1) providing 1.6 g
(98%) of
2,2,2-trifluoro-N-[8-[(4-hydroxybenzene)sulfonamido]octyl]acetamide
(INT-C4) as a white solid.
[0881] Step E: To a 50-mL round-bottom flask was added phenol
INT-C4 (1.6 g, 4.04 mmol, 1 equiv), THF (18 mL), and aminoindanol
INT-18F (1.78 g, 4.44 mmol, 1.1 equiv). This was followed by the
addition of PPh3 (1.79 g, 6.82 mmol, 1.7 equiv) in several batches
with heating at 40.degree. C. To this was added DIAD (1.27 mL, 1.6
equiv) dropwise with stirring at 40.degree. C. over 30 min. The
resulting solution was stirred for 1 h at 40.degree. C. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with petroleum ether/ethyl acetate
(2:1) providing 2.8 g (89%) of tert-butyl
(3R)-1-((1S,2S)-4,6-dichloro-1-(4-(N-(8-(2,2,2-trifluoroacetamido)octyl)s-
ulfamoyl)phenoxy)-2,3-dihydro-1H-inden-2-yl)piperidin-3-ylcarbamate
(INT-C5) as a yellow solid.
[0882] Step F: To a 250-mL round-bottom flask was added INT-C5 (2.8
g, 3.59 mmol, 1 equiv), methanol (30 mL), and sodium hydroxide
(3M.sub.(aq), 4 mL). The resulting solution was stirred for 1 h at
60.degree. C. The resulting solution was extracted with 3.times.100
mL of ethyl acetate. The organic layers combined and washed with
2.times.150 mL of brine. The mixture was dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The
residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (5:1) providing 2.2 g (90%) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-[4-[(8-aminooctyl)sulfamoyl]phenoxy]-4,6-dichloro-2,-
3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate (INT-C6) as a
yellow solid.
[0883] The following intermediates are made by applying the above
procedures to the appropriate starting aminoindanols INT-I8 and
sulfonyl chlorides INT-L3:
##STR00149##
General Scheme for Synthesis of Alkyl Linker Dimer Products:
Example 62:
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydr-
o-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[-
(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]ben-
zene) sulfonamido]octyl]carbamoyl)amino]butyl]urea;
bis(trifluoroacetic acid)
##STR00150##
[0885] Step A: To a 0.50-mL round-bottom flask, was added amine
INT-C6 (300 mg, 0.44 mmol, 1 equiv), DMF (3 mL), and
1,4-diisocyanatobutane (25 mL, 0.45 equiv). The resulting solution
was stirred for 1 h at 60.degree. C. The resulting mixture was
concentrated under vacuum. The resulting solution was diluted with
2 mL of CH.sub.2Cl.sub.2. The residue was applied onto a silica gel
column with CH.sub.2Cl.sub.2/methanol (8:1) providing 260 mg (39%)
of text-butyl
N-[(3R)-1-[(1S,2S)-1-[4-([8-[([4-[([8-[4-[[(1S,2S)-2-[(3R)-3-[[(tert-buto-
xy)carbonyl]amino]piperidin-1-yl]-4,6
dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]carbamoy-
l)amino]butyl]carbamoyl)amino]octyl]sulfamoyl)p
henoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbamate
(INT-C10) as a yellow solid.
[0886] Step B: To a 25-mL round-bottom flask was added dimer
INT-C10 (260 mg, 0.17 mmol, 1 equiv), CH.sub.2Cl.sub.2 (8 mL), and
trifluoroacetic acid (1.5 mL). The resulting solution was stirred
for 1 h at room temperature. The resulting mixture was concentrated
under vacuum and diluted with 4 mL of methanol. The solids were
filtered out. The crude product was purified by preparative HPLC
with the following conditions: Column, XBridge C18 OBD Preparative
Column, 19*250 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (18.0% CH.sub.3CN up to 32.0% in 8 min); Detector, UV
254 nm.
Example 62:
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydr-
o-1H-inden-1-yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[-
(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]ben-
zene) sulfonamido]octyl]carbamoyl)amino]butyl]urea;
bis(trifluoroacetic acid)
[0887] Steps A and B provided 136.5 mg (52%) of the title compound
as a white solid. MS (m/z): 1307 [M+H].sup.+ NMR (Methanol-d4, 400
MHz) .delta. 7.92-7.83 (m, 4H), 7.46 (d, J=1.8 Hz, 2H), 7.37-7.28
(m, 4H), 7.17 (dd, J=1.9, 0.8 Hz, 2H), 6.08 (d, J=5.5 Hz, 2H), 3.75
(dt, J=13.6, 7.4 Hz, 2H), 3.39 (dt, J=9.8, 5.0 Hz, 4H), 3.33-3.24
(m, 2H), 3.16-2.93 (m, 13H), 2.88 (t, J=7.0 Hz, 4H), 2.77 (s, 2H),
2.71-2.61 (m, 5H), 1.92 (s, 4H), 1.71 (s, 2H), 1.61 (d, J=8.8 Hz,
3H), 1.48 (dp, J=11.6, 4.4, 3.8 Hz, 12H), 1.33-1.27 (m, 16H).
Example 63:
3-[8-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydr-
o-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-
-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]o-
ctyl]carbamoyl)amino]butyl]urea
##STR00151##
[0889] Beginning with INT-C7 and INT-18F, Steps A and B provided
73.6 mg (24%) of the title compound as a pink solid. MS (m/z):
1335.95 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.87-7.74 (m, 4H), 7.63-7.52 (m, 4H), 7.02 (s, 2H), 6.87 (d, J=6.2
Hz, 2H), 4.61 (d, J=7.6 Hz, 2H), 3.92-3.70 (m, 7H), 3.49 (dd,
J=24.0, 11.8 Hz, 2H), 3.35 (s, 4H), 3.19-3.06 (m, 8H), 2.90 (t,
J=6.8 Hz, 4H), 2.33 (s, 6H), 2.30-2.05 (m, 6H), 1.79 (d, J=12.8 Hz,
2H), 1.55-1.44 (m, 12H), 1.30 (s, 16H).
Example 64:
3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1--
yl]oxy]benzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dichloro-2-(-
dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]octyl]carbamoyl)amino]butyl]urea; bis(trifluoroacetic
acid)
##STR00152##
[0891] Beginning with INT-C8 and INT-18C, Step A provided 185 mg
(48%) of the title compound as a white solid. MS (m/z): 1197
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.95-7.87
(m, 4H), 7.57-7.51 (m, 2H), 7.41-7.32 (m, 4H), 7.11 (d, 1.3 Hz,
2H), 6.44 (d, J=6.8 Hz, 2H), 4.44 (td, J=8.6, 6.9 Hz, 2H), 3.67
(dd, J=16.5, 8.5 Hz, 2H), 3.23 (dd, J=16.4, 8.5 Hz, 2H), 3.14-3.02
(m, 21H), 2.88 (t, J=6.9 Hz, 4H), 1.45 (dt, J=14.2, 5.0 Hz, 13H),
1.27 (s, 15H).
Example 65:
3-[8-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1--
yl]oxy]-3-methylbenzene)sulfonamido]octyl]-1-[4-[([8-[(4-[[(1S,2S)-4,6-dic-
hloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)
sulfonamido]octyl]carbamoyl)amino]butyl]urea
##STR00153##
[0893] Beginning with INT-C9 and INT-IBC, Step A provided 100.3 mg
(14%) of the title compound as a white solid. MS (m/z): 1227.65
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.82 (d,
J=8.8 Hz, 2H), 7.77 (s, 2H), 7.55 (s, 2H), 7.49 (d, J=8.8 Hz, 2H),
7.09 (s, 2H), 6.48 (s, 2H), 4.50-4.40 (m, 2H), 3.75-3.65 (m, 2H),
3.35-3.20 (m, 2H), 3.17-2.96 (m, 20H), 2.92-2.83 (m, 4H), 2.33 (s,
6H), 1.53-1.40 (m, 12H), 1.28 (s, 18H).
General Scheme for Synthesis of Diverse Amine Dimer Products:
##STR00154##
[0895] Step A: To a round-bottom flask was added epoxide INT-17C (1
equiv), the desired amine R.sup.2R.sup.3NH (2 equiv), and
CH.sub.3CN (0.16M). The resulting solution was heated to reflux for
16 h. The resulting mixture was concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:3-1:2) providing the aminoindanol
INT-A1.
[0896] Step B: To a round-bottom flask was added aminoindanol
INT-A1 (1 equiv) and tetrahydrofuran (0.2M), followed by the
addition of phenol linker INT-LGA (1.1 equiv) and heating to
40.degree. C. To this slurry was added PPh3 (2 equiv) and DIAD (1.5
equiv). The resulting solution was stirred for 1.5 h at 40.degree.
C. The resulting mixture was concentrated under vacuum and diluted
with CH.sub.2Cl.sub.2. The residue was applied onto a silica gel
column with ethyl acetate/petroleum ether (1:1) providing indane
monomer INT-A2.
[0897] Step C: To a round-bottom flask was added indane monomer
INT-A2 (1 equiv), methanol (0.1M), and sodium hydroxide
(3M.sub.(aq), 3 equiv). The resulting solution was stirred for 1.5
h at 60.degree. C. The resulting mixture was concentrated under
vacuum and diluted with CH.sub.2Cl.sub.2. The residue was applied
onto a silica gel column with ethyl acetate (100%) providing indane
amine monomer INT-A3.
[0898] Step D: To a round-bottom flask was added INT-A3 (1 equiv),
N,N-dimethylformamide (DMF, 0.12M), and 1,4-di isocyanatobutane
(0.40 equiv). The resulting solution was stirred for 2 h at
60.degree. C. The resulting mixture was concentrated under vacuum
and diluted with of CH.sub.2Cl.sub.2. The residue was applied onto
a silica gel column with chloroform/methanol (10:1) providing
compounds of structure (I). Final products were purified by
preparative HPL with the following conditions: Column, XBridge C18
OBD Preparative Column, 19*250 mm, 5 um; mobile phase, water (0.05%
TFA) and CH.sub.3CN (10.0% CH.sub.3CN up to 70.0% in 8 min);
Detector, UV 254 nm. The final products were generally isolated as
the free base, TFA salts, or hydrochloride salts.
Example 66:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-(-
[[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2R)-2-methylpiperidin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl-
]amino)butyl]urea
##STR00155##
[0900] Following the General Scheme with (2R)-2-methylpiperidine,
Steps A-D provided 112.8 mg (15%) of the title compound as a white
solid. MS (m/z): 1313.5 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400
MHz): .delta. 7.86 (d, J=8.8 Hz, 4H), 7.39 (s, 2H), 7.35 (d, J=8.8
Hz, 4H), 7.13 (s, 2H), 6.12 (d, J=5.6 Hz, 2H), 4.16-4.04 (m, 2H),
3.60-3.46 (m, 16H), 3.40-3.20 (m, 8H), 3.16-3.04 (m, 8H), 2.98-2.90
(m, 2H), 2.87-2.78 (m, 2H), 2.76-2.65 (m, 2H), 2.32 (t, 8.8 Hz,
2H), 1.40-1.26 (m, 12H), 1.16 (d, J=6.0 Hz, 6H).
Example 67:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-
-dihydro-1H-inden-1-yl]oxy])benzene)sulfonamido]ethoxy]ethoxyl)ethyl]-1-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(2S)-2-methylpiperidin-1-yl]-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamo-
yl]amino)butyl]urea
##STR00156##
[0902] Following the General Scheme with (2S)-2-methylpiperidine,
Steps A-D provided 46.8 mg (26%) of the title compound as a white
solid. MS (m/z): 1313.5 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400
MHz) .delta. 7.73 (d, J=6.8 Hz, 4H), 7.34 (q, J=4.8 Hz, 6H), 7.16
(d, J=1.2 Hz, 2H), 5.80 (d, J=4.0 Hz, 2H), 3.95 (q, J=4.8 Hz, 2H),
3.50-3.36 (m, 16H), 3.20-3.15 (m, 4H), 3.05-2.95 (m, 10H),
2.90-2.80 (m, 2H), 2.52 (d, J=7.4 Hz, 4H), 2.10 (t, J=3.8 Hz, 2H),
1.62 (d, J=9.6 Hz, 4H), 1.54-1.43 (m, 4H), 1.39-1.32 (m, 4H),
1.31-1.20 (m, 4H), 1.18 (s, 2H), 1.00 (q, J=6.4 Hz, 6H).
Example 68:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[[2.2.1]heptan-2-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.1]heptan-2-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]ca-
rbamoyl]amino)butyl]urea
##STR00157##
[0904] Following the General Scheme with
2-azabicyclo[2.2.1]heptane, Steps A-D provided 76.6 mg (14%) of the
title compound as a white solid. MS (m/z): 1309.5 [M+H].sup.+.
.sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.90 (d, J=8.0 Hz, 2H),
7.42 (s, 2H), 7.35-7.26 (m, 4H), 7.09 (s, 2H), 6.00 (s, 2H),
3.93-3.20 (m, 28H), 3.18-3.04 (m, 8H), 3.00-2.83 (m, 3H), 2.70-2.60
(m, 1H), 2.47 (s, 3H), 2.13-1.80 (m, 2H), 1.80-1.35 (m, 15H).
Example 69:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[2-Azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy])benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[-
4-([[2-(2-[2-[(4-[[(1S,2S)-2-[2-azabicyclo[2.2.2]octan-2-yl]-4,6-dichloro--
2,3-dihydro-1H-inden-1-yl]oxy])benzene)sulfonamido]ethoxy]ethoxy)ethyl]car-
bamoyl]amino)butyl]urea
##STR00158##
[0906] Following the General Scheme with 2-azabicyclo[2.2.2]octane,
Steps A-D provided 46.7 mg (18%) of the title compound as a white
solid. MS (m/z): 1337.5 [M+H].sup.+. .sup.1H NMR (Methanol-d.sub.4,
400 MHz): .delta. 7.86 (d, J=9.2 Hz, 4H), 7.38 (s, 2H), 7.27 (d,
J=8.8 Hz, 4H), 7.04 (s, 2H), 5.91 (d, J=6.8 Hz, 2H), 3.76 (q, J=7.7
Hz, 2H), 3.57-3.46 (m, 18H), 3.30-3.27 (m, 4H), 3.13-3.06 (m, 8H),
3.01 (d, J=9.6 Hz, 2E1), 2.86-2.72 (m, 6H), 2.05-1.93 (m, 4H),
1.65-1.46 (m, 18H).
Example 70:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-2-[8-azabicyclo[3.2.1]octan-8-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carba-
moyl]amino)butyl]urea
##STR00159##
[0908] Following the General Scheme with 8-azabicyclo[3.2.1]octane,
Steps A-D provided 59.1 mg (30%) of the title compound as a white
solid. MS (m/z): 1337.0 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400
MHz): .delta. 7.78 (d, J=8.8 Hz, 4H), 7.29 (s, 2H), 7.17 (d, J=9.2
Hz, 4H), 6.93 (s, 2H), 5.85 (d, J=6.4 Hz, 2H), 3.75 (q, J=7.2 Hz,
2H), 3.50-3.47 (m, 3H), 3.47-3.35 (m, 11H), 3.29-3.22 (m, 6H),
3.21-3.18 (m, 3H), 2.98 (t, J=5.6 Hz, 7H), 2.69 (q, J=8.2 Hz, 2H),
2.00-1.83 (m, 8H), 1.72 (d, J=2.8 Hz, 2H), 1.65-1.55 (m, 6H),
1.43-1.31 (m, 6H), 1.29-1.15 (m, 611).
Example 71:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[9-Azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-
-([[2-(2-[2-[(4-[[(1S,2S)-2-[9-azabicyclo[3.3.1]nonan-9-yl]-4,6-dichloro-2-
,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carba-
moyl]amino)butyl]urea
##STR00160##
[0910] Following the General Scheme with 9-azabicyclo[3.3.1]nonane
hydrochloride (and added sodium hydroxide), Steps A-D provided 59.8
mg (16%) of the title compound as a white solid. MS (m/z): 1365.5
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.77 (d,
J=8.8 Hz, 4H), 7.29 (s, 2H), 7.16 (d, J=8.8 Hz, 4H), 6.93 (s, 2H),
5.81 (d, J=6.8 Hz, 2H), 4.34 (q, J=8.0 Hz, 2H), 3.48-3.37 (m, 16H),
3.27-3.17 (m, 6H), 3.03-2.96 (m, 8H), 2.86 (s, 4H), 2.62 (q, J=8.2
Hz, 2H), 2.13-1.96 (m, 12H), 1.65-1.52 (m, 4H), 1.45-1.37 (m,
12H).
Example 72:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihy-
dro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(-
2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihydro-1H--
inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)but-
yl]urea a; bis(trifluoroacetic acid)
##STR00161##
[0912] Following the General Scheme with 1-methylpiperazine, Steps
A-D provided 72.8 mg (56%) of the title compound as a light yellow
solid. MS (m/z): 1315 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300
MHz) .delta. 7.94-7.82 (m, 4H), 7.43 (d, J=1.8 Hz, 2H), 7.37-7.25
(m, 4H), 7.18-7.10 (m, 2H), 6.06 (d, J=5.9 Hz, 2H), 3.70 (td,
J=7.8, 5.9 Hz, 2H), 3.64-3.46 (m, 17H), 3.37 (s, 4H), 3.32-3.20 (m,
6H), 3.16-2.83 (m, 20H), 2.80 (s, 6H), 1.53-1.42 (m, 4H).
Example 73:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(4-methylpiperazin-1-yl)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(4-methylpiperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00162##
[0914] Following the General Scheme with 1-methylpiperazine and
INT-L6C, Steps A-D provided 50.4 mg (39%) of the title compound as
a light yellow solid. MS (m/z): 672.5[M/2+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.82-7.67 (m, 4H), 7.43 (dd, J=5.4,
3.5 Hz, 4H), 7.12 (s, 2H), 6.07 (d, J=6.0 Hz, 2H), 3.72 (q, J=7.3
Hz, 3H), 3.53 (dt, J=15.9, 4.7 Hz, 17H), 3.38 (s, 3H), 3.33-2.79
(m, 27H), 2.70 (s, 4H), 2.27 (s, 6H), 1.46 (d, J=5.5 Hz, 4H).
Example 74:
3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihy-
dro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]1-[4-([[2-(2-
-[2-[(4-[[1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-in-
den-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl-
]urea
##STR00163##
[0916] To a 50-mL round-bottom flask was added the compound from
Example 31 (300 mg, 0.23 mmol, 1 equiv), CH.sub.2Cl.sub.2 (12 mL),
triethylamine (0.163 mL), and acetyl chloride (0.050 mL). The
resulting solution was stirred for 0.5 h at 0-5.degree. C. in a
watertice bath. The resulting slurry was concentrated under vacuum.
The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(30.0% CH.sub.3CN up to 52.0% in 8 min); Detector, UV 254 nm. This
resulted in 200.5 mg (63%) of the title compound as a white solid.
MS (m/z): 1371 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz)
.delta. 7.99-7.89 (m, 4H), 7.54 (d, J=1.7 Hz, 2H), 7.44-7.34 (m,
4H), 7.15 (d, J=1.0 Hz, 2H), 6.48 (d, J=6.5 Hz, 2H), 4.32 (q, J=7.9
Hz, 2H), 3.84 (s, 8H), 3.72-3.47 (m, 19H), 3.40 (s, 5H), 3.34-3.18
(m, 8H), 3.11 (t, J=5.4 Hz, 8H), 2.16 (s, 6H), 1.48 (d, J=6.2 Hz,
4H).
Example 75:
3-[2-(2-[2-[(4-[[(1S,2S)-2-(4-Acetylpiperazin-1-yl)-4,6-dichloro-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-2-(4-acetylpiperazin-1-yl)-4,6-dichloro-2,3-di-
hydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00164##
[0918] Beginning with the compound in Example 32, the procedure for
the synthesis of Example 74 was employed to provide 150.9 mg (41%)
of the title compound as a white solid. MS (m/z): 1399 [M+H].sup.+.
.sup.1H NMR (Methanol-d4, 300 MHz) .delta. 7.82-7.67 (m, 4H),
7.51-7.40 (m, 4H), 7.09-7.01 (m, 2H), 6.43 (d, J=6.4 Hz, 2H), 4.26
(q, J=8.0 Hz, 2H), 3.77 (s, 9H), 3.66-3.42 (m, 18H), 3.28-3.12 (m,
6H), 3.05 (q, J=5.8 Hz, 8H), 2.26 (s, 6H), 2.10 (s, 6H), 1.49-1.38
(m, 4H).
Example 76:
4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6--
dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl-
]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]carbamoyl]amino)eth-
oxy]ethoxy]et
hyl)sulfamoyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperazine--
1-carboxamide
##STR00165##
[0920] To a 50-mL round-bottom flask was added the compound from
Example 31 (300 mg, 0.23 mmol, 1 equiv), CH.sub.2Cl.sub.2 (8 mL),
N,N-dimethylcarbamoyl chloride (75.2 mg, 0.70 mmol, 3 equiv), and
triethylamine (0.162 mL). The resulting solution was stirred for 1
h at room temperature. The resulting mixture was concentrated under
vacuum. The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(30% CH.sub.3CN up to 52% in 8 min); Detector, UV 254 nm. This
resulted in 236.9 mg (71%) of the title compound as a white solid.
MS (m/z): 1429 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz)
.delta. 8.01-7.89 (m, 4H), 7.56 (d, J=1.7 Hz, 2H), 7.45-7.34 (m,
4H), 7.17-7.10 (m, 2H), 6.58 (d, J=6.9 Hz, 2H), 4.48 (q, J=8.2 Hz,
2H), 3.80-3.23 (m, 39H), 3.12 (t, J=5.5 Hz, 9H), 2.91 (s, 12H),
1.54-1.43 (m, 4H).
Example 77:
4-[(1S,2S)-4,6-dichloro-1-[4-[(2-[2-[2-([[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6--
dichloro-2-[4-(dimethylcarbamoyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl-
]oxy]-3-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)buty-
l]carbamoyl]amino)et
hoxy]ethoxy]ethyl)sulfamoyl]-2-methylphenoxy]-2,3-dihydro-1H-inden-2-yl]--
N,N-dimethylpiperazine-1-carboxamide; bis(trifluoreacetic acid)
##STR00166##
[0922] Beginning with the compound in Example 32, the procedure for
the synthesis of Example 76 was employed to provide 198 mg (52%) of
the title compound as a white solid. MS (m/z): 1455 [M+H].sup.+.
.sup.1H NMR (Methanol-d4, 300 MHz) .delta. 7.83-7.68 (m, 4H),
7.53-7.40 (m, 4H), 7.03 (d, J=1.7 Hz, 2H), 6.54 (d, J=6.6 Hz, 2H),
4.45 (q, J=8.1 Hz, 2H), 3.68 (dd, J=16.4, 8.6 Hz, 3H), 3.60-3.42
(m, 28H), 3.36 (d, J=9.1 Hz, 5H), 3.24 (d, J=5.4 Hz, 4H), 3.05 (q,
J=5.6 Hz, 8H), 2.86 (s, 12H), 2.27 (s, 6H), 1.48-1.38 (m, 4H).
Scheme for the Synthesis of Example 78:
Example 78:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino-
]piperidin-1-yl]2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichlo-
ro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inde-
n-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]u-
rea; bis(trifluoroacetic acid)
##STR00167## ##STR00168##
[0924] Step A: To a 50-mL sealed tube was added tert-butyl
(3S)-3-(methanesulfonyloxy)piperidine-1-carboxylate (5 g, 17.9
mmol, 1 equiv), methanol (15 mL), and methyl(propan-2-yl)amine (3.9
g, 53.3 mmol, 3 equiv). The resulting solution was stirred for 72
hrs at 90.degree. C. The resulting mixture was concentrated under
vacuum. The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (0-5%) providing 2 g (44%) of tart-butyl
(3R)-3-[methyl(propan-2-yl)amino]piperidine-1-carboxylate as a
yellow oil.
[0925] Step B: To a 100-mL round-bottom flask was added tert-butyl
(3R)-3-[methyl(propan-2-yl)amino]piperidine-1-carboxylate (1.7 g,
6.63 mmol, 1 equiv) and hydrogen chloride in methanol (40 mL). The
final reaction mixture was stirred overnight at room temperature.
The resulting mixture was concentrated under vacuum to provide 1.52
g (100%) of (3R)--N-isopropyl-N-methylpiperidin-3-amine
dihydrochloride as a white solid.
[0926] Step C: To a 50-mL round-bottom flask was added epoxide
INT-17C (300 mg, 1.49 mmol, 1 equiv),
(3R)--N-isopropyl-N-methylpiperidin-3-amine dihydrochloride (684
mg, 2.98 mmol, 2 equiv), MeCN (10 mL), and sodium
hydroxide(3M.sub.(aq), 3 mL). The resulting solution was stirred
for 1 h at 70.degree. C. in an oil bath. The resulting solution was
extracted with 3.times.50 mL of ethyl acetate and the organic
layers combined and concentrated under vacuum. The residue was
applied onto a silica gel column with CH.sub.2Cl.sub.2/methanol
(8:1) providing 530 mg (99%) of
(1R,2R)-4,6-dichloro-1-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]--
2,3-dihydro-1H-inden-2-ol (INT-A4) as a red oil.
[0927] Step D: To a 50-mL round-bottom flask was added aminoindanol
INT-A4 (570 mg, 1.60 mmol, 1 equiv), phenol INT-L6A (716 mg, 1.77
mmol, 1.1 equiv), THF (3.7 mL), and PPh3 (627 mg, 2.39 mmol, 1.5
equiv). Heating at 40.degree. C. in an oil bath DIAD (0.47 mL, 1.5
equiv) was added dropwise with stirring over 30 min. The resulting
solution was stirred for 1 h at 40.degree. C. in an oil bath. The
residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (10:1) providing 600 mg (51%) of
tert-butyl
N-[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino-
]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]-
ethoxy)ethyl]carbamate (INT-A5) as a yellow oil.
[0928] Step E: To a 100-mL round-bottom flask was added INT-A5 (600
mg, 0.81 mmol, 1 equiv), CH.sub.2Cl.sub.2 (10 mL), and TFA (2 mL).
The resulting solution was stirred for 1 h at room temperature. The
pH value of the solution was adjusted to 8 with saturated aqueous
sodium bicarbonate and extracted with 3.times.50 mL of
CH.sub.2Cl.sub.2. The organic layers were combined and concentrated
under vacuum. The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (8:1) providing 420 mg (81%) of
N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[[(1S,2S)-4,6-dichloro-2-[(3R)-3-[-
methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]ben-
zene-1-sulfonamide (INT-A6) as a yellow oil.
[0929] Step F: To a 50-mL round-bottom flask was added amine INT-A6
(400 mg, 0.62 mmol, 1 equiv), DMF (5 mL), and
1,4-diisocyanatobutane (68 mg, 0.25 mmol, 0.40 equiv). The
resulting solution was stirred for 1 h at 60.degree. C. in an oil
bath. The resulting mixture was concentrated under vacuum. The
crude product was purified by preparative HPLC with the following
conditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm,
5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN (25.0%
CH.sub.3CN up to 45.0% in 8 min); Detector, UV 254 nm.
Example 78:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-[(3R)-3-[methyl(propan-2-yl)amino-
]piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichlo-
ro-2-[(3R)-3-[methyl(propan-2-yl)amino]piperidin-1-yl]-2,3-dihydro-1H-inde-
n-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)ethyl]
carbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)
[0930] Steps A-F provided 203.1 mg (20%) of the title compound as a
white solid. MS (m/z): 714.5 [M/2+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.91-7.81 (m, 4H), 7.42 (d, J=1.7
Hz, 2H), 7.30 (d, J=8.5 Hz, 4H), 7.11 (d, J=2.4 Hz, 2H), 6.18 (m,
2H), 3.98-3.66 (m, 4H), 3.54 (dq, J=5.6, 2.0 Hz, 8H), 3.47 (t,
J=5.5 Hz, 10H), 3.29 (m, 3H), 3.27-3.23 (m, 4H), 3.12-2.99 (m,
10H), 2.94 (m, 4H), 2.77-2.62 (m, 6H), 2.58 (m, 3H), 2.08 (m, 2H),
1.89 (m, 2H), 1.70 (m, 4H), 1.49-1.38 (m, 4H), 1.31 (m, 10H), 1.20
(d, J=6.5 Hz, 2H).
General Scheme for Synthesis of Disubstituted Sulfonamide Dimer
Products:
##STR00169##
[0932] Step A: To a round-bottom flask was added aminoindanol
INT-18 (1 equiv) and tetrahydrofuran (0.2M), followed by the
addition of phenol linker TNT-L6 (0.1 equiv) and heating to
40.degree. C. To this slurry was added PPh3 (2 equiv) and DIAD (1.5
equiv). The resulting solution was stirred for 1-3 h at 40.degree.
C. The resulting mixture was concentrated under vacuum and diluted
with CH.sub.2Cl.sub.2. The residue was applied onto a silica gel
column with petroleum ether/ethyl acetate (1:1) providing indane
monomer INT-D1.
[0933] Step B: To a round-bottom flask was added indane monomer
INT-D1 (1 equiv), methanol (0.1M), and sodium hydroxide
(3M.sub.(aq), 3-5 equiv). The resulting solution was stirred for
1-2 h at 60.degree. C. The resulting mixture was concentrated under
vacuum and diluted with CH.sub.2Cl.sub.2. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (10:1)
providing indane amine monomer INT-D2.
[0934] Step C: To a round-bottom flask was added INT-D2 (1 equiv),
dimethylformamide (DMF, 0.1M), and 1,4-diisocyanatobutane (0.4-0.5
equiv). The resulting solution was stirred for 2 h at 60.degree. C.
The resulting mixture was concentrated under vacuum and diluted
with of CH.sub.2Cl.sub.2. The residue was applied onto a silica gel
column with chloroform/methanol (10:1) providing the desired dimer
of structure (I). Final products were purified by preparative HPLC.
The final products were generally isolated as the free based
amines, TFA salts, or hydrochloride salts.
[0935] Step D (for Boc-protected intermediates): To a round-bottom
flask was added Boc-protected dimer (I) (1 equiv) and 5:1
CH.sub.2Cl.sub.2:TFA (.about.0.05M). The resulting solution was
stirred for 2 h at room temperature. The resulting mixture was
concentrated under vacuum. The crude product was purified by
preparative HPLC. The final products were generally isolated as the
free based amines, TFA salts, or hydrochloride salts.
Example 79:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3,5 dimethyl
benzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2--
[(3R)-3-aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-
,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]u-
rea; hydrochloride
##STR00170##
[0937] Beginning with INT-LCD and INT-I8F, Steps A-D provided
Example 79 which was purified by preparative HPLC with the
following conditions: Column, XBridge Preparative OBD C18 Column,
19*250 mm, 5 um; mobile phase, water (0.05% HCl) and CH.sub.3CN
(40.0% CH.sub.3CN up to 70.0% in 8 min); Detector, UV 254 nm. This
resulted in 129.2 mg (48%) of the title compound as a yellow solid.
MS (m/z): 1370.85 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.60 (d, J=15.2 Hz, 6H), 6.45 (s, 2H), 6.30 (s, 2H), 4.70
(d, J=3.2 Hz, 2H), 3.95-3.80 (m, 6H), 3.70-3.50 (m, 20H), 3.40-3.35
(m, 8H), 3.17 (s, 4H), 3.05 (t, J=5.4 Hz, 4H), 2.30-2.10 (m, 18H),
1.88 (5, 2H), 1.54 (s, 4H).
Example 80:
1-[2-(2-[2-[(3-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-2,4-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-
-1-yl]oxy]-3,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]a-
mino)butyl]urea
##STR00171##
[0939] Beginning with INT-L6D and INT-I8C, Steps A-C provided
Example 80 which was purified by preparative HPLC with the
following conditions: Column, XBridge BEH130 Preparative C18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (75.0% CH.sub.3CN up to 84.0% in 9 min); Detector, UV
254 nm. This resulted in 91.5 mg (28%) of the title compound as a
white solid. MS (m/z): 1261.20 [M+].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.56 (s, 4H), 7.43 (d, J=1.6 Hz,
2H), 6.50 (d, J=1.2 Hz, 2H), 5.68 (d J=2.4 Hz, 2H), 4.82-4.78 (m,
2H), 3.58 (q, J=5.0 Hz, 8H), 3.55-3.50 (m, 8H), 3.42-3.37 (m, 2H),
3.35-3.30 (m, 4H), 3.13 (s, 4H), 3.08-2.96 (m, 6H), 2.30 (s, 12H),
2.15 (d, J=9.6 Hz, 12H), 1.50 (s, 4H).
Example 81:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2,5-dimethylbenzene)
sulfonamido]ethoxy]ethoxy)ethyl]1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-a-
minopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2,5-dimeth-
ylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]
carbamoyl]amino)butyl]urea
##STR00172##
[0941] Beginning with INT-L6E and INT-I8F, Steps A-D provided
Example 81 which was purified by preparative HPLC with the
following conditions: Column, XBridge Preparative OBD C.sub.18
Column, 19*250 mm, 5 um; mobile phase, water (10 mmol/L
NH.sub.4HCO.sub.3+0.1% NH.sub.4OH) and CH.sub.3CN (50.0% CH.sub.3CN
up to 60.0% in 13 min); Detector, UV 254 nm. This resulted in 113.6
mg (30%) of the title compound as a light yellow solid. MS (m/z):
1371.75 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.83 (s, 2H), 7.54 (s, 2H), 7.48 (s, 2H), 7.01 (d, J=1.8 Hz, 2H),
6.88 (d, J=6.0 Hz, 2H), 4.61 (d, J=8.0 Hz, 2H), 3.87-3.71 (m, 8H),
3.70-3.51 (m, 20H), 3.50-3.33 (m, 8H), 3.21 (d, J=6.0 Hz, 4H), 3.11
(t, J=5.6 Hz, 4H), 2.71 (s, 6H), 2.30-2.11 (m, 10H), 1.83 (s, 2H),
1.56 (s, 5H).
Example 82:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([-
[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-
-1-yl]oxy]-2,5-dimethylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]a-
mino)butyl]urea
##STR00173##
[0943] Beginning with INT-L6E and INT-I8C, Steps A-C provided
Example 82 which was purified by preparative HPLC with the
following conditions (2.pi.-AnalyseHPLC-SHIMADZU(HPLC-10)): Column,
XBridge C18 OBD Preparative Column, 19*250 mm, 5 um; mobile phase,
water (0.05% NH.sub.4OH) and CH.sub.3CN (85.0% CH.sub.3CN up to
89.0% in 11 min); Detector, UV 254 nm. This resulted in 74.8 mg
(14%) of the title compound as a white solid. MS (m/z): 1261.55
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.77 (s,
2H), 7.42 (s, 2H) 7.30 (s, 2H), 7.09 (s, 2H), 5.99 (d, J=6.2 Hz,
2H), 3.63-3.42 (m, 18H), 3.30 (q, J=5.6 Hz, 6H), 3.20-3.04 (m, 8H),
2.91 (dd, J=16.4, 8.0 Hz, 2H), 2.66 (s, 6H), 2.37 (s, 12H), 2.22
(s, 6H), 1.53 (s, 4H).
Example 83:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]eth-
oxy)ethyl]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,-
6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amido)butyl]urea;
hydrochloride
##STR00174##
[0945] Beginning with INT-L6F and INT-18F, Steps A-D provided
Example 83 which was purified by preparative HPLC with the
following conditions: Column, XBridge Preparative OBD C18 Column,
19*250 mm, 5 um; mobile phase, water (0.05% HCl) and CH.sub.3CN
(20.0% CH.sub.3CN up to 70.0% in 8 min); Detector, UV 254 nm. This
resulted in 317.6 mg (64%) of the title compound as a light yellow
solid. MS (m/z): 1380.80 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400
MHz) .delta. 7.66 (d, J=11.2 Hz, 2H), 7.65 (s, 2H), 7.62 (s, 2H),
6.70 (s, 4H), 4.67 (s, 2H), 3.99-3.80 (m, 8H), 3.68-3.48 (m, 19H),
3.46-3.28 (m, 7H), 3.21 (s, 4H), 3.11 (t, J=5.2 Hz, 4H), 2.14 (s,
6H), 2.30-2.10 (m, 6H), 1.93-1.78 (m, 2H), 1.57 (s, 4H).
Example 84:
1-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-3--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H--
inden-1-yl]oxy]-3-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea
##STR00175##
[0947] Beginning with INT-L6F and INT-18C, Steps A-C provided
Example 84 which was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(45.0% CH.sub.3CN up to 65.0% in 8 min); Detector, UV 254 nm. This
resulted in 109.6 mg (30%) of the title compound as a white solid.
MS (m/z): 1269.45 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.59 (t, J=13.4 Hz, 4H), 7.44 (s, 2H), 6.93 (s, 2H), 5.92
(d, J=4.0 Hz, 2H), 3.72-3.65 (m, 3H), 3.60-3.50 (m, 16H), 3.38-3.29
(m, 5H), 3.13-3.08 (m, 8H), 2.93 (dd, J=16.8, 5.6 Hz, 2H), 2.32 (s,
12H), 2.15 (s, 6H), 1.49 (s, 4H).
##STR00176##
Example 85:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-3,5-difluorobenzene)
sulfonamido]ethoxy]ethoxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3--
aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-3,5-diflu-
orobenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamoyl]
amino)butyl]urea; bis(trifluoroacetic acid)
[0948] Beginning with INT-L6H and INT-18F, Steps A-D provided
Example 85 which was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19 mm*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(25% CH.sub.3CN up to 65% in 8 min); Detector, UV 254 nm. This
resulted in 192.3 mg (57%) of the title compound as a white solid.
MS (m/z): 1387 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.59 (d, J=7.2 Hz, 4H), 7.46 (d, J=1.8 Hz, 2H), 7.22-7.16
(m, 2H), 5.89 (d, J=4.9 Hz, 2H), 3.89 (q, J=6.4 Hz, 2H), 3.62-3.47
(m, 17H), 3.31-3.22 (m, 5H), 3.20-3.06 (m, 10H), 3.04-2.93 (m, 4H),
2.69 (s, 2H), 2.56-2.40 (m, 4H), 1.97-1.88 (m, 2H), 1.78 (d, J=12.4
Hz, 2H), 1.54-1.36 (m, 8H).
Example 86:
4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-
-N-[26-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-
-yl]oxy)-3,5-difluorophenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,-
11,16,18-tetraazahexacosyl]-3,5-difluorobenzenesulfonamide;
bis(trifluoroacetic acid)
##STR00177##
[0950] Beginning with INT-L6H and INT-I8C, Steps A-C provided
Example 86 which was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(25.0% CH.sub.3CN up to 38.0% in 9 min); Detector, UV 254 nm. This
resulted in 225.1 mg (52%) of the title compound as a white solid.
MS (m/z): 1277 [H+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.70-7.59 (m, 4H), 7.57 (d, J=1.8 Hz, 2H), 7.07-7.01 (m,
2H), 6.31 (d, J=4.1 Hz, 2H), 4.54 (ddd, J=8.4, 5.7, 4.1 Hz, 2H),
3.72 (dd, J=17.5, 8.5 Hz, 2H), 3.61-3.46 (m, 17H), 3.27 (t, J=5.4
Hz, 5H), 3.16-3.05 (m, 8H), 3.02 (s, 12H), 1.47 (p, J=3.3 Hz,
4H).
Example 87:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]eth-
oxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,-
6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00178##
[0952] Beginning with INT-L6G and INT-18F, Steps A-D provided
Example 87 which was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19 mm*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(15.0% CH.sub.3CN up to 65.0% in 8 min); Detector, UV 254 nm. This
resulted in 254 mg (50%) of the title compound as a white solid. MS
(m/z): 1379 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.74 (d, J=11.1 Hz, 2H), 7.49-7.42 (m, 4H), 7.17-7.12 (m, 2H), 6.17
(d, J=5.8 Hz, 2H), 3.86 (q, J=7.4 Hz, 2H), 3.62-3.42 (m, 16H),
3.41-3.24 (m, 8H), 3.15-2.98 (m, 13H), 2.88 (s, 2H), 2.64 (s, 8H),
1.97 (s, 3H), 1.88 (s, 1H), 1.58 (dd, 12.8, 8.9 Hz, 2H), 1.51-1.42
(m, 4H).
Example 88:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H--
inden-1-yl]oxy]-5-fluoro-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea
##STR00179##
[0954] Beginning with INT-L6G and INT-I8C, Steps A-C provided
Example 88 which was purified by preparative HPLC with the
following conditions: Column, XBridge Preparative C18 OBD Column,
19*150 mm, 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (5.0% CH.sub.3CN up to 75.0% in 1 min, up to 86.0% in 6
min); Detector, UV 254/220 nm. This resulted in 80.2 mg (18%) of
the title compound as a white solid. MS (m/z): 1269 [M+H].sup.+.
.sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.72 (d J=11.2 Hz, 2H),
7.50-7.39 (m, 4H), 7.16-7.10 (m, 2H), 5.97 (d, J=5.8 Hz, 2H),
3.61-3.41 (m, 19H), 3.37-3.20 (m, 6H), 3.10 (t, J=5.4 Hz, 9H), 2.90
(dd, J=16.6, 7.4 Hz, 2H), 2.63 (s, 6H), 2.34 (s, 12H), 1.51-1.43
(m, 4H).
Example 89:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]eth-
oxy)ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,-
6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea;
bis(trifluoroacetic acid)
##STR00180##
[0956] Beginning with INT-L6I and INT-18F, Steps A-D provided
Example 89 which was purified by preparative HPLC with the
following conditions: Column, XBridge Preparative OBD C18 Column,
19*250 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(55.0% CH.sub.3CN up to 80.0% in 8 min); Detector, UV 254 nm. This
resulted in 234.1 mg (74%) of the title compound as a white solid.
MS (m/z): 690.5 [M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.66 (d, J=8.1 Hz, 2H), 7.45 (d, J=1.7 Hz, 2H), 7.38 (d,
J=12.2 Hz, 2H), 7.19-7.14 (m, 2H), 6.04 (d, J=5.5 Hz, 2H), 3.74 (s,
2H), 3.63-3.46 (m, 15H), 3.31-3.22 (m, 4H), 3.19-2.92 (m, 13H),
2.75 (s, 2H), 2.63 (d, J=9.6 Hz, 2H), 2.54 (s, 3H), 2.19 (s, 5H),
1.95 (s, 3H), 1.85 (s, 2H), 1.68 (s, 2H), 1.55 (d, J=10.6 Hz, 2H),
1.47 (d, J=3.7 Hz, 3H).
Example 90:
3-[2-(2-[2-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-in-
den-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]-1--
[4-([[2-(2-[2-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dihydro-1H--
inden-1-yl]oxy]-2-fluoro-5-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl]c-
arbamoyl]amino)butyl]urea; bis(trifluoroacetic acid)
##STR00181##
[0958] Beginning with INT-L6I and INT-18C, Steps A-C provided
Example 90 which was purified by preparative HPLC with the
following conditions: Column, XSelect CSH Preparative C18 OBD
Column, 19*250 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (25.0% CH.sub.3CN up to 40.0% in 10 min); Detector, UV
254 nm. This resulted in 216.8 mg (58%) of the title compound as a
white solid. MS (m/z): 1291 [M+Na].sup.+ .sup.1H NMR (Methanol-d4,
400 MHz) .delta. 7.75-7.67 (m, 2H), 7.55 (d, J=1.7 Hz, 2H), 7.41
(d, J=11.6 Hz, 2H), 7.17-7.07 (m, 2H), 6.46 (d, J=6.7 Hz, 2H), 4.50
(td, J=8.5, 6.6 Hz, 2H), 3.74-3.63 (m, 3H), 3.61-3.46 (m, 18H),
3.31-3.20 (m, 6H), 3.20-3.01 (m, 25H), 2.26 (d, J=7.6 Hz, 7H), 1.46
(td, J=6.4, 3.2 Hz, 4H).
Scheme for the Synthesis of Pyrrolidinone Linkers:
##STR00182## ##STR00183##
[0960] Step A: To a 500-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added
2-(2-aminoethoxy)ethan-1-ol (16.1 g, 153 mmol, 1 equiv),
CH.sub.2Cl.sub.2 (160 mL), and triethylamine (22.4 mL, 1.05 equiv).
This was followed by the addition of CbzCl (28.7 g, 168.24 mmol,
1.1 equiv) dropwise with stirring at 5-10.degree. C. The resulting
solution was stirred overnight at room temperature. The reaction
was then quenched by the addition of 100 mL of water and extracted
with 3.times.100 mL of CH.sub.2Cl.sub.2. The organic layers were
combined and washed with 1.times.100 mL of brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The solid was dried in an oven under reduced pressure. The residue
was applied onto a silica gel column with petroleum ether/ethyl
acetate (1:1) providing 32 g (87%) of benzyl
N-[2-(2-hydroxyethoxy)ethyl]carbamate (INT-P1) as a yellow oil.
[0961] Step B: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added alcohol INT-P1 (5 g,
20.90 mmol, 1 equiv), phthalimide (3.07 g, 20.9 mmol, 1 equiv), and
tetrahydrofuran (49 mL). This was followed by the addition of
PPh.sub.3 (8.22 g, 31.34 mmol, 1.5 equiv) in several portions at
40.degree. C. To this was added DIAD (6.17 mL, 1.5 equiv) dropwise
with stirring at 40.degree. C. over 30 min. The resulting solution
was stirred for 1 h at 40.degree. C. in an oil bath. The resulting
slurry was diluted with water and extracted with 3.times.100 mL of
ethyl acetate. The organic layers combined and concentrated under
vacuum. The residue was applied onto a silica gel column with
petroleum ether/ethyl acetate (1:1) providing 6.5 g (84%) of benzyl
N-[2-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethoxy]ethyl]
carbamate (INT-P2) as a yellow oil.
[0962] Step C: To a 1-L round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added phthalimide INT-P2
(6.5 g, 17.6 mmol, 1 equiv), ethanol (500 mL), and
NH.sub.2NH.sub.2.H.sub.2O (8.8 g, 10 equiv). The resulting solution
was stirred for 3 h at 85.degree. C. in an oil bath. The resulting
mixture was concentrated under vacuum. The residue was applied onto
a silica gel column with CH.sub.2Cl.sub.2/methanol (5:1) providing
4 g (95%) of benzyl N-[2-(2-aminoethoxy)ethyl]carbamate (INT-P3) as
a yellow oil.
[0963] Step D: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added Boc-Met-OH (3.77 g,
15.1 mmol, 1 equiv), amine INT-P3 (3.6 g, 15.1 mmol, 1 equiv), THF
(54 mL), HOBT (2.04 g, 15.1 mmol, 1 equiv), and
diisopropylethylamine (5 mL, 2 equiv). This was followed by the
addition of DIC (2.5 mL, 1.05 equiv) dropwise with stirring at
0.degree. C. The resulting solution was stirred for 1 h at room
temperature. The resulting mixture was concentrated under vacuum.
The residue was applied onto a silica gel column with
H.sub.2O/CH.sub.3CN (3:2) providing 5.2 g (73%) of tert-butyl
N-[(1S)-1-[[2-(2-[[(benzyloxy)carbonyl]amino]ethoxy)ethyl]carbamoyl]-3-(m-
ethylsulfonyl)propyl]carbamate (INT-P4) as a yellow oil.
[0964] Step E: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added INT-P4 (5.2 g, 11.07
mmol, 1 equiv) and iodomethane (50 mL). The resulting solution was
stirred for 3 days at room temperature. The resulting mixture was
concentrated under vacuum. This resulted in 5.3 g (99%) of
tert-butyl
N-[(1S)-1-[[2-(2-[[(benzyloxy)carbonyl]amino]ethoxy)ethyl]
carbamoyl]-3-(dimethylsulfaniumyl)propyl]carbamate (INT-P5) as a
light yellow oil.
[0965] Step F: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added INT-P5 (5.3 g, II
0.8 mmol, 1 equiv), DMF (60 mL), CH.sub.2Cl.sub.2 (60 mL), and
lastly sodium hydride (900 mg, 37.5 mmol, 3.2 equiv) in portions.
The resulting slurry was stirred for 2.5 h at 0.degree. C. in an
ice/salt bath. The resulting mixture was concentrated under vacuum.
The residue was diluted with CH.sub.2Cl.sub.2 and washed with
3.times.100 mL of brine. The organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum providing
4.6 g (93%) of benzyl
N-(2-[2-[(3S)-3-[[(tert-butoxy)carbonyl]amino]-2-oxopyrrolidin-1-yl]ethox-
y]ethyl)carbamate (INT-P6) as a yellow oil.
[0966] Step G: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added pyrrolidinone INT-P6
(4.5 g, 10.68 mmol, 1 equiv), CH.sub.2Cl.sub.2 (50 mL), and
trifluoroacetic acid (8 mL). The resulting solution was stirred for
3 h at room temperature. The resulting mixture was concentrated
under vacuum. The reaction was quenched by the addition of 100 mL
of water. The pH of the solution was adjusted to 8 with saturated
aqueous sodium bicarbonate and extracted with 5.times.100 mL of
ethyl acetate. The organic layers were combined, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
This resulted in 3.4 g (100%) of benzyl
N-(2-[2-[(3S)-3-amino-2-oxopyrrolidin-1-yl]ethoxy]ethyl) carbamate
(INT-P7) as a yellow oil.
[0967] Step H: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added CH.sub.2Cl.sub.2 (20
mL), triethylamine (4.6 mL, 2.9 equiv), and amine INT-P7 (3.3 g,
10.3 mmol, 0.9 equiv). To this mixture was added a solution of
4-(benzyloxy)-3-methylbenzene-1-sulfonyl chloride (INT-L3 with
R.sup.1=m-Me, 3.4 g, 11.5 mmol, 1 equiv) in CH.sub.2Cl.sub.2 (30
mL) dropwise with stirring over 20 min. The resulting solution was
stirred for 2 h at room temperature. The reaction was quenched by
the addition of 100 mL of water and extracted with 3.times.200 mL
of ethyl acetate. The organic layers were combined and washed with
1.times.100 mL of brine. The organic layer was dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The
residue was applied onto a silica gel column with petroleum
ether/ethyl acetate (3:7) providing 4.2 g (63%) of benzyl
N-(2-[2-[(3S)-3-[[4-(benzyloxy)-3-methylbenzene]sulfonamido]-2-oxo-
pyrrolidin-1-yl]ethoxy]ethyl)carbamate (INT-P8) as a yellow
oil.
[0968] Step I: To a 500-mL round-bottom flask purged and maintained
with an inert atmosphere of hydrogen was added benzyl ether INT-P8
(4.2 g, 7.22 mmol, 1 equiv) and methanol (50 mL). This was followed
by the addition of palladium on carbon (2.1 g, 60% of water). The
resulting slurry was stirred for 2 days at room temperature. The
solids were filtered out. The mixture was dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. This
resulted in 2.3 g (88%) of
N-[(3S)-1-[2-(2-aminoethoxy)ethyl]-2-oxopyrrolidin-3-yl]-4-hydroxy-3-meth-
ylbenzene-1-sulfonamide (INT-P9) as a white solid.
[0969] Step J: To a 500-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added amine INT-P9 (2.3 g,
6.43 mmol, 1 equiv), methanol (30 mL), triethylamine (0.2 mL, 0.20
equiv), and ethyl 2,2,2-trifluoroacetate (2.35 mL, 3 equiv). The
resulting solution was stirred for 3 h at room temperature. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with hexane/ethyl acetate (3:7)
providing 2 g (69%) of
2,2,2-trifluoro-N-(2-[2-[(3S)-3-[(4-hydroxy-3-methylbenzene)sulfonamido]--
2-oxopyrrolidin-1-yl]ethoxy]ethyl)acetamide (INT-P10) as a white
solid.
Scheme for the Synthesis of Pyrrolidinone Dimer Products:
Example 91:
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethox-
y]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolid-
in-1-yl]ethoxy]ethyl]carbamoyl]amino]butylurea
##STR00184##
[0971] Step A: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added phenol INT-P10 (300
mg, 0.66 mmol, 1 equiv), aminoindanol INT-18C (163 mg, 0.66 mmol, 1
equiv), and THF (1.5 mL). This was followed by the addition of
PPh.sub.3 (260 mg, 0.99 mmol, 1.5 equiv) at 40.degree. C. To this
was added DIAD (0.2 mL, 1.5 equiv) dropwise with stirring at
40.degree. C. over 30 min. The resulting solution was stirred for 1
h at 40.degree. C. in an oil bath. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with hexane/ethyl acetate (1:2) providing 400 mg (89%)
of
N-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-
-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-
-yl]ethoxy]ethyl)-2,2,2-trifluoroacetamide (INT-P11) as a yellow
oil.
[0972] Step B: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added monomer intermediate
INT-P11 (400 mg, 0.59 mmol, 1 equiv) and methanol (10 mL). This was
followed by the addition of sodium hydroxide (3M.sub.(aq), 1.5 mL).
The resulting solution was stirred for 1 h at 60.degree. C. in an
oil bath. The resulting solution was diluted with water and
extracted with 3.times.100 mL of ethyl acetate. The organic layers
were combined and washed with 1.times.100 mL of brine. The organic
layer was dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with CH.sub.2Cl.sub.2/methanol (5:1) providing 320 mg
(93%) of
N-[(3S)-1-[2-(2-aminoethoxy)ethyl]-2-oxopyrrolidin-3-yl]-4-[[(1S,2S)-4,6--
dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene--
1-sulfonamide (INT-P12) as a yellow oil.
[0973] Step C: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added amine INT-P12 (320
mg, 0.55 mmol, 1 equiv), DMF (3.6 mL), and 1,4-diisocyanatobutane
(34.5 mg, 0.25 mmol, 0.45 equiv). The resulting solution was
stirred for 2 h at 60.degree. C. in an oil bath. The resulting
mixture was concentrated under vacuum and purified by preparative
HPLC as below.
Example 91:
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro--
1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]ethox-
y]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-4,6-dichloro-2-(dimethylamino)-
-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolid-
in-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea
[0974] Crude compound of Steps A-C was purified by preparative HPLC
with the following conditions: Column, XBridge Preparative OBD C18
Column, 19*250 mm, 5 um; mobile phase, water (0.05% NH.sub.4OH) and
CH.sub.3CN (73.0% CH.sub.3CN to 86.0% in 8 min); Detector, UV 220
nm. This resulted in 139 mg (19%) of the title compound as a white
solid. MS (m/z): 1311 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400
MHz) .delta. 7.85-7.74 (m, 4H), 7.46-7.37 (m, 4H), 7.11-7.06 (m,
2H), 5.96 (d, J=6.1 Hz, 2H), 4.05 (dd, J=9.8, 8.5 Hz, 2H),
3.60-3.31 (m, 18H), 3.31-3.20 (m, 6H), 3.12 (t, J=5.3 Hz, 4H), 2.89
(dd, J=16.5, 7.8 Hz, 2H), 2.34 (s, 12H), 2.25 (s, 8H), 1.78 (dq,
J=12.4, 9.3 Hz, 2H), 1.49 (p, J=3.2 Hz, 4H).
Scheme for Synthesis of Cyano-Containing Pyrrolidinone Dimer
Product:
Example 92:
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Choro-4-cyano-2-(dimethylamino)-2,3-dihyd-
ro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]et-
hoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethy-
lamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxop-
yrrolidin-1-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea;
bis(trifluoroacetic acid)
##STR00185##
[0976] Step A: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added phenol INT-P10 (500
mg, 1.1 mmol, 1 equiv), aminoindanol INT-18B (320 mg, 1.1 mmol, 1
equiv), and THF (2.6 mL). This was followed by the addition of
PPh.sub.3 (434 mg, 1.65 mmol, 1.5 equiv) at 40.degree. C. To this
slurry was added DIAD (0.33 mL) dropwise with stirring at
40.degree. C. over 30 min. The resulting solution was stirred for 1
h at 40.degree. C. in an oil bath. The resulting mixture was
concentrated wider vacuum. The residue was applied onto a silica
gel column with petroleum ether/ethyl acetate (2/1) providing 570
mg (71%) of
N-(2-[2-[(3S)-3-[(4-[[(1S,2S)-4-bromo-6-chloro-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]e-
thoxy]ethyl)-2,2,2-tri fluoroacetamide (INT-P13) as a yellow
oil.)
[0977] Step B: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added INT-P13 (570 mg,
0.79 mmol, 1.00 equiv), NMP (6 mL), Zn(CN).sub.2 (55.4 mg, 0.6
equiv), and Pd(PPh.sub.3).sub.4 (91 mg, 0.08 mmol, 0.1 equiv). The
resulting solution was stirred for overnight at 100.degree. C. in
an oil bath. The reaction was then quenched by the addition of 10
ml, of water and extracted with 3.times.20 mL of ethyl acetate. The
organic layers were combined and washed with 3.times.50 mL of
brine. The organic layer was dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. The residue was applied
onto a silica gel column with ethyl acetate/petroleum ether (1/1)
providing 400 mg (76%) of
N-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]e-
thoxy]ethyl)-2,2,2-trifluoroacetamide (INT-P14) as a yellow
oil.
[0978] Step C: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added INT-P14 (400 mg,
0.60 mmol, 1 equiv), methanol (7 mL), and sodium hydroxide
(3M.sub.(aq), 1 mL). The resulting solution was stirred for 2 h at
room temperature. The resulting solution was extracted with
3.times.50 mL of ethyl acetate and the organic layers combined. The
resulting mixture was washed with 1.times.50 mL of brine, dried
over anhydrous sodium sulfate, filtered, and concentrated under
vacuum. The residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (5/1) providing 300 mg (87%) of
N-[(3S)-1-[2-(2-aminoethoxy)ethyl]-2-oxopyrrolidin-3-yl]-4-[[(1S,2S)-6-ch-
loro-4-cyano-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenz-
ene-1-sulfonamide (INT-P15) as a yellow oil.
[0979] Step D: To a 50-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen, was added amine INT-P15 (144
mg, 0.25 mmol, 1 equiv), DMF (2 mL), and 1,4-diisocyanatobutane
(0.012 mL, 0.4 equiv). The resulting solution was stirred for 2 h
at 60.degree. C. in an oil bath. The resulting mixture was
concentrated under vacuum and purified by preparative HPLC as
below.
Example 92:
1-(2-[2-[(3S)-3-[(4-[[(1S,2S)-6-Chloro-4-cyano-2-(dimethylamino)-2,3-dihy-
dro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxopyrrolidin-1-yl]e-
thoxy]ethyl)-3-(4-[[(2-[2-[(3S)-3-[4-[[(1S,2S)-6-chloro-4-cyano-2-(dimethy-
lamino)-2,3-dihydro-1H-inden-1-yl]oxy]-3-methylbenzene)sulfonamido]-2-oxop-
yrrolidin-1-yl]ethoxy]ethyl]carbamoyl]amino]butyl)urea;
bis(trifluoroacetic acid)
[0980] Crude compound of Steps A-D was purified by preparative HPLC
with the following conditions: Column, XBridge Shield RP18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (15.0% CH.sub.3CN up to 40.0% in 10 min); Detector, UV
254 nm. This resulted in 51.5 mg (14%) of the title compound as a
white solid. MS (m/z): 1293 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
400 MHz) .delta. 7.91-7.79 (m, 6H), 7.49 (d, J=8.8 Hz, 2H),
7.45-7.39 (m, 2H), 6.52 (d, J=6.7 Hz, 2H), 4.54 (td, J=8.5, 6.6 Hz,
2H), 4.07 (dd, J=9.9, 8.5 Hz, 2H), 3.81 (dd, J=16.7, 8.5 Hz, 2H),
3.59-3.32 (m, 19H), 3.22 (t, J=5.4 Hz, 4H), 3.07 (s, 17H), 2.31 (s,
8H), 1.80 (dq, J=12.6, 9.3 Hz, 2H), 1.52-1.44 (m, 4H).
Representative Scheme for Synthesis of Cyclic-Substituted
Sulfonamide Linkers:
##STR00186##
[0982] Step A: To a 250-mL round-bottom flask was added
2-(2-chloroethoxy)ethan-1-ol (7.8 g, 62.62 mmol, 1 equiv) and water
(300 mL). This was followed by the addition of a solution of sodium
azide (7.7 g, 118.4 mmol, 2 equiv) in water (40 mL) dropwise with
stirring. The resulting solution was stirred overnight at
80.degree. C. The reaction mixture was cooled to 0.degree. C. with
a watertice bath and extracted with 3.times.500 mL of
CH.sub.2Cl.sub.2. The organic layers were combined, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum
providing 10 g (crude) of 2-(2-azidoethoxy)ethan-1-ol (INT-Y1) as a
colorless oil.
[0983] Step B: To a 500-mL round-bottom flask was added
azidoalcohol INT-Y1 (10 g crude from Step A, theoretical 62.6 mmol,
1 equiv), dichloromethane (300 mL), 4-methylbenzene-1-sulfonyl
chloride (18 g, 94.42 mmol, 1.3 equiv), and triethylamine (10 mL,
1.15 equiv). The resulting solution was stirred for 2 h at room
temperature. The reaction was then quenched by the addition of 50
mL of water and extracted with 3.times.300 mL of dichloromethane.
The organic layers were combined, dried over anhydrous sodium
sulfate, filtered, and concentrated under vacuum. The residue was
applied onto a silica gel column with petroleum ether/ethyl acetate
(1:3) providing 15 g (69%) of
1-[[2-(2-azidoethoxy)ethoxy]sulfonyl]-4-methylbenzene (INT-Y2) as a
colorless oil.
[0984] Step C: To a 100-mL round-bottom flask was added tert-butyl
(3R)-3-hydroxypyrrolidine-1-carboxylate (700 mg, 3.74 mmol, 1
equiv), DMF (30 mL), and tosylate INT-Y2 (900 mg, 3.15 mmol, 0.84
equiv). This was followed by the addition of sodium hydride (300
mg, 12.50 mmol, 3.34 equiv) in several portions at 0.degree. C. The
resulting slurry was stirred overnight at 40.degree. C. The
resulting mixture was diluted with 50 mL of ethyl acetate and
quenched by the addition of 50 mL of water. The resulting solution
was extracted with 2.times.150 mL of ethyl acetate and the organic
layers combined. The resulting mixture was washed with 2.times.150
mL of brine, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. This resulted in 940 mg (84%) of
tert-butyl
(3R)-3-[2-(2-azidoethoxy)ethoxy]pyrrolidine-1-carboxylate (INT-Y3)
as a light brown solid.
[0985] Step D: To a 100-mL round-bottom flask was added azide
INT-Y3 (940 mg, 3.13 mmol, 1 equiv), CH.sub.2Cl.sub.2 (50 mL), and
trifluoroacetic acid (12 mL). The resulting solution was stirred
for 30 min at room temperature. The pH value of the solution was
adjusted to 12 with saturated aqueous potassium carbonate and
extracted with 2.times.150 mL of CH.sub.2Cl.sub.2. The combined
organic layers were washed with 2.times.150 mL of brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
This resulted in 630 mg (crude) of
(3R)-3-[2-(2-azidoethoxy)ethoxy]pyrrolidine (INT-Y4) as a light
brown oil.
[0986] Step E: To a 250-mL round-bottom flask was added amine
INT-Y4 (702 mg, 3.5 mmol, 1 equiv), CH.sub.2Cl.sub.2 (50 mL),
4-(benzyloxy)benzene-1-sulfonyl chloride (INT-L3 with
R.sup.1.dbd.H, 1 g, 3.5 mmol, 1 equiv), and triethylamine (2.8 mL).
The resulting solution was stirred for 30 min at room temperature.
The resulting solution was diluted with water and extracted with
3.times.200 mL of CH.sub.2Cl.sub.2. The combined organic layers
were washed with 2.times.200 mL of brine, dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The
residue was applied onto a silica gel column with petroleum
ether/ethyl acetate (3:1) providing 380 mg (24%) of
(3R)-3-[2-(2-azidoethoxy)ethoxy]-1-[[4-(benzyloxy)benzene]sulfonyl]pyrrol-
idine (INT-Y5) as a light yellow oil.
[0987] Step F: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of H.sub.2 was added azide INT-Y5 (700 mg,
1.57 mmol, 1 equiv), methanol (40 mL), and palladium on carbon (200
mg). The resulting slurry was stirred overnight at room
temperature. The resulting solution was diluted with 200 mL of
methanol, filtered, and concentrated under vacuum. The residue was
applied onto a silica gel column with
CH.sub.2Cl.sub.2:methanol:triethylamine (100:10:1) providing 380 mg
(73%) of
4-[(3R)-3-[2-(2-aminoethoxy)ethoxy]pyrrolidine-1-sulfonyl]phenol
(INT-Y6) as a light brown oil.
[0988] Step G: To a 250-mL round-bottom flask was added amine
INT-Y6 (380 mg, 1.15 mmol, 1 equiv), methanol (30 mL), and ethyl
2,2,2-trifluoroacetate (817.6 mg, 6.48 mmol, 5.6 equiv). The
resulting solution was stirred overnight at room temperature. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with petroleum ether/ethyl acetate
(1:2). This resulted in 390 mg (80%) of
2,2,2-trifluoro-N-[2-(2-[[(3R)-1-[(4-hydroxybenzene)sulfonyl]pyr-
rolidin-3-yl]oxy]ethoxy)ethyl]acetamide (INT-Y7) as a light brown
oil.
[0989] Other cyclic amine intermediates were generated from the
analogous procedure beginning with the appropriate Boc-aminoalcohol
starting materials.
##STR00187##
Representative Scheme for Synthesis of Cyclic-Substituted Dimer
Products:
Example 93:
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethyl]--
1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dic-
hloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]e-
thoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00188##
[0991] Step A: To a 250-mL round-bottom flask was added phenol
INT-Y7 (390 mg, 0.91 mmol, 1 equiv), tetrahydrofuran (20 mL), and
aminoindanol INT-18F (369 mg, 0.92 mmol, 1 equiv). This was
followed by the addition of PPh.sub.3 (480 mg, 1.83 mmol, 2 equiv)
in several portions at 0.degree. C. and subsequently DIAD (370 mg,
1.83 mmol, 2 equiv) dropwise at 0.degree. C. The resulting solution
was stirred for 40 min at room temperature. The resulting mixture
was concentrated under vacuum. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2:methanol:triethylamine
(100:10:1) providing 2 g of tert-butyl
N-[(3R)-1-[(1S,2S)-4,6-dichloro-1-[4-[(3R)-3-[2-[2-(trifluoroacetamido)et-
hoxy]ethoxy
(pyrrolidine-1-sulfonyl]phenoxy]-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl-
]carbamate (INT-Y10) as a dark oil.
[0992] Step B: To a 250-mL round-bottom flask was added INT-Y10 (2
g, 2.47 mmol, 1 equiv) and methanol (60 mL). This was followed by
the addition of sodium hydroxide (3M.sub.(aq),10 mL). The resulting
solution was stirred for 1 h at 60.degree. C. The resulting
solution was extracted with 2.times.200 mL of CH.sub.2Cl.sub.2. The
combined organic layers were washed with 1.times.150 ml, of brine,
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate/petroleum ether (150:120) providing 370 mg (21%) of
tert-butyl
N-[(3R)-1-[(1S,2S)-1-[4-[(3R)-3-[2-(2-aminoethoxy)ethoxy]pyrrolidine-1-su-
lfonyl]phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carb-
amate (INT-Y11) as a light brown oil.
[0993] Step C: To a 100-mL round-bottom flask was added amine
INT-Y11 (370 mg, 0.52 mmol, 1 equiv), DMF (15 mL), and
1,4-diisocyanatobutane (36.3 mg, 0.26 mmol, 0.5 equiv). The
resulting solution was stirred for 1 h at 60.degree. C. The
resulting mixture was concentrated under vacuum. The residue was
applied onto a silica gel column with
CH.sub.2Cl.sub.2:methanol:triethylamine (100:10:1). This resulted
in 210 mg (26%) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-[4-[(3R)-3-[2-[2-([[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-
-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethoxy)ethy-
l]carbamoyl]amino)butyl]carbamoyl]amino)ethoxy]ethoxy]pyrrolidine-1-sulfon-
yl]phenoxy]-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl](carbama-
te (INT-Y12) as an off-white solid.
[0994] Step D: To a 100-mL round-bottom flask was added dimer
INT-Y12 (210 mg, 0.13 mmol, 1 equiv), CH.sub.2Cl.sub.2 (10 mL), and
trifluoroacetic acid (1.5 mL). The resulting solution was stirred
for 1 h at room temperature. The pH value of the solution was
adjusted to 12 with saturated aqueous potassium carbonate and
extracted with 2.times.200 mL of CH.sub.2Cl.sub.2. The combined
organic layers were washed with 1.times.200 mL of brine and
concentrated under vacuum to provide crude compound Example 93.
Example 93:
3-[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethox-
y)ethyl]-1-[4-([[2-(2-[[(3R)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl-
]-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-
-yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea
[0995] Crude product of Steps A-D was purified by preparative HPLC
with the following conditions: Column, XBridge Shield RP18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (28.0% CH.sub.3CN up to 39.0% in 10 min); Detector, UV
254 nm. This resulted in 81.4 g (38%) of the title compound as an
off-white solid. MS (m/z): .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.86 (d, J=8.8 Hz, 4H), 7.45 (s, 2H), 7.34 (d, J=8.8 Hz,
4H), 7.15 (s, 2H), 6.14 (d, J=5.6 Hz, 2H), 4.06 (s, 2H), 3.88-3.84
(m, 2H), 3.50-3.40 (m, 16H), 3.40-3.37 (m, 6H), 3.29-3.22 (m, 7H),
3.09-3.03 (m, 8H), 2.86 (s, 2H), 2.75-2.67 (m, 4H), 1.99-1.87 (m,
8H), 1.79-1.68 (m, 2H), 1.64-1.62 (m, 2H), 1.60 (s, 4H), 1.29 (s,
1H).
Example 94:
3-[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3-yl]oxy]ethox-
y)ethyl]1-[4-([[2-(2-[[(3S)-1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-
-4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]pyrrolidin-3--
yl]oxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea
##STR00189##
[0997] Beginning with INT-18F and INT-Y8, the crude product of
Steps A-D was purified by preparative HPLC with the following
conditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm,
5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN (30.0%
CH.sub.3CN up to 36.0% in 9 min); Detector, UV 220 nm. This
resulted in 22 mg (13%) of the title compound as a brown solid. MS
(m/z): 1368 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz):
.delta. 7.87 (d, J=8.8 Hz, 5H), 7.46 (s, 2H), 7.35 (d, J=8.8 Hz,
5H), 7.20 (s, 2H), 6.03 (d, J=7.8 Hz, 2H), 4.08 (s, 2H), 3.70 (s,
2H), 3.55 (s, 3H), 3.51-3.49 (m, 11H), 3.49-3.35 (m, 8H), 3.19-2.91
(m, 10H), 2.90 -2.80 (m, 2H), 2.70-2.61 (m, 7H), 1.95-1.80 (m, 8H),
1.70-1.48 (m, 5H) 1.40 (s, 4H), 1.32 (s, 2H).
Example 95:
3-[2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-
-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethoxy]ethy-
l]-1[4-[([2-[2-([1-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonyl]piperidin-4-yl]oxy)ethox-
y]ethyl]carbamoyl)amino]butyl]urea
##STR00190##
[0999] Beginning with INT-18F and INT-Y9, the crude product of
Steps A-D was purified by preparative HPLC with the following
conditions: Column, XBridge Shield RP18 OBD Column, Sum, 19*150 mm,
5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN (29.0%
CH.sub.3CN up to 36.0% in 13 min); Detector, UV 254 nm. This
resulted in 112.8 mg (28%) of the title compound as an off-white
solid. MS (m/z): 1395.4 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400
MHz): .delta. 7.80 (d, J=6.8 Hz, 4H), 7.44 (s, 2H), 7.34 (d, J=8.8
Hz, 4H), 7.17 (s, 2H), 6.04 (d, J=5.2 Hz, 2H), 3.75-3.72 (m, 2H),
3.69 (s, 8H), 3.55-3.35 (m, 6H), 3.31-3.21 (m, 11H), 3.13-3.01 (m,
6H), 2.99-2.72 (m, 7H), 2.71 (s, 2H), 2.65-2.60 (m, 6H), 1.93-1.84
(m, 8H), 1.70-1.46 (m, 8H), 1.29 (s, 4H).
Representative Scheme for Synthesis of .alpha.-Alkyl-substituted
Sulfonamide Linkers:
##STR00191##
[1001] Step A: To a 250-mL round-bottom flask, was added
(2S)-2-aminopropan-1-ol (2.1 g, 28 mmol, 4 equiv) and
CH.sub.2Cl.sub.2 (50 mL). This was followed by the dropwise
addition of a solution of 4-(benzyloxy)benzene-1-sulfonyl chloride
(INT-L3 with R.sup.1.dbd.H, 2 g, 7.07 mmol, 1 equiv) in
CH.sub.2Cl.sub.2 (50 mL). The resulting solution was stirred for 40
min at room temperature. The resulting mixture was concentrated
under vacuum. The residue was applied onto a silica gel column with
ethyl acetate (100%) providing 2.33 g of
(S)-4-(benzyloxy)-N-(1-hydroxypropan-2-yl)benzenesulfonamide
(INT-B1) as a white solid.
[1002] Step B: To a 250-mL round-bottom flask, was added alcohol
INT-B1 (960 mg, 3 mmol, 1 equiv), azidotosylate INT-Y2 (870 mg, 3
mmol, 1 equiv), DMF (40 mL), and lastly sodium hydride (360 mg,
15.00 mmol, 5 equiv) in portions. The resulting slurry was stirred
overnight at room temperature. The reaction was quenched by the
addition of 100 mL of water and extracted with 3.times.150 mL of
ethyl acetate. The combined organic layers were dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:1) providing 300 mg (23%) of
N-[(2S)-1-[2-(2-azidoethoxy)ethoxy]propan-2-yl]-4-(benzyloxy)benzene-1-su-
lfonamide (INT-B2) as a yellow oil.)
[1003] Step C: To a 250-mL round-bottom flask was added azide
INT-B2 (200 mg, 0.46 mmol, 1 equiv), methanol (20 mL), and
palladium on carbon (100 mg). Hydrogen gas was introduced into the
flask. The resulting slurry was stirred for 3 h at room
temperature. The solids were removed by filtration and the filtrate
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate (100%) providing 100 mg (68%) of
N-[(2S)-1-[2-(2-aminoethoxy)ethoxy]propan-2-yl]-4-hydroxybenzene-1-sulfon-
amide (INT-B3) as a colorless oil.
[1004] Step D: To a 250-mL round-bottom flask, was added amine
INT-B3 (400 mg, 1.26 mmol, 1 equiv), methanol (35 mL), and ethyl
2,2,2-trifluoroacetate (892 mg). The resulting solution was stirred
for 30 min at room temperature. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate/petroleum ether (1:2) providing 430
mg (83%) of
(S)-2,2,2-trifluoro-N-(2-[2-(2-[(4-hydroxyphenyl)sulfonamide]propoxy)etho-
xy]ethyl)acetamide (INT-B4) as a light yellow oil.
[1005] Other .alpha.-alkyl-substituted sulfonamide intermediates
were generated from the analogous procedure beginning with the
appropriate aminoalcohol starting materials.
##STR00192##
[1006] The germinal dimethyl version of these
.alpha.-alkyl-substituted sulfonamide linkers was made through the
following procedure.
##STR00193##
[1007] Step A: To a 100-mi, 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen was added methyl
3-hydroxy-2,2-dimethylpropanoate (1.32 g, 10 mmol, 1 equiv),
CH.sub.2Cl.sub.2 (40 mL), and 2,6-lutidine (1.6 g, 15 mmol, 1.5
equiv). This was followed by the dropwise addition of triflic
anhydride (Tf.sub.2O, 3.39 g, 12 mmol, 1.2 equiv) -78.degree. C.
The resulting solution was stirred for 15 min at -78.degree. C. and
then gradually warmed to room temperature over 3 h. The resulting
solution was diluted with 100 mL of ethyl acetate and sequentially
washed with 1.times.50 mL of water, 2.times.40 mL of 2M hydrogen
chloride, and 2.times.40 mL of brine. The mixture was dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
This resulted in 2.64 g (100% crude) of methyl
2,2-dimethyl-3-[(trifluoromethane)sulfonyloxy]propanoate INT-B8 as
a brown oil.
[1008] Step B: To a 100-mL round-bottom flask was added triflate
INT-B8 (2.64 g, 10 mmol, 2 equiv), 2-(2-azidoethoxy)ethan-1-ol
(INT-Y2, 650 mg, 5 mmol, 1 equiv), and DMF (40 mL). This was
followed by the addition of sodium hydride (60% in oil, 400 mg, 10
mmol, 2 equiv) in portions at 0.degree. C. The resulting slurry was
stirred for 14 h at room temperature. The reaction was quenched by
the slow addition of 100 mL of water and extracted with 3.times.50
mL of ethyl acetate. The combined organic layers were washed with
1.times.100 mL of water and 1.times.100 mL of brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
This resulted in 1.23 g (100% crude) of methyl
3-[2-(2-azidoethoxy)ethoxy]-2,2-dimethylpropanoate (INT-B9) as a
brown oil.
[1009] Step C: To a 100-mL round-bottom flask was added ester
INT-B9 (3.68 g, 15 mmol, 1 equiv), tetrahydrofuran (30 mL), and
water (20 mL). This was followed by the addition of LiOH--H.sub.2O
(1.26 g, 30 mmol, 2 equiv) in portions at room temperature. The
resulting solution was stirred for 4 h at 50.degree. C. The
reaction mixture was cooled to room temperature and diluted with of
water. The volatiles were removed under vacuum and the resulting
mixture washed with 2.times.30 mL of petroleum ether. The pH of the
aqueous layer was adjusted to 1-2 with 3M aqueous hydrogen chloride
and extracted with 3.times.40 mL of CH.sub.2Cl.sub.2. The combined
organic layers were washed with 1.times.50 mL of water and
1.times.50 mL of brine, dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. This resulted in 2.4 g
(69% crude) of 3-[2-(2-azidoethoxy)ethoxy]-2,2-dimethylpropanoic
acid (INT-B10) as a light yellow oil.
[1010] Step D: To a 100-mL round-bottom flask was added carboxylic
acid INT-B10 (2.4 g, 10.4 mmol, 1 equiv), toluene (30 mL), and
triethylamine (2.1 g, 20.8 mmol, 2 equiv). This was followed by the
dropwise addition of DPPA (4.1 g, 14.9 mmol, 1.5 equiv) with
stirring at room temperature. The resulting solution was stirred
for 1 h at room temperature. Water (10 mL) was added and the
resulting slurry allowed to react with stirring for an additional
14 h at reflux. The resulting solution was diluted with 40 mL of
water and hydrogen chloride (3M.sub.(aq), 20 mL). The resulting
mixture was washed with 1.times.50 mL of petroleum ether. The pH
value of the aqueous layer was adjusted to 13-14 with sodium
hydroxide and extracted with 3.times.50 mL of CH.sub.2Cl.sub.2. The
combined organic layers were washed with 1.times.50 mL of water and
1.times.50 mL of brine, dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. This resulted in 1.5 g
(71% crude) of 1-(2-amino-2-methylpropoxy)-2-(2-azidoethoxy)ethane
(INT-B11) as a light yellow oil.
[1011] Step E: To a 100-mL round-bottom flask was amine INT-B11
(1.5 g, 7.42 mmol, 1.5 equiv), CH.sub.2Cl.sub.2 (40 mL), and
triethylamine (1.5 g, 14.8 mmol, 2 equiv). This was followed by the
addition of 4-(benzyloxy)benzene-1-sulfonyl chloride (INT-L3 with
R.sup.1.dbd.H, 1.41 g, 5 mmol, 1 equiv) in portions at room
temperature. The resulting solution was stirred overnight at room
temperature. The resulting solution was diluted with 200 mL of
ethyl acetate and washed with 2.times.100 mL of water and
1.times.100 mL of brine. The mixture was dried over anhydrous
sodium sulfate, filtered, and concentrated under vacuum. The
residue was applied onto a silica gel column with petroleum
ether/ethyl acetate (8:1-2:1) providing 1.8 g (80%) of
N-[1-[2-(2-azidoethoxy)ethoxy]-2-methylpropan-2-yl]-4-(benzyloxy)benzene--
1-sulfonamide (INT-B12) as a light yellow oil.
[1012] Step F: To a 100-mL round-bottom flask was added azide
INT-B12 (1.8 g, 4.0 mmol, 1 equiv), methanol (40 mL), and palladium
on carbon (180 mg, 0.10 equiv). To the above, hydrogen (1 atm) was
introduced in and the resulting slurry stirred overnight at room
temperature. The solids were filtered out. The resulting mixture
was concentrated under vacuum providing 1.33 g (100%) of
N-[1-[2-(2-aminoethoxy)ethoxy]-2-methylpropan-2-yl]-4-hydroxybenzene-1-su-
lfonamide (INT-B13) as a colorless oil.
[1013] Step G: To a 100-mL round-bottom flask was added amine
INT-B13 (1.33 g, 4.0 mmol, 1 equiv) and CH.sub.2Cl.sub.2 (40 Ml)
followed by the dropwise addition of ethyl 2,2,2-trifluoroacetate
(2.84 g, 20 mmol, 5 equiv) at room temperature. To this was added
triethylamine (40 mg, 0.40 mmol, 0.1 equiv). The resulting solution
was stirred for 1 h at room temperature. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with petroleum ether/ethyl acetate (4:1-2:1) providing
1.57 g (92%) of
2,2,2-trifluoro-N-[2-(2-[2-[(4-hydroxybenzene)sulfonamido]-2-methylpropox-
y]ethoxy)ethyl]acetamide (INT-B14) as a light yellow oil.
Representative Scheme for Synthesis of .alpha.-Alkyl-substituted
Dimer Products:
Example 96:
1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-
-(4-[[(2-[2[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-
carbamoyl]amino]butyl)urea; hydrochloride
##STR00194##
[1015] Step A: To a 100-mL round-bottom flask was added phenol
INT-B4 (430 mg, 1.04 mmol, 1 equiv), tetrahydrofuran (25 mL),
aminoindanol INT-18F (416 mg, 1.04 mmol, 1 equiv), and PPh.sub.3
(408 mg, 1.56 mmol, 1.5 equiv). This was followed by the dropwise
addition of a solution of DIAD (314 mg, 1.55 mmol, 1.5 equiv) in
tetrahydrofuran (2 mL) over 20 min. The resulting solution was
stirred for 40 min at 40.degree. C. The resulting mixture was
concentrated under vacuum. The residue was applied onto a silica
gel column with ethyl acetate (100%) providing 1 g of tert-butyl
N-[(3R)-1-[(1S,2S)-4,6-dichloro-1-(4-[[(2S)-1-[2-[2-(trifluoroacetamido)e-
thoxy]ethoxy]propan-2-yl]sulfamoyl]phenoxy)-2,3-dihydro-1H-inden-2-yl]pipe-
ridin-3-yl]carbamate (INT-B15) as a brown oil.
[1016] Step B: To a 250-ml, round-bottom flask was added INT-B15 (1
g, 1.25 mmol, 1 equiv) and methanol (50 mL) followed by the
addition of sodium hydroxide (3M.sub.(aq), 8 mL). The resulting
solution was stirred for 45 min at 60.degree. C. The resulting
slurry was extracted with 3.times.150 mL of CH.sub.2Cl.sub.2. The
combined organic layers were dried over anhydrous sodium sulfate,
filtered, and concentrated under vacuum. This resulted in 230 mg
(26%) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-(4-[[(2S)-1-[2-(2-aminoethoxy)ethoxy]propan-2-yl]sul-
famoyl]phenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carb-
amate (INT-B16) as a light yellow solid.
[1017] Step C: To a 100-mL round-bottom flask was added amine
monomer INT-B16 (230 mg, 0.33 mmol, 1 equiv), DMF (20 mL), and
1,4-diisocyanatobutane (23 mg, 0.16 mmol, 0.5 equiv). The resulting
solution was stirred for 1 h at 60.degree. C. The resulting mixture
was concentrated under vacuum. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/methanol (10:1) providing
150 mg (30%) of tert-butyl
N-[(3R)-1-[(1S,2S)-1-(4-[[(2S)-1-[2-(2-[[(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-
-2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]piperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)carbamo-
yl]amino]butyl)carbamoyl]amino]e
thoxy)ethoxy]propan-2-yl]sulfamoyl]phenoxy)-4,6-dichloro-2,3-dihydro-1H-i-
nden-2-yl]piperidin-3-yl]carbamate (INT-B17) as a light brown
solid.
[1018] Step D: To a 100-mL round-bottom flask was added Boc-dimer
B17 (150 mg, 0.10 mmol, 1 equiv), CH.sub.2Cl.sub.2 (10 mL), and
trifluoroacetic acid (1.5 mL). The resulting solution was stirred
for 1 h at room temperature. The pH value of the solution was
adjusted to 12 with saturated aqueous potassium carbonate and
extracted with 100 mL of CH.sub.2Cl.sub.2. The organic layer was
washed with 2.times.100 mL of brine, dried over anhydrous sodium
sulfate, filtered, and concentrated under vacuum to provide crude
compound Example 96.
Example 96:
1-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-3-
-(4-[[(2-[2-[(2S-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-
carbamoyl]amino]butyl)urea; hydrochloride
[1019] Crude product of Steps A-D was purified by preparative HPLC
with the following conditions: Column, XBridge Preparative C18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% HCl) and
CH.sub.3CN (25.0% CH.sub.3CN up to 55.0% in 10 min); Detector, UV
254 nm. This resulted in 20.8 mg (16%) of the title compound as a
light yellow solid. MS (m/z): 1343.7 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.96 (d, J=8.8 Hz, 4H), 7.52 (s,
2H), 7.40 (d, J=8.8 Hz, 4H), 7.04 (s, 2H), 6.78 (d, J=4.0 Hz, 2H),
4.60-4.42 (m, 2H), 3.90-3.66 (n, 8H), 3.55-3.49 (n, 18H), 3.32-3.10
(m, 10H), 3.09 (s, 4H), 2.28-2.00 (m, 6H), 1.78-1.66 (m, 2H), 1.46
(s, 4H), 1.30-1.28 (m, 1H), 1.07 (d, J=6.4 Hz, 6H).
Example 97:
3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-1-
-(4-[[2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]propoxy]ethoxy]ethyl)-
carbamoyl]amino]butyl)urea
##STR00195##
[1021] Beginning with INT-I8F and INT-B5, the crude product of
Steps A-D was purified by preparative HPLC with the following
conditions: Column, XBridge C18 OBD Preparative Column, 19*250 mm,
5 um; mobile phase, waters (0.05% TEA) and CH.sub.3CN (17.0%
CH.sub.3CN up to 60.0% in 8 min); Detector, UV 254 nm. This
resulted in 150.7 mg (43%) of the title compound as a white solid.
MS (m/z): 1343.25 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.96-7.86 (m, 4H), 7.45 (d, J=1.6 Hz, 2H), 7.30 (d, J=8.8
Hz, 4H), 7.12 (s, 2H), 6.20 (d, J=5.6 Hz, 2H), 3.92-3.78 (m, 2H),
3.56-3.50 (m, 12H), 3.50-3.30 (m, 8H), 3.29-3.26 (m, 6H), 3.13-3.04
(m, 8H), 3.04-2.82 (m, 2H), 2.78-2.73 (m, 4H), 1.96-1.88 (m, 4H),
1.63-1.61 (m, 2H), 1.61-1.55 (m, 2H), 1.44 (s, 4H), 1.06 (d, J=6.4
Hz, 6H).
Example 98:
3-(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy])benzene)sulfonamido]-3-methylbutoxy]ethoxy-
]ethyl)-1-(4-[[(2-[2-[(2S)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]--
4,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)
sulfonamido]-3-methylbutoxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea
dihydrochloride
##STR00196##
[1023] Beginning with INT-I8F and INT-B6, the crude product of
Steps A-D was purified by preparative HPLC with the following
conditions: Column, XBridge Preparative C18 OBD Column, 19*150 mm,
5 um; mobile phase, water (0.05% HCl) and CH.sub.3CN (40.0%
CH.sub.3CN up to 60.0% in 10 min); Detector, UV 254 nm. This
resulted in 82.8 mg (18%) of the title compound as a white solid.
MS (m/z): 1400 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.98 (d, J=8.4 Hz, 4H), 7.55 (s, 2H), 7.42 (d, J=8.4 Hz,
4H), 7.05 (s, 2H), 6.86 (d, J=6.4 Hz, 2H), 4.57 (q, J=8.0 Hz, 2H),
3.84-3.71 (m, 8H), 3.59-3.27 (m, 24H), 3.22 (q, J=5.4 Hz, 2H), 3.12
(s, 4H), 2.33-2.19 (m, 6H), 1.97-1.69 (m, 4H), 1.50 (s, 4H), 0.90
(t, J=6.4 Hz, 12H).
Example 99:
3-(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-
-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbutoxy]ethoxy]-
ethyl)-1-(4-[[(2-[2-[(2R)-2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4-
,6-dichloro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-3-methylbut-
oxy]ethoxy]ethyl)carbamoyl]amino]butyl)urea
##STR00197##
[1025] Beginning with INT-I8F and INT-B7, the crude product of
Steps A-D was purified by preparative HPLC with the following
conditions: Column, XBridge Shield RP18 OBD Column, 19*150 mm, 5
um; mobile phase, water (0.05% TFA) and CH.sub.3CN (30.0%
CH.sub.3CN up to 47.0% in 8 min); Detector, UV 254 nm. This
resulted in 48.6 mg (56%) of the title compound as a white solid.
MS (m/z): 1400 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz):
.delta. 7.95-7.87 (d, J=9.2 Hz, 4H), 7.46 (d, J=1.6 Hz, 2H), 7.30
(d, J=6.4 Hz, 4H), 7.14 (s, 2H), 6.15 (d, J=8.8 Hz, 2H), 3.80 (q,
J=5.6 Hz, 2H), 3.56-3.34 (m, 18H), 3.34-3.26 (m, 4H), 3.22-3.18 (m,
2H), 3.13-2.99 (m, 8H), 2.83 (s, 2H), 2.78-2.66 (m, 4H), 2.03-1.82
(m, 6H), 1.79-1.57 (m, 4H), 1.46 (s, 4H), 0.89 (t, J=6.4 Hz,
12H).
Example 100:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]ethoxy)ethy-
l]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlo-
ro-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]-2-methylpropoxy]etho-
xy)ethyl]carbamoyl]amino)butyl]urea; hydrochloride
##STR00198##
[1027] Beginning with INT-I8F and INT-B14, the crude product of
Steps A-D was purified by preparative HPLC with the following
conditions: Column, XBridge Preparative C18 OBD Column, 19*150 mm,
5 um; mobile phase, water (0.05% HCl) and CH.sub.3CN (30%
CH.sub.3CN up to 60% in 10 min); Detector, UV 254 nm. This resulted
in 217.6 mg (45%) of the title compound as a light yellow solid. MS
(m/z): 1371.25 [M+H].sup.+. .sup.1H NMR (Methanol-d.sub.4, 400 MHz)
.delta. 7.99 (d, =8.8 Hz, 4H), 7.54 (s, 2H), 7.42 (d, J=8.8 Hz,
4H), 7.05 (s, 2H), 6.85 (d, J=6.0 Hz, 2H), 4.55 (q, J=7.8 Hz, 2H),
3.92-3.73 (m, 8H), 3.64-3.56 (m, 12H), 3.47 (q, J=8.2 Hz, 2H),
3.42-3.29 (m, 14H), 3.10 (s, 4H), 2.26-2.12 (m, 6H), 1.85-1.70 (m,
2H), 1.48 (s, 4H), 1.23 (s, 12H).
General Scheme for Synthesis of Ortho-Substituted Sulfonamide Dimer
Products:
##STR00199##
[1029] Step A: To a round-bottom flask was added aminoindanol
INT-I8F (1 equiv) and tetrahydrofuran (0.2M), followed by the
addition of phenol linker INT-L6 (1.1 equiv) and heating to
40.degree. C. To this slurry was added PPh.sub.3 (2 equiv) and DIAD
(1.5 equiv). The resulting solution was stirred for 1-3 h at
40.degree. C. The resulting mixture was concentrated under vacuum
and diluted with CH.sub.2Cl.sub.2. The residue was applied onto a
silica gel column with petroleum ether/ethyl acetate (1:1)
providing indane monomer INT-E1.
[1030] Step B: To a round-bottom flask was added indane monomer
INT-E1 (1 equiv), methanol (0.1M), and sodium hydroxide
(3M.sub.(aq), 3-5 equiv). The resulting solution was stirred for
1-2 h at 60.degree. C. The resulting mixture was concentrated under
vacuum and diluted with CH.sub.2Cl.sub.2. The residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (10:1)
providing indane amine monomer INT-D2.
[1031] Step C: To a round-bottom flask was added INT-E2 (1 equiv),
N,N-dimethylformamide (DMF, 0.1M), and 1,4-diisocyanatobutane
(0.4-0.5 equiv). The resulting solution was stirred for 2 h at
60.degree. C. The resulting mixture was concentrated under vacuum
and diluted with of CH.sub.2Cl.sub.2. The residue was applied onto
a silica gel column with chloroform/methanol (10:1) providing the
desired dimer of structure (I). Final products were purified by
preparative HPLC. The final products were generally isolated as the
free based amines, TFA salts, or hydrochloride salts.
[1032] Step D: To a round-bottom flask was added Boc-protected
dimer (I) (1 equiv) and 5:1 CH.sub.2Cl.sub.2:TFA (.about.0.05M).
The resulting solution was stirred for 2 h at room temperature. The
resulting mixture was concentrated under vacuum. The crude product
was purified by preparative HPLC. The final products were generally
isolated as the free based amines, TFA salts, or hydrochloride
salts.
Example 101:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethoxy)ethy-
l]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-2-methoxybenzene)sulfonamido]ethoxy]ethox-
y)ethyl]carbamoyl]amino)butyl]urea
##STR00200##
[1034] Beginning with INT-L6J and INT-I8F, Steps A-D provided
Example 101 which was purified by preparative HPLC with the
following conditions: Column, XBridge Shield RP18 OBD Column,
19*150 mm, 5 um; mobile phase, water (0.05% TFA) and CH.sub.3CN
(15.0% CH.sub.3CN up to 50.0% in 8 min); Detector, UV 254 nm. This
resulted in 0.146 g (100%) of the title compound as a white solid.
MS (m/z): 1375.80 [M+H].sup.+. .sup.1H NMR (Methanol-d4,400 MHz):
.delta. 7.83 (d, J=8.8 Hz, 2H), 7.44 (s, 2E1), 7.18 (s, 2H),
6.93-6.86 (m, 4H), 6.05 (s, 2H), 3.96 (s, 6H), 3.70 (s, 2H),
3.60-3.53 (m, 9H), 3.51-3.48 (m, 9H), 3.40-3.31 (m, 8H), 3.12-3.09
(m, 6H), 3.03 (t, J=5.41-1z, 6H), 2.71 (d, J=8.0 Hz, 2H), 2.62-2.58
(m, 4H), 1.96-1.91 (m, 2H), 1.84 (s, 2H), 1.80-1.68 (m, 2H),
1.65-1.50 (m, 2H), 1.46 (s, 4H).
Example 102:
3-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy)ethyl-
]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-2-methylbenzene)sulfonamido]ethoxy]ethoxy-
)ethyl]carbamoyl]amino)butyl]urea
##STR00201##
[1036] Beginning with INT-L6K and INT-18F, Steps A-D provided
Example 102 which was purified by preparative HPLC with the
following conditions: Column, XSelect CSH Preparative C18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (25.0% CH.sub.3CN up to 37.0% in 10 min); Detector, UV
254 nm. This resulted in 30.4 mg (20%) of the title compound as a
solid. MS (m/z): 1343.4 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400
MHz) .delta. 7.95 (d, J=8.8 Hz, 2H), 7.46 (s, 2H), 7.19-7.11 (m,
6H), 6.12 (d, J=5.8 Hz, 2H), 3.78 (q, J=7.4 Hz, 2H), 3.63-3.45 (m,
17H), 3.41-3.35 (m, 2H), 3.35-3.25 (m, 8H), 3.13-3.05 (m, 8H),
3.05-2.98 (m, 4H), 2.85 (s, 2H), 2.70-2.60 (m, 9H), 2.00-1.85 (m,
4H), 1.73 (d, J=9.0 Hz, 2H), 1.59 (d, J=8.8 Hz, 2H), 1.46 (s, 4H),
1.33 (t, J=8.8 Hz, 2H).
Example 103:
1-[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3--
dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy)ethyl-
]-3-[4-([[2-(2-[2-[(4-[[(1S,2S)-2-[(3R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy]-2-fluorobenzene)sulfonamido]ethoxy]ethoxy-
)ethyl]carbamoyl]amino)butyl]urea
##STR00202##
[1038] Beginning with INT-L6L and INT-I8F, Steps A-D provided
Example 103 which was purified by preparative HPLC with the
following conditions: Column, XSelect CSH Preparative C18 OBD
Column, 19*150 mm, 5 um; mobile phase, water (0.05% TFA) and
CH.sub.3CN (23.0% CH.sub.3CN up to 41.0% in 8 min); Detector, UV
254 nm. This resulted in 53.2 mg (69%) of the title compound as a
white solid. MS (m/z): 1351.75 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.88 (t, J=8.6 Hz, 2H), 7.47 (d,
J=1.8 Hz, 2H), 7.23-7.10 (m, 6H), 6.11 (d, J=16.4 Hz, 2H), 3.76 (s,
2H), 3.63-3.49 (m, 16H), 3.42-3.36 (m, 4H), 3.36-3.29 (m, 6H),
3.29-3.20 (m, 4H), 3.20-3.10 (m, 4H), 3.10-2.96 (m, 4H), 2.96-2.56
(m, 6H), 1.94 (d, J=32.2 Hz, 4H), 1.66 (d, J=46.6 Hz, 4H), 1.49 (s,
4H).
Scheme for Synthesis of Example 104:
Example 104:
4-([(1S,2S)-2-[(R)-3-Aminopiperidin-1-yl]-4,6-dichloro-2,3-dihydro-1H-ind-
en-1-yl]oxy)-N-[26-([4-([(1S,2S)-2-[(R)-3-aminopiperidin-1-yl]-4,6-dichlor-
o-2,3-dihydro-1H-inden-1-yl]oxy)-2-chlorophenyl]sulfonamido)-10,17-dioxo-3-
,6,21,24-tetraoxa-9,11,16,18-tetraazahexacasyl]-2-chlorobenzenesulfonamide-
; bis(trifluroacetic acid)
##STR00203##
[1040] Step A: To a round-bottom flask was added aminoindanol
INT-18F (0.602 g, 1.5 mmol, 1 equiv) and tetrahydrofuran (3.5 mL),
followed by the addition of 4-bromo-3-chlorophenol (0.374 g, 1.8
mmol, 1.2 equiv) and heating to 45.degree. C. To this slurry was
added PPh3 (0.590 g, 2.25 mmol, 1.5 equiv) followed DIAD (0.443 mL,
2.25 mmol, 1.5 equiv) dropwise. The resulting solution was stirred
for 3 h at 40.degree. C. The resulting mixture was concentrated
under vacuum and diluted with CH.sub.2Cl.sub.2. The residue was
applied onto a silica gel column with hexanes/ethyl acetate (0-50%)
providing 0.886 g (99%) of tert-butyl
[(R)-1-[(1S,2S)-1-(4-bromo-3-chlorophenoxy)-4,6-dichloro-2,3-dihydro-1H-i-
nden-2-yl)piperidin-3-yl]carbamate (INT-E3) as a pale pink
foam.
[1041] Step B: To a round-bottom flask purged and maintained with
an inert atmosphere of nitrogen was added arylbromide INT-E3 (0.870
g, 1.47 mmol, 1 equiv), 1,4-dioxane (7.4 mL),
N,N-diisopropylethylamine (0.381 g, 2.95 mmol, 2 equiv),
Pd.sub.2(dba).sub.3.CHCl.sub.3 (33.7 mg, 0.037 mmol, 0.025 equiv),
and Xantphos (38.9 mg, 0.067 mmol, 0.05 equiv). The solution was
degassed with nitrogen bubbling for 5 min before the addition of
benzylmercaptan (0.219 g, 1.76 mmol, 1.2 equiv) in one portion. The
resulting solution was stirred overnight at 90.degree. C. The
resulting slurry was concentrated under vacuum. The residue was
applied onto a silica gel column with hexanes/acetone (0-20%)
providing 0.607 g (65%) of tert-butyl
[(R)-1-[(1S,2S)-1-(4-(benzylthio)-3-chlorophenoxy)-4,6-dichloro-2,3-dihyd-
ro-1H-inden-2-yl]piperidin-3-yl]carbamate (INT-E4) as a light
orange solid.
[1042] Step C: To a round-bottom flask was added thioether INT-E4
(0.607 g, 0.95 mmol, 1 equiv), acetic acid (3 mL), and water (1
mL). This was followed by the addition of N-chlorosuccinimide
(0.384, 2.87 mmol, 3 equiv) in several batches at room temperature.
The resulting solution was stirred for 2 h at room temperature. The
resulting slurry was diluted with 50 mL of ethyl acetate and
treated with 4.6 g of sodium bicarbonate. Water (50 mL) was added
and the layers separated. The organic layer was washed with
1.times.50 mL saturated aqueous sodium bicarbonate and 1.times.50
mL brine. The organic layer was dried over anhydrous sodium
sulfate, filtered, and concentrated under vacuum. This provided 740
mg of crude tert-butyl
[(R)-1-[(1S,2S)-4,6-dichloro-1-[3-chloro-4-(chlorosulfonyl)phenoxy]-2,3-d-
ihydro-1H-inden-2-yl]piperidin-3-yl]carbamate (INT-E5) as a pasty
solid that was used without further purification.
[1043] Step D: To a round-bottom flask was added crude sulfonyl
chloride INT-E5 (theoretical 0.95 mmol) from Step C and
CH.sub.2Cl.sub.2 (1 mL). To this mixture was added
2,2'-(ethane-1,2-diylbis(oxy))bis(ethan-1-amine) (1.04 g, 7 mmol, 7
equiv) dropwise over 2 min. The reaction solution was stirred
overnight at room temperature. The reaction slurry was diluted with
15 mL of CH.sub.2Cl.sub.2 and 10 mL of ethyl acetate. The organic
layer was washed with 3.times.30 mL of water and 2.times.30 mL of
brine. The resulting mixture was concentrated under vacuum and
diluted with of CH.sub.2Cl.sub.2. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/methanol (0-15%) providing
0.335 g (49% over 2 steps) of tert-butyl
[(R)-1-[(1S,2S)-1-(4-[N-(2-[2-(2-aminoethoxy)ethoxy]ethyl)sulfamoyl]-3-ch-
lorophenoxy)-4,6-dichloro-2,3-dihydro-1H-inden-2-yl]piperidin-3-yl]carbama-
te (INT-E6) as a white foam.
[1044] Step E: To a round-bottom flask was added INT-E6 (0.181 g,
0.25 mmol, 1 equiv), DMF (5 mL), and 1,4-diisocyanatobutane (15.8
mg, 0.113 mmol, 0.45 equiv). The resulting solution was stirred for
4 h at room temperature. The resulting mixture was concentrated
under vacuum and used directly in Step F.
[1045] Step F: The crude material from Step E (theoretical 0.113
mmol) was diluted in 3:1 CH.sub.2Cl.sub.2:TFA (4 mL). The resulting
solution was stirred for 1 h at room temperature. The resulting
mixture was concentrated under vacuum. The crude product was
purified by preparative HPLC.
[1046] Steps A-F provided Example 104 which was purified by
Preparative HPLC with the following conditions: Column, Atlantis T3
OBD Column, 19*150 mm, 10 um; mobile phase, water (0.1% TFA) and
CH.sub.3CN (0.1% TFA, 20% CH.sub.3CN up to 70.0% in 40 min);
Detector, UV 254 nm. This resulted in 0.174 g (100%) of the title
compound as a white solid. MS (m/z): 1383 [M+H].sup.+. .sup.1H NMR
(Methanol-d.sub.4, 400 MHz): .delta. 8.06 (d, J=8.9 Hz, 2H),
7.48-7.40 (m, 4H), 7.27 (dd, J=8.9, 1.8 Hz, 2H), 7.16 (s, 2H), 6.20
(d, J=5.4 Hz, 2H), 3.89 (dd, J=13.4, 7.3 Hz, 2H), 3.74-3.43 (m,
19H), 3.43-3.28 (m, 15H), 3.20-3.10 (m, 16H), 2.95 (s, 2H),
2.84-2.58 (m, 4H), 2.00 (s, 2H), 1.92 (s, 2H), 1.77 (d, J=9.6 Hz,
1H), 1.74-1.30 (m, 7H).
Representative Scheme for the Synthesis of Linker Amine Dimers:
##STR00204##
[1048] Step A: To a 500-mL round-bottom flask was added tert-butyl
N-[(3R)-pyrrolidin-3-yl]carbamate (10 g, 53.7 mmol, 1 equiv),
1-[[2-(2-azidoethoxy)ethoxy]sulfonyl]-4-methylbenzene (INT-Y2,
16.85 g, 59.1 mmol, 1.1 equiv), CH.sub.3CN (100 mL), and potassium
carbonate (22.26 g, 161 mmol, 3 equiv). The resulting solution was
stirred overnight at 60.degree. C. The solids were filtered out and
the resulting mixture was concentrated under vacuum providing 13 g
(81%) of tert-butyl
N-[(3R)-1-[2-(2-azidoethoxy)ethyl]pyrrolidin-3-yl]carbamate
(INT-RD1) as a yellow oil.
[1049] Step B: To a 250-mL round-bottom flask flushed with N.sub.2
was added ethanol (100 mL), Raney Ni (10 g), azide INT-RD1 (6 g, 20
mmol, 1 equiv), and NH.sub.4OH (28%, 10 mL). To the above
H.sub.2(g) was introduced in followed by a purging/filling cycle,
leaving the slurry under an atmosphere of H.sub.2(g). The resulting
slurry was stirred for 2 h at room temperature. The solids were
filtered out and the resulting mixture concentrated under vacuum
providing 4.8 g (88%) of tert-butyl
N-[(3R)-1-[2-(2-aminoethoxy)ethyl]pyrrolidin-3-yl]carbamate
(INT-RD2) as a yellow oil.
[1050] Step C: To a 500-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added amine INT-RD2 (10 g,
36.6 mmol, 1 equiv), DMF (250 mL), and 1,4-diisocyanatobutane (2.6
mL, 0.45 equiv). The resulting solution was stirred for 2 h at
60.degree. C. The resulting slurry was concentrated under vacuum.
The residue was applied onto a silica gel column with
CH.sub.3CN:H.sub.2O (35:65) providing 9.0 g of tert-butyl
N-[(3R)-1-[2-(2-[[(4-[[(2-[2-[(3R)-3-[[(tert-butoxy)carbonyl]amino]pyrrol-
idin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)carbamoyl]amino]ethoxy)ethyl]-
pyrrolidin-3-yl]carbamate (INT-RD3) as a white solid.
[1051] Step D:
3-(2-[2-[(3R)-3-Aminopyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-a-
minopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl] amino]butyl)urea
hydrochloride. To a 250-mL round-bottom flask was added Boc-diamine
INT-RD3 (3.0 g, 4.37 mmol, 1 equiv), CH.sub.2Cl.sub.2 (15 mL),
CH.sub.3CN (15 mL), and hydrogen chloride (4M.sub.(aq), 15 mL). The
resulting solution was stirred for 2 h at room temperature. The
resulting mixture was concentrated under vacuum. This resulted in
2.2099 g (91%) of the title compound as a brown oil. MS (m/z): 487
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz) .delta. 4.29-4.12
(m, 3H), 4.01-3.73 (m, 7H), 3.75-3.48 (m, 10H), 3.40 (t, J=4.9 Hz,
6H), 3.19 (d, J=5.8 Hz, 4H), 2.70 (tt, J=24.7, 11.1 Hz, 2H), 2.30
(qd, J=8.0, 3.7 Hz, 2H), 1.60-1.49 (m, 4H).
##STR00205##
[1052] Through Steps A-D, 2.2449 g (92%) of
3-(2-[2-[(3S)-3-aminopyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3S)-3-a-
minopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea
hydrochloride (INT-SD4) was prepared as a brown solid. MS (m/z):
487 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz) .delta. 4.26
(s, 2H), 4.18 (s, 1H), 3.98 (d, J=12.5 Hz, 2H), 3.83 (t, J=4.5 Hz,
5H), 3.77-3.50 (m, 10H), 3.41 (t, J=5.2 Hz, 5H), 3.26-3.16 (m, 4H),
2.74 (s, 2H), 2.31 (ddd, J=13.8, 8.4, 5.0 Hz, 2H), 1.62-1.51 (m,
4H).
Representative Scheme for the Synthesis of Thioether Indane
Scaffolds:
##STR00206##
[1054] Step A: To a 1000-mL round-bottom flask purged and
maintained with an inert atmosphere of nitrogen was added
4-bromo-2-fluorophenol (20 g, 104.7 mmol, 1 equiv), dioxane (240
mL), Xantphos (7.28 g, 12.6 mmol, 0.12 equiv),
diisopropylethylamine (34.6 mL), Pd.sub.2(dba).sub.3.CHCl.sub.3
(6.52 g), and benzylmercaptan (24.6 mL). The resulting solution was
stirred overnight at 100.degree. C. in an oil bath. The resulting
mixture was concentrated under vacuum. The resulting residue was
slurried in water and extracted with 3.times.500 mL of ethyl
acetate. The combined organic layers were washed with 3.times.500
mL of brine, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with hexane/ethyl acetate (0-10%) providing 14 g (57%)
of 4-(benzylsulfonyl)-2-fluorophenol (INT-TE1) as a yellow
solid.
[1055] Step B: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added aminoindanol INT-18M
(3 g, 6.95 mmol, 1 equiv), tetrahydrofuran (16.2 mL), phenol
INT-TE1 (1.71 g, 7.30 mmol, 1.05 equiv), and PPh3 (2.92 g, 11.1
mmol, 1.6 equiv). This was followed by the dropwise addition of
DIAD (2.12 g, 10.5 mmol, 1.55 equiv) at 40.degree. C. over 45 min.
The resulting solution was stirred for 1 h at 40.degree. C. in an
oil bath. The resulting mixture was concentrated under vacuum. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:40) providing 3.3 g (73%) of tert-butyl
4-[(1S,2S)-1-[4-(benzylsulfanyl)-2-fluorophenoxy]-4-bromo-6-chloro-2,3-di-
hydro-1H-inden-2-yl]piperazine-1-carboxylate (INT-TE2) as a purple
solid.
[1056] Step C: To a 100-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added arylbromide INT-TE2
(3.3 g, 5.09 mmol, 1 equiv), NMP (33 mL), Zn(CN).sub.2 (312 mg,
0.52 equiv), and Pd(PPh.sub.3).sub.4 (589 mg, 0.10 equiv). The
resulting solution was stirred overnight at 100.degree. C. in an
oil bath. The resulting solution was diluted with water and
extracted with 3.times.30 mL of ethyl acetate. The combined organic
layers were washed with 3.times.30 mL of brine and concentrated
under vacuum. The residue was applied onto a silica gel column with
petroleum ether/ethyl acetate (7:1) providing 2.05 g (68%) of
tert-butyl
4-[(1S,2S)-1-[14-(benzylsulfonyl)-2-fluorophenoxy]-6-chloro-4-cyano-2,3-d-
ihydro-1H-inden-2-yl]piperazine-1-carboxylate (INT-TE3) as a gray
solid. MS (m/z): 594 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300
MHz) .delta. 7.71 (d, J=2.0 Hz, 1H), 7.49-7.41 (m, 1H), 7.33-7.02
(m, 8H), 5.80 (d, J=6.1 Hz, 1H), 4.07 (s, 2H) 3.70-3.56 (m, 1H),
3.34 (t, J=4.8 Hz, 4H), 3.02 (dd, J=16.7, 7.8 Hz, 1H), 2.51 (qd,
J=11.6, 5.3 Hz, 4H), 1.42 (s, 9H).
##STR00207##
[1057] Using INT-18C, Steps A and B provided crude INT-TE4. The
residue was applied onto a silica gel column with ethyl
acetate/petroleum ether (1:10) providing 3.2 g (62%) of
(1S,2S)-1-[4-(benzyl
sulfonyl)-2-fluorophenoxy]-4,6-dichloro-N,N-dimethyl-2,3-dihydro-1H-inden-
-2-amine (INT-TE4) as a white solid. MS (m/z): 462 [M+H].sup.+.
.sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.40 (d, J=1.7 Hz, 1H),
7.30-7.15 (m, 6H). 7.17-7.04 (m, 3H), 5.78 (d, J=5.7 Hz, 1H), 4.09
(s, 2H), 3.46 (td, J=7.7, 5.8 Hz, 1H), 3.26 (dd, J=16.6, 8.1 Hz,
1H), 2.85 (dd, J=16.6, 7.4 Hz, 1H), 2.31 (s, 6H).
##STR00208##
[1058] Using INT-IBL, Steps A-C provided crude INT-TE5. The residue
was applied onto a silica gel column with ethyl acetate/petroleum
ether (1:10) providing 2.31 g (59%) of tert-butyl
4-[(1S,2S)-1-[4-(benzylsulfanyl)-2-fluorophenoxy]-4,6-dichloro-2,3-dihydr-
o-1H-inden-2-yl]piperazine-1-carboxylate (INT-TE5) as a light
purple solid. MS (m/z): 603 [M+H].sup.+. .sup.1H NMR (DMSO-d6, 400
MHz) .delta. 7.57 (d, J=1.8 Hz, 1H), 7.45 (t, J=8.8 Hz, 1H),
7.33-7.09 (m, 8H), 5.89 (d, J=5.6 Hz, 1H), 4.19 (s, 2H), 3.61-3.51
(m, 1H), 3.30 (s, 4H), 3.08 (dd, J=16.7, 8.0 Hz, 1H), 2.83 (dd,
J=16.7, 7.1 Hz, 1H), 2.40 (dp, J=21.7, 5.6, 4.9 Hz, 4H), 1.36 (s,
911).
##STR00209##
[1059] Using INT-18M and 4-bromophenol, Steps A-C provided crude
INT-TE6. The residue was applied onto a silica gel column with
petroleum ether/ethyl acetate (10%) providing 2.05 g (79%) of
tert-butyl
4-[(1S,2S)-1-[4-(benzylsulfonyl)phenoxy]-6-chloro-4-cyano-2,3-dihydro-1H--
inden-2-yl]piperazine-1-carboxylate (INT-TE6) as a gray solid. MS
(m/z): 576 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz) .delta.
8.10-8.01 (m, 1. H), 7.46 (d, J=8.5 Hz, 1H), 3.94 (t, J=6.2 Hz,
1H), 3.05 (t, J=6.9 Hz, 1H), 2.64 (d, J=13.8 Hz, 1H), 2.22 (d,
J=11.8 Hz, 1H), 2.02 (s, 1H), 1.73 (q, J=13.3, 9.8 Hz, 3H), 1.43
(d, J=13.6 Hz, 3H), 1.33-1.11 (m, 2H), 0.86 (s, 1H).
Scheme for the Synthesis of Thioether INT-TE8
##STR00210##
[1061] The thioether INT-TE8 was synthesized by reversing the steps
from the previous method as shown in the scheme above.
[1062] Step A: To a 100-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of nitrogen was added
aminoindanol INT-19C (2.5 g, 8 mmol, 1 equiv),
4-bromo-2-methylphenol (1.82 g, 9.73 mmol, 1.2 equiv),
tetrahydrofuran (19 mL), and PPh3 (3.2 g, 12.2 mmol, 1.5 equiv).
This was followed by the dropwise addition of DIAD (2.4 mL) at
40-45.degree. C. over 15 min. The resulting solution was stirred
for 2 h at 40-45.degree. C. in an oil bath. The resulting mixture
was concentrated under vacuum. The residue was applied onto a
silica gel column with CH.sub.2Cl.sub.2/methanol (5:1) providing
3.25 g (84%) of
(3R)-1-[(1S,2S)-1-(4-bromo-2-methylphenoxy)-6-chloro-4-methyl-2,3-dihydro-
-1H-inden-2-yl]-N,N-dimethylpiperidin-3-amine (INT-TE7) as a red
oil.
[1063] Step B: To a 250-mL round-bottom flask purged and maintained
with an inert atmosphere of nitrogen was added arylbromide INT-TE7
(4.58 g, 9.58 mmol, 1 equiv), dioxane (66 mL), benzylmercaptan
(2.38 g, 192 mmol, 2 equiv), Xantphos (665 mg, 1.15 mmol, 0.12
equiv), and diisopropylethylamine (2.48 g, 19.2 mmol, 2 equiv), and
Pd.sub.2(dba).sub.3.CHCl.sub.3 (595 mg). The resulting solution was
stirred overnight at 100.degree. C. in an oil bath. The resulting
mixture was concentrated under vacuum. The resulting solution was
diluted with water and extracted with 3.times.100 mL of ethyl
acetate. The combined organic layers were washed with 2.times.200
mL of brine, dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with hexane/ethyl acetate (10%) providing 2.07 g (42%)
of
(3R)-1-[(1S,2S)-1-[4-(benzylsulfanyl)-2-methylphenoxy]-6-chloro-4-methyl--
2,3-dihydro-1H-inden-2-yl]-N,N-dimethylpiperidin-3-amine (INT-TE8)
as a light red oil. MS (m/z): 521 [M+H].sup.+. .sup.1H NMR
(Methanol-d4, 300 MHz) .delta. 7.33-7.08 (m, 9H), 6.95 (d, J=1.1
Hz, 1H), 5.79 (d, J=6.3 Hz, 1H), 4.04 (s, 2H), 3.43 (td, J=8.1, 6.2
Hz, 1H), 3.24 (dd, J=15.8, 8.1 Hz, 1H), 3.06 (dd, J=30.1, 11.1 Hz,
2H), 2.77 (dd, J=15.9, 8.1 Hz, 1H), 2.30 (s, 5H), 2.20-1.88 (m,
12H), 1.88-1.77 (m, 1H), 1.62 (t, J=12.8 Hz, 1H), 1.28 (ddd,
J=14.5, 6.8, 4.2 Hz, 2H).
Representative Scheme for the Synthesis of Dimer Products from
Diamine Linkers:
Example 105:
4-([(1S,2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy-
)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-d-
ihydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-
-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluorobenzen-
esulfonamide; tetra(trifluoroacetate)
##STR00211##
[1065] Step A: To a 20 mL glass vial was added thioether INT-TE5
(0.530 g, 0.88 mmol, 1 equiv), acetic acid (6.75 mL), and water
(2.25 mL). Then N-chlorosuccinimide (0.350, 2.62 mmol, 3 equiv) was
added at room temperature. The resulting solution was stirred for 2
h at room temperature. The slurry was diluted with 50 mL of ethyl
acetate and organic solution was washed with 2.times.15 mL
saturated aqueous sodium bicarbonate and 1.times.15 mL brine. The
organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated under vacuum. The residue was applied onto a
silica gel column with hexanes/ethyl acetate (0-30%) providing
0.429 g (84%) of tert-butyl
4-((1S,2S)-1-(4-(benzylthio)-2-fluorophenoxy)-4,6-dichloro-2,3-dihydro-1H-
-inden-2-yl)piperazine-1-carboxylate (INT-TE9) as a white
solid.
[1066] Step B: To a 5 mL glass vial was added of
3-(2-[2-[(3R)-3-aminopyrrolidin-1-yl]ethoxy]ethyl)-1-(4-[[(2-[2-[(3R)-3-a-
minopyrrolidin-1-yl]ethoxy]ethyl)carbamoyl]amino]butyl)urea
hydrochloride (INT-RD4, 96 mg, 0.15 mmol, 1 equiv),
CH.sub.2Cl.sub.2 (0.5 mL), and triethylamine (0.15 mL, 1.10 mmol, 8
equiv). The mixture stirred for 15 minutes at room temperature,
then solution of sulfonyl chloride INT-TE9 (0.198 g, 0.34 mmol, 2.3
equiv) in CH.sub.2Cl.sub.2 (1.0 mL) was added dropwise. The
reaction mixture stirred for 3 h at room temperature. The resulting
mixture was concentrated under vacuum providing 0.270 g of crude
tert-butyl
4-((1S,2S)-1-(4-(N--((R)-1-(20-((R)-3-((4-(((1S,2S)-2-(4-(tert-butoxycarb-
onyl)piperazin-1-yl)-4,6-dichloro-2,3-dihydro-1H-inden-1-yl)oxy)-3-fluorop-
henyl)sulfonamido)pyrrolidin-1-yl)-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraaz-
aicosyl)pyrrolidin-3-yl)sulfamoyl)-2-fluorophenoxy)-4,6-dichloro-2,3-dihyd-
ro-1H-inden-2-yl)piperazine-1-carboxylate (INT-TE10) as a tan foam
which was used for the next step without purification.
[1067] Step C: To the crude material from Step B (theoretical 0.15
mmol) was added 4M hydrochloric acid in dioxane (1 mL) and the
mixture was stirred for 2 h at room temperature. The resulting
slurry was concentrated under vacuum. The crude product was
purified by preparative HPLC to provide the desired product.
[1068] Steps A-C provided the crude product which was purified by
preparative HPLC with the following conditions: Column, Atlantis
Preparative T3 OBD Column, 19*150 mm, 10 um; mobile phase, water
(0.1% TFA) and CH.sub.3CN (10.0% CH.sub.3CN up to 70.0% in 40 min);
Detector, UV 214 nm. This resulted in 0.061 g (22%) of the title
compound as a white solid. MS (m/z): 686.2 [M/2+H.sup.+. .sup.1H
NMR (Methanol-d4, 400 MHz) .delta. 7.81-7.61 (m, 6H), 7.46 (d,
J=1.7 Hz, 2H), 7.17 (s, 2H), 6.08 (d, J=5.7 Hz, 2H), 3.79-3.68 (m,
10H), 3.54 (t, J=5.4 Hz, 5H), 3.40 (m, 6H), 3.28-3.18 (m, 16H),
3.13 (s, 6H), 2.99 (dd, J=16.6, 7.5 Hz, 2H), 2.90-2.75 (m, 10H),
1.50 (s, 4H).
Example 106:
4-([(1S2S)-4,6-Dichloro-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-
-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14--
dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolin-3-yl]-3-fluorobenzenesu-
lfonamide; tetra(trifluoroacetate)
##STR00212##
[1070] Beginning with INT-TE5 and INT-SD4, Steps A-C provided 121.8
mg (48%) of the title compound as a white solid. MS (m/z): 686.2
[M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.77-7.65
(m, 6H), 7.44 (d, J=1.7 Hz, 2H), 7.16 (d, J=1.2 Hz, 2H), 6.06 (d,
J=5.7 Hz, 2H), 3.81-3.61 (m, 10H), 3.52 (t, J=5.3 Hz, 5H), 3.43 (m,
6H), 3.25-3.18 (m, 16H), 3.11 (s, 6H), 2.98 (dd, J=16.6, 7.2 Hz,
2H), 2.91-2.76 (m, 10H), 1.48 (s, 4H).
Example 107:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14--
dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonami-
de; tetra(trifluoroacetate)
##STR00213##
[1072] Beginning with INT-TE6 and INT-SD4, Steps A-C provided 84.9
mg (34%) of the title compound as a white solid. MS (m/z): 659.4
[M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.91 (d,
J=8.9 Hz, 4H), 7.79 (d, J=1.7 Hz, 2H), 7.46 (d, J=1.3 Hz, 2H), 7.36
(d, J=8.9 Hz, 4H), 6.09 (d, J=6.0 Hz, 2H), 3.80-3.70 (m, 10E1),
3.54 (t, J=5.4 Hz, 5H), 3.48-3.33 (m, 11H), 3.24 (t, J=5.1 Hz,
10H), 3.19-3.08 (m, 8H), 2.94-2.79 (m, 10H), 1.50 (s, 4H).
Example 108:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14--
dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonami-
de; tetra(trifluoroacetate)
##STR00214##
[1074] Beginning with INT-TE6 and INT-RD4, Steps A-C provided 71.0
mg (26%) of the title compound as a white solid. MS (m/z): 659.3
[M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.91 (d,
J=8.9 Hz, 4H), 7.79 (d, J=1.9 Hz, 2H), 7.46 (s, 2H), 7.36 (d, J=8.9
Hz, 4H), 6.09 (d, J=6.0 Hz, 2H), 3.78-3.71 (m, 10H), 3.54 (t, J=5.3
Hz, 5H), 3.49-3.34 (m, 11H), 3.24 (t, 5.2 Hz, 10H), 3.19-3.08 (m,
8H), 2.94-2.78 (m, 10H), 1.50 (s, 4H).
Example 109:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(R)-1-(20-[(R)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1--
yl]-7,14-dioxo-3,18-dioxo-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluo-
robenzenesulfonamide; tetra(trifluoroacetate)
##STR00215##
[1076] Beginning with INT-TE3 and INT-RD4, Steps A-C provided 74.0
mg (36%) of the title compound as a white solid. MS (m/z): 677.3
[M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) 7.78 (d, J=1.8
Hz, 2H), 7.77-7.62 (m, 6H), 7.50 (d, J=1.7 Hz, 2H), 6.08 (d, J=5.8
Hz, 2H), 3.81 (dd, J=13.8, 7.8 Hz, 2H), 3.74 (t, J=5.0 Hz, 6H),
3.53 (t, 1=5.3 Hz, 5H), 3.46-3.31 (m, 11H), 3.21 (m, 13H), 3.14
(dd, J=16.6, 7.4 Hz, 9H), 2.93-2.77 (m, 10H), 1.46 (s, 4H).
Example 110:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-[(S)-3-[(4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)-3-fluorophenyl)sulfonamide)pyrrolidin-1--
yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-fluo-
robenzenesulfonamide; tetra(trifluoroacetate)
##STR00216##
[1078] Beginning with INT-TE3 and INT-SD4, Steps A-C provided 44.9
mg (17%) of the title compound as a white solid. MS (m/z): 677.3
[M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.78 (d,
J=1.8 Hz, 2H), 7.77-7.62 (m, 6H), 7.49 (d, J=1.7 Hz, 2H), 6.07 (d,
0.1-5.8 Hz, 2H), 3.81 (dd, J=13.8, 7.8 Hz, 2H), 3.74 (t, J=5.0 Hz,
6H), 3.53 (t, J=5.4 Hz, 5H), 3.47-3.31 (m, 11H), 3.22 (dd, J=11.9,
7.3 Hz, 13H), 3.14 (dd, J=16.6, 7.4 Hz, 9H), 2.94-2.77 (m, 10H),
1.45 (s, 4H).
Example 111:
4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-
-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-d-
ioxo-3,18-dioxa-6,8,13,15-tetraazaicos)pyrrolidin-3-yl)-3-fluorobenzenesul-
fonamide; tetra(trifluoroacetate)
##STR00217##
[1080] Beginning with INT-TE4 and INT-SD4, Steps A-B provided
Example 111 which was purified by preparative HPLC with the
following conditions: Column, Atlantis Preparative T3 OBD Column,
19*150 mm, 10 um; mobile phase, water (0.1% TFA) and CH.sub.3CN
(10.0% CH.sub.3CN up to 60.0% in 40 min); Detector, UV 214 nm. This
resulted in 15.9 mg (5.4%) of the title compound as a white solid.
MS (m/z): 645.3 [M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz):
.delta. 7.83-7.74 (m, 4H), 7.67 (t, J=8.5 Hz, 2H), 7.56 (d, J=1.7
Hz, 2H), 7.13 (s, 2H), 6.53 (d, 6.3 Hz, 2H), 3.76 (t, J=5.0 Hz,
7H), 3.68 (dd, J=16.8, 8.6 Hz, 2H), 3.55 (t, J=5.3 Hz, 7H), 3.45
(m, 6H), 3.29-3.22 (m, 2H), 3.13 (s, 4H), 3.03 (s, 23H), 1.50 (s,
4H).
Example 112:
4-([(1S,2S)-4,6-Dichloro-2-(dimethylamino)-2,3-dihydro-1H-inden-1-yl]oxy)-
-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-4,6-dichloro-2-(dimethylamino)-2,3-dih-
ydro-1H-inden-1-yl]oxy)-3-fluorophenyl]sulfonamido)pyrrolidin-1-yl]-7,14-d-
ioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl)-3-fluorobenzenes-
ulfonamide; tetra(trifluoroacetate)
##STR00218##
[1082] Beginning with INT-TE4 and INT-RD4, Steps A-B provided
Example 112 which was purified by preparative HPLC with the
following conditions: Column, Atlantis Preparative T3 OBD Column,
19*150 mm, 10 um; mobile phase, water (0.1% TFA) and CH.sub.3CN
(10.0% CH.sub.3CN up to 60.0% in 40 min); Detector, UV 214 nm. This
resulted in 10.9 mg (3.1%) of the title compound as a white solid.
MS (m/z): 645.3 [M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz):
.delta. 7.83-7.75 (m, 4H), 7.67 (t, J=8.2 Hz, 2H), 7.56 (d, J=1.6
Hz, 2H), 7.13 (s, 2H), 6.52 (d, =6.1 Hz, 2H), 3.76 (t, J=5.0 Hz,
7H), 3.68 (dd, J=16.8, 8.7 Hz, 2H), 3.55 (t, 5.4 Hz, 7H), 3.46 (m,
6H), 3.30-3.20 (m, 2H), 3.14 (s, 4H), 3.03 (s, 23H), 1.48 (s,
4H).
Example 113:
4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-
-dihydro-1H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-2--
[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,-
13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;
tetra(trifluoroacetate)
##STR00219##
[1084] Beginning with INT-TE8 and INT-RD4 Steps A-B provided
Example 113 which was purified by preparative HPLC with the
following conditions: Column, Atlantis Preparative T3 OBD Column,
19*150 mm, 10 um; mobile phase, water (0.1% TFA) and CH.sub.3CN
(10.0% CH.sub.3CN up to 60.0% in 40 min); Detector, UV 214 nm. This
resulted in 16.9 mg (4.8%) of the title compound as a white solid.
MS (m/z): 704.4 [M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz):
.delta. 7.80 (d, J=8.8 Hz, 2H), 7.73 (s, 2H), 7.47 (t, J 8.8 Hz,
2H), 7.18 (s, 2H), 6.96 (s, 2H), 6.05 (s, 2H), 3.82-3.69 (m, 13H),
3.54 (m, 6H), 3.48-3.34 (m, 6H), 3.21 (dd, J=16.2, 8.0 Hz, 2H),
3.13 (s, 4H), 2.92 (m, 2H), 2.87 (m, 23H), 2.28 (m, 25H), 1.50 (s,
4H).
Example 114:
4-([(1S,2S)-6-Chloro-2-[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-
-dihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-2--
[(R)-3-(dimethylamino)piperidin-1-yl]-4-methyl-2,3-dihydro-1H-inden-1-yl]o-
xy)-3-methylphenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,-
13,15-tetraazaicosyl)pyrrolidin-3-yl]-3-methylbenzenesulfonamide;
tetra(trifluoroacetate)
##STR00220##
[1086] Steps A-C were followed to prepare Example 114 with the
addition of a free-basing of the initial amine INT-SD4 with basic
resin (Dowex Monosphere 550A hydroxide form) prior to addition of
the sulfonyl chloride in Step B. The crude product obtained was
purified by preparative HPLC with the following conditions: Column,
Atlantis Preparative T3 OBD Column, 19*150 mm, 10 um; mobile phase,
water (0.1% TFA) and CH.sub.3CN (10% CH.sub.3CN up to 60.0% in 40
min); Detector, UV 214 nm. This resulted in 68.0 mg (16%) of the
title compound as a white solid. MS (m/z): 704.4 [M/2+H].sup.+.
.sup.1H NMR (Methanol-d4, 400 MHz): .delta. 7.84-7.67 (m, 4H), 7.48
(t, J=8.8 Hz, 2H), 7.18 (s, 2H), 6.95 (s, 2H), 6.07 (d, J=5.8 Hz,
2H), 3.82-3.69 (m, 13H), 3.54 (t, J=5.3 Hz, 6H), 3.48-3.34 (m, 6H),
3.22 (dd, J=16.2, 8.0 Hz, 2H), 3.19 (s, 4H), 2.90 (m, 2H), 2.83 (m,
23H), 2.29 (m, 25H), 1.47 (s, 4H).
Scheme for Dimer Product Synthesis via Stepwise Linker
Construction:
Example 115:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo--
5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;
bis(trifluoroacetate)
##STR00221## ##STR00222## ##STR00223##
[1088] Step A: tert-Butyl
4-((1S,2S)-1-(4-(benzylthio)phenoxy)-6-chloro-4-cyano-2,3-dihydro-1H-inde-
n-2-yl)piperazine-1-carboxylate (580 mg, 1.00 mmol) was dissolved
in CH.sub.2Cl.sub.2 (3 mL) and trifluoroacetic acid (0.5 mL, 6.52
mmol, 6.5 equiv) was added at 0.degree. C. The reaction mixture was
allowed to warm to room temperature and stirred for 18 h. The
reaction mixture was diluted with ethyl acetate (50 mL) and washed
with 1M aqueous sodium hydroxide (2.times.10 mL), water (10 mL),
and brine (10 mL). The aqueous layers were back-extracted with
ethyl acetate (20 mL). The combined organic layers were dried over
sodium sulfate, filtered, and concentrated providing 500 mg of
crude
(1S,2S)-1-(4-(benzylthio)phenoxy)-6-chloro-2-(piperazin-1-yl)-2,3-dihydro-
-1H-indene-4-carbonitrile (INT-SLC1) as a brownish resin. MS (m/z):
476.2 [M+H].sup.+.
[1089] Step B: To a solution of crude material INT-SLC1 from Step A
(theoretical 1 mmol) in methanol (3 mL) was added ethyl
trifluoroacetate (0.5 mL, 4.2 mmol) at room temperature. After
stirring at room temperature for 1.5 h another portion of ethyl
trifluoroacetate (0.3 mL, 2.5 mmol) was added, followed by
triethylamine (50 .mu.L, 0.36 mmol). The reaction mixture stirred
for 1 h and then concentrated under vacuum. The residue was applied
onto a silica gel column with hexanes/ethyl acetate (0-35%)
providing 556 mg (97%) of
(1S,2S)-1-[4-(benzylthio)phenoxy]-6-chloro-2-[4-(2,2,2-tri
fluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-indene-4-carbonitrile
(INT-SLC2) as a clear brownish oil. MS (m/z): 572.1
[M+H].sup.+.
[1090] Step C: To a solution of thioether INT-SLC2 (556 mg, 0.97
mmol) in a mixture of acetic acid (6.75 mL) and water (2.25 mL),
N-chlorosuccinimide (388 mg, 2.91 mmol, 3 equiv) was added at room
temperature. The reaction mixture stirred for 2 h at room
temperature and diluted with ethyl acetate (50 mL). The resulting
solution was washed with saturated aqueous sodium bicarbonate
(2.times.15 mL) and brine (15 mL). The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum
providing 760 mg of crude
4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-tri
fluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)benzene-1-sulf-
onyl chloride (INT-SLC3) as a yellowish oil. MS (m/z): 548.0
[M+].sup.+.
[1091] Step D: To a solution of crude material INT-SLC3 from Step C
(theoretical 0.48 mmol) in CH.sub.2Cl.sub.2 (2 mL) was added
tert-butyl 4-aminopiperidine-1-carboxylate (147 mg, 0.74 mmol),
followed by triethylamine (95 .mu.L, 0.67 mmol). The reaction
mixture stirred for 20 h at room temperature and concentrated under
vacuum. The residue was applied onto a silica gel column with
hexanes/ethyl acetate (0-50%) providing 221 mg (65%) of tert-butyl
4-([4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1--
yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidine-1-carboxyl-
ate (INT-SLC4) as a white solid. MS (m/z): 734.2 [M+Na].sup.+.
[1092] Step E: To a solution of sulfonamide INT-SLC4 (50 mg, 0.07
mmol) in CH.sub.2Cl.sub.2 (0.7 mL) was added trifluoroacetic acid
(0.05 mL, 0.87 mmol, 12.3 equiv) and the mixture stirred for 20 h
at room temperature. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (5 mL) and washed with 1M aqueous sodium hydroxide
(2.times.2 mL) and brine (3 mL). The organic layer was dried over
anhydrous sodium sulfate, filtered, and concentrated providing 50
mg of crude
4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]--
2,3-dihydro-1H-inden-1-yl]oxy)-N-(piperidin-4-yl)benzenesulfonamide
(INT-SLC5) as a white solid. MS (m/z): 612.2 [M+H].sup.+.
[1093] Step F: The crude material INT-SLC5 from Step E (theoretical
0.07 mmol), 4-[(tert-butoxycarbonyl)amino]butanoic acid (24.7 mg,
0.122 mmol, 1.7 equiv), HATU (61.9 mg, 0.163 mmol, 2.3 equiv), and
crushed 3 .ANG. molecular sieves were suspended in DMF (0.8 mL). To
this slurry was added diisopropylethylamine (56.7 .mu.L, 0.326
mmol, 4.6 equiv) and the reaction mixture stirred for 2 h. The
volatiles were removed under vacuum and the residue was applied
onto a silica gel column with CH.sub.2Cl.sub.2/methanol (0-10%)
providing 50 mg (77%) of tert-butyl
[4-(4-[4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-
-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenylsulfonamido]piperidin-1-yl)-4-o-
xobutyl]carbamate (INT-SLC6) as a brownish solid. MS (m/z): 797.3
[M+H].sup.+.
[1094] Step G: Trifluoroacetic acid (50 .mu.L, 0.65 mmol, 10 equiv)
was added to a solution of Boc-amine INT-SLC6 (50 mg, 0.063 mmol)
in CH.sub.2Cl.sub.2 (0.7 mL). The reaction mixture stirred for 5 h
at room temperature. After completion (TLC and LCMS), the reaction
mixture was diluted in CH.sub.2Cl.sub.2 (4 mL) and washed with 1M
aqueous sodium hydroxide (2.times.1.5 mL) and brine (1.5 mL). The
organic layer was dried over anhydrous sodium sulfate, filtered,
and concentrated under vacuum providing 45 mg of crude
N-[1-(4-aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-[4-(-
2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)benzen-
esulfonamide (INT-SLC7) as a tan solid. MS (m/z): 697.2
[M+H].sup.+.
[1095] Step H: To the solution of crude material INT-SLC7 from Step
G (theoretical 0.063 mmol) in DMF (0.6 mL) was added
1,4-diisocyanatobutane (3.5 mg, 0.025 mmol, 0.4 equiv). The
reaction mixture was stirred for 15 h at room temperature. The
reaction mixture was concentrated under vacuum and the residue was
applied onto a silica 12 gel column with CH.sub.2Cl.sub.2/methanol
(0-12%) providing 7 mg (18%) of
4-[(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2-
,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-
-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)p-
henyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadec-
anoyl)piperidin-4-yl]benzenesulfonamide (INT-SLC8) as a white
solid. MS (m/z): 767.3 [M/2+H].sup.+.
[1096] Step I: To a solution of dimer INT-SLC8 from Step H (7 mg,
0.0046 mmol) in methanol (0.3 mL) was added aqueous sodium
hydroxide (3M, 10 .mu.L, 0.03 mmol, 6.5 equiv) at room temperature.
The reaction mixture stirred for 16 h at room temperature,
concentrated under vacuum, and the residue purified by reverse
phase chromatography.
[1097] Compound 115:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-6,13,18-trioxo--
5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benzenesulfonamide;
bis(trifluoroacetate)
[1098] The crude product obtained through Steps A-I was purified by
preparative HPLC with the following conditions: Column, Atlantis
Preparative T3 OBD, 19*150 mm, 10 um; mobile phase, water (0.1%
TFA) and CH.sub.3CN (10.0% CH.sub.3CN up to 70.0% in 40 min);
Detector, UV 214 nm. This procedure provided 2.9 mg (40%) of the
title compound as a white solid. MS (m/z): 671.3 [M/2+H]+. .sup.1H
NMR (Methanol-d4, 400 MHz) .delta. 7.88 (d, J=8.8 Hz, 4H), 7.76 (m,
2H), 7.45 (m, 2H), 7.31 (d, J=8.9 Hz, 4H), 6.05 (d, J=5.8 Hz, 2H),
3.48-3.44 (m, 2H), 3.40-3.33 (m, 8H), 3.25-3.20 (m, 8H), 3.15-3.08
(m, 14H), 2.92-2.76 (m, 16H), 2.39-2.32 (m, 4H), 1.74-1.66 (m, 4H),
1.47 (s, 4H).
General Scheme for the Synthesis of Dimers with Peptidic
Linkers:
##STR00224##
[1099] Indane dimer products such as (II) are synthesized with
amino acid/peptidic linkers using the following methods.
[1100] Step A: The sulfonyl chloride INT-PL1, synthesized as
outlined in this work, is combined with tert-butyl
3-aminopyrrolidine-1-carboxylate in CH.sub.2Cl.sub.2 with
trimethylamine to provide the desired sulfonamide adduct INT-PR2.
The crude material is washed with water and brine, dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The product is purified by normal phase chromatography to provide
clean INT-PL2.
[1101] Step B: The Boc-protected amine INT-PL2 is slurried in
CH.sub.2Cl.sub.2 and treated with trifluoroacetic acid. Once
removal of the protecting group is complete based on TLC and/or
LCMS, the volatiles are removed under vacuum and the residue
dissolved in ethyl acetate. The organic layer is washed with
saturated sodium bicarbonate and brine, dried over dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The product is purified by normal phase chromatography to provide
clean INT-PL3.
[1102] Step C: The amine product INT-PL3 is diluted in a suitable
solvent such as tetrahydrofuran or DMF and treated with a
Boc-protected amino acid, diisopropylethylamine, and a coupling
reagent such as HATU. Once reaction is complete based on TLC and/or
LCMS, the volatiles are removed under vacuum and the residue
dissolved in CH.sub.2Cl.sub.2 or other suitable solvent. The
organic layer is washed with saturated sodium bicarbonate and
brine, dried over dried over anhydrous sodium sulfate, filtered,
and concentrated under vacuum. The product is purified by normal
phase chromatography to provide clean INT-PL4.
[1103] Step D: The Boc-protected amine INT-PL4 is slurried in
CH.sub.2Cl.sub.2 and treated with trifluoroacetic acid. Once
removal of the protecting group is complete based on TLC and/or
LCMS, the volatiles are removed under vacuum and the residue
dissolved in ethyl acetate. The organic layer is washed with
saturated sodium bicarbonate and brine, dried over dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The product is purified by normal phase chromatography to provide
clean INT-PL5.
[1104] Steps C and D can be repeated to extend the linker peptide
with more amino acids as desired.
[1105] Step E: The amine INT-PL5 is diluted in DMF and treated with
a limiting amount of 1,4-diisocyanatobutane. The resulting solution
was stirred at room temperature (or heated as required to drive
completion). The resulting mixture was concentrated under vacuum to
provide crude INT-PR6. If the product contains protecting groups
such as tert-butyl carbamates or trifluoroacetamides, they are
deprotected with the appropriate conditions at this stage. The
final product of structure (II) is purified by preparative HPLC in
watertCH.sub.3CN and lyophilized to provide the pure products as
salts.
[1106] Through Steps A-E for the synthesis of compound of structure
(II), the following Examples are prepared.
Example 116:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[(S)-1-(14-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl-
)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-4,11,1-
4-trioxo-3,5,10,12-tetraazatetradecanoyl)pyrrolidin-3-yl]benzenesulfonamid-
e
##STR00225##
[1108] The title compound was prepared from INT-TE6 and Boc-Gly-OH.
MS (m/z): 629.3 [M/2+H]+. 1H NMR (Methanol-d4, 400 MHz) .delta.
7.80 (dd, J=13.3, 5.1 Hz, 4H), 7.68 (t, J=2.0 Hz, 2H), 7.40 (d,
J=6.4 Hz, 2H), 7.25 (dd, J=9.0, 7.0 Hz, 5H), 5.99 (d, J=6.7 Hz,
2H), 3.85-3.60 (m, 9H), 3.27 (d, J=16.6 Hz, 8H), 3.18-2.94 (m,
21H), 2.86-2.68 (m, 10H), 1.96-1.81 (m, 1H), 1.40 (s, 4H).
Example 117:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-[(2S,13S)-14-[(S)-3-([4-[(1S,2S)-6-chloro-4-cyano-2-(piper-
azin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-y-
l]-2,13-dimethyl-4,11,14-trioxo-3,5,10,12-tetraazatetradecanoyl]pyrrolidin-
-3-yl]benzenesulfonamide
##STR00226##
[1110] The title compound is prepared from INT-TE6 and
Boc-Ala-OH.
Example 118:
N.sup.1,N.sup.14-bis(2-[(S)-3-([4-[[(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-
-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide
##STR00227##
[1112] The title compound was prepared from INT-TE6 and
Boc-Gly-Gly-OH. MS (m/z): 686.3 [M/2+H].sup.+. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.88 (t, J=8.5 Hz, 4H), 7.75 (s,
2H), 7.50 -7.45 (m, 2H), 7.32 (t, J=8.4 Hz, 4H), 6.07 (s, 2H),
3.96-3.81 (m, 5H), 3.78 (d, J=4.1 Hz, 7H), 3.59-3.41 (m, 3H), 3.18
(dt, J=32.4, 6.6 Hz, 20H), 2.87 (s, 9H), 1.50 (s, 4H).
Example 119:
N.sup.1,N.sup.14-bis(2-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl
oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12--
tetraazatetradecanediamide
##STR00228##
[1114] The title compound was prepared from INT-TE6 and
Boc-Gly-Gly-OH. MS (m/z): 686.3 [M/2+H]+. 1H NMR (Methanol-d4, 400
MHz) .delta. 7.87 (d, J=8.9 Hz, 4H), 7.77-7.73 (m, 2H), 7.49-7.45
(m, 2H), 7.31 (d, J=8.9 Hz, 4H), 6.09-6.03 (m, 2H), 3.78 (d, J=4.3
Hz, 11H), 3.58-3.32 (m, 2H), 3.26-3.04 (m, 21H), 2.87 (s, 10H),
1.51 (s, 4H).
Example 120:
N.sup.1,N.sup.18-Bis(1-([4-([1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2-
,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)piperidin-4-yl)-6,13-dioxo-5,-
7,12,14-tetraazaoctadecanediamide
##STR00229##
[1116] The title compound is prepared from
4-[(tert-butoxycarbonyl)amino]butanoic acid, tert-butyl
piperidin-4-ylcarbamate, and INT-TE6.
[1117] Scheme for the Synthesis of Diastereomeric
Dimethylaminopiperidine Analogs:
Example 121:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3--
dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfona-
mido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenes-
ulfonamide
##STR00230## ##STR00231##
[1119] Step A: To a 25-mL round-bottom flask was added aminoindanol
INT-I8K (600 mg, 1.61 mmol, 1 equiv), tert-butyl
N-[2-([2-[2-[(4-hydroxybenzene)sulfonamido]ethoxy]ethoxy)ethyl]carbamate
(736 mg, 1.82 mmol, 1.1 equiv), PPh.sub.3 (629 mg, 2.40 mmol, 1.5
equiv), and THF (3.7 mL). To the above was added DIAD (485 mg, 2.40
mmol, 1.50 equiv) slowly at 45.degree. C. over 25 min. The
resulting solution was stirred for 3 h at 45.degree. C. and then
concentrated under vacuum after diluting with CH.sub.2Cl.sub.2. The
residue was applied onto a silica gel column with
CH.sub.2Cl.sub.2/methanol (10:1) providing 920 mg (75%) of
tell-butyl
N-[2-(2-[2-[(4-[[(1S,2S)-4-bromo-6-chloro-2-[(3R)-3-(dimethylamino)piperi-
din-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)-
ethyl]carbamate (INT-DMP1) as a yellow oil.
[1120] Step B: To a To a 50-mL round-bottom flask purged and
maintained with an inert atmosphere of nitrogen was added
arylbromide INT-DMP1 (960 mg, 1.26 mmol, 1 equiv), Zn(CN).sub.2 (82
mg, 0.55 equiv), NMP (10 mL), and Pd(PPh3).sub.4 (147 mg, 0.13
mmol, 0.1 equiv). The resulting solution was stirred overnight at
100.degree. C. The resulting solution was diluted with water and
extracted with 3.times.50 mL of ethyl acetate. The combined organic
layers were dried over anhydrous sodium sulfate, filtered, and
concentrated under vacuum. The residue was applied onto a silica
gel column with CH.sub.2Cl.sub.2/methanol (10:1) providing 600 mg
(67%) of tert-butyl
N-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)piperi-
din-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]ethoxy)-
ethyl]carbamate (INT-DMP2) as a yellow oil.
[1121] Step C: To a To a 100-mL round-bottom flask was added
Boc-amine INT-DMP2 (600 mg, 0.85 mmol, 1 equiv), CH.sub.2Cl.sub.2
(5 mL), and trifluoroacetic acid (I mL). The resulting slurry was
stirred for 30 min at room temperature. The pH value of the
solution was adjusted to 9 with saturated aqueous sodium
bicarbonate and extracted with 5.times.20 mL of CH.sub.2Cl.sub.2.
The combined organic layers were dried over anhydrous sodium
sulfate, filtered, and concentrated under vacuum. The residue was
applied onto a silica gel column with CH.sub.2Cl.sub.2/methanol
(10:1) providing 470 mg (91%) of
N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]-4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-
-3-(dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene-1--
sulfonamide (INT-DMP3) as a yellow oil.
[1122] Step D: To a To a 25-mL round-bottom flask was added amine
INT-DMP3 (470 mg, 0.78 mmol, 1 equiv), DMF (2 mL), and
1,4-diisocyanatobutane (48 mg, 0.34 mmol, 0.45 equiv). The
resulting solution was stirred for 1 h at 60.degree. C. The crude
product was purified by preparative H PLC.
Example 121:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-(dimethylamino)piperidin-1-yl]-2,3--
dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfona-
mido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenes-
ulfonamide
[1123] The crude product was purified by Preparative HPLC with the
following conditions: Column, XBridge Preparative C18 OBD Column,
19*150 mm 5 um; mobile phase, Water (0.05% NH.sub.4OH) and ACN
(hold 47.0% ACN in 10 min); Detector, UV 254/220 nm. This resulted
in 275.9 mg (26%) of
3-[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(dimethylamino)
piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfonamido]ethoxy]-
ethoxy)
ethyl]-1-[4-([[2-(2-[2-[(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-(d-
imethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy]benzene)sulfona-
mido]ethoxy]ethoxy)ethyl]carbamoyl]amino)butyl]urea as a white
solid.
[1124] MS (m/z): 1353.7 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300
MHz) .delta. 7.89-7.78 (m, 4H), 7.72 (d, J=2.0 Hz, 2H), 7.50-7.42
(m, 2H), 7.37-7.26 (m, 4H), 5.99 (d, J=5.9 Hz, 2H), 3.67-3.42 (m,
18H), 3.40-3.21 (m, 5H), 3.14-2.97 (m, 12H), 2.86 (d, J=11.1 Hz,
2H), 2.35-2.22 (m, 2H), 2.15 (s, 16H), 1.93 (d, J=11.8 Hz, 2H),
1.77 (d, J=13.4 Hz, 2H), 1.60-1.39 (m, 6H), 1.29-1.13 (m, 3H).
Example 122:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-(dimethylamino)piperidin-1-yl]-2,3--
dihydro-1H-inden-1-yl]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S)-3-(-
dimethylamino)piperidin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfona-
mido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,16,18-tetraazahexacosyl]benzenes-
ulfonamide
##STR00232##
[1126] The title compound was prepared in the same manner as
Example 121, beginning with the enantiomer
(S)--N,N-dimethylpiperidin-3-amine. The crude product was purified
by preparative HPLC with the following conditions: Column, XBridge
Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, water (0.05%
NH.sub.4OH) and ACN (42.0% ACN up to 56.0% in 10 min); Detector, UV
254 nm. This resulted in 93.7 mg (56%) of the title compound as a
white solid. MS (m/z): 1353 [M+H].sup.+. .sup.1H NMR (Methanol-d4,
400 MHz) .delta. 7.91-7.83 (m, 4H), 7.76 (d, J=1.9 Hz, 2H),
7.52-7.47 (m, 2H), 7.38-7.29 (m, 4H), 6.05 (d, J=5.9 Hz, 2H), 3.75
(td, J=7.9, 5.9 Hz, 2H), 3.61-3.46 (m, 18H), 3.28 (d, J=5.4 Hz,
3H), 3.20-3.01 (m, 13H), 2.91 (s, 2H), 2.76 (d, J=11.3 Hz, 2H),
2.62 (s, 12H), 2.50 (d, J=11.0 Hz, 2H), 2.42 (d, J=10.8 Hz, 2H),
1.94 (s, 2H), 1.79 (d, J=12.8 Hz, 2H), 1.56 (s, 4H), 1.51-1.43 (m,
4H).
Scheme for the Synthesis of Example 123:
Example 123:
4-([1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]-
oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dih-
ydro-1H-inden-1-yl]oxy)phenyl]sulfonamide]piperidin-1-yl]-7,14-dioxo-3,18--
dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide
##STR00233##
[1128] Step A:
4-[(1S,2S)-6-Chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2-
,3-dihydro-1H-inden-1-yl]oxy)-N-(piperidin-4-yl)benzenesulfonamide
(INT-SLC5, 164 mg, 0.27 mmol), 2-(2-azidoethoxy)ethyl
4-methylbenzenesulfonate (91.3 mg, 0.32 mmol, 1.2 equiv), and
potassium carbonate (110 mg, 0.80 mmol, 3 equiv) were suspended in
acetonitrile (2.5 mL) and the mixture stirred for 46 h at
50.degree. C. The reaction mixture was concentrated under vacuum
and the residue was applied on silica gel column
dichloromethane/methanol (0-10%) providing 112 mg (58%) of
N-(1-[2-(2-azidoethoxy)ethyl]piperidin-4-yl)-4-([(1S,2S)-6-chloro-4-cy-
ano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]-
oxy)benzenesulfonamide was collected as a white solid. MS (m/z):
725.2 [M+H].sup.+.
[1129] Step B: Platinum on carbon 5 wt. % (25 mg) was added to a
solution of INT-SLC9 (63 mg, 0.087 mmol) in ethyl acetate (2 mL).
Three vacuum/hydrogen cycles were performed and the reaction
mixture stirred under hydrogen (1 atm) for 2 h at room temperature.
The reaction mixture was diluted with ethyl acetate and filtered
through 0.2 .mu.m Aerodisc.RTM. filter. The filtrates were
concentrated under vacuum providing 55 mg of crude
N-(1-[2-(2-aminoethoxy)ethyl]piperidin-4-yl)-4-yl)-4-[(1S,2S)-6-chloro-4--
cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-y-
l]oxy)benzenesulfonamide product (INT-SLC10) as a white solid. MS
(m/z): 699.3 [M+H].sup.+.
[1130] Step C: Solution of 1,4-diisocyanatobutane (4.3 mg, 0.031
mmol, 0.39 equiv) in dichloromethane (0.1 mL) was added to a
solution of amine INT-SLC10 (55 mg, 0.079 mmol) in dichloromethane
(1.2 mL) followed by triethylamine (10 .mu.L, 0.078 mmol). The
reaction mixture stirred for 3 h at room temperature and
concentrated under vacuum. The residue was applied onto a silica
gel column gradient wash with dichloromethane/methanol (0-20%)
followed by dichloromethane/methanol/triethylamine (80:20:2.5)
providing 38 mg (80%) of
4-([(1S,2S)-6-chloro-4-cyano-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-y-
l]-2,3-dihydro-1H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cya-
no-2-[4-(2,2,2-trifluoroacetyl)piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]o-
xy)phenyl]sulfonamido)piperidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetr-
aazaicosyl)piperidin-4-yl]benzenesulfonamide as a white solid. MS
(m/z): 770.0 [M/2+H].sup.+.
[1131] Step D: Aqueous sodium hydroxide (3M, 24 .mu.L, 0.07 mmol, 3
equiv) was added to a solution of dimer from Step C (37 mg, 0.024
mmol) in tetrahydrofuran/methanol (0.5:0.05 mL). The reaction
mixture stirred for 1.5 h at room temperature and then quenched
with trifluoroacetic acid (50 .mu.L) at 0.degree. C. The mixture
was concentrated under vacuum and the residue purified by reverse
phase chromatography to yield
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy)phenyl]sulfonamido]piperidin-1-yl)-7,14-dioxo-3,18-
-dioxa-6,8,13,15-tetraazaicosyl]piperidin-4-yl)benzenesulfonamide
(Example 123).
Representative Scheme for the Synthesis of N-Acylsulfonamide Dimer
Products:
Example 124:
N.sup.1,N.sup.18-Bis([4-[(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3--
dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)-6,13-dioxo-5,7,12,14-tetraazaoc-
tadecanediamide
##STR00234## ##STR00235##
[1133] Step A: The thioether intermediate INT-TE6 is deprotected by
treatment with a protic acid such as trifluoroacetic acid or
HCl.
[1134] Step B: The secondary amine of INT-NAI is protected as a
trifluoroacetamide by treatment with ethyl trifluoroacetate in the
presence of a base such as triethylamine or pyridine.
[1135] Step C: The sulfonyl chloride INT-NA3 is obtained by
oxidative chlorination with NCS or chlorine gas.
[1136] Step D: Treatment of the sulfonyl chloride with an ammonia
equivalent through addition of ammonia in methanol or ammonium
hydroxide yields sulfonamide INT-NA4.
[1137] Step E: The N-acylsulfonamide is obtained through standard
coupling conditions with the carboxylic acid using reagents
including EDC, DCC, CDI, HATU, and the like, or alternatively,
through reactions with acid chlorides, all in the presence of a
suitable base such as triethylamine or pyridine.
[1138] Step F: The Boc-intermediate INT-NA5 is deprotected by
treatment with a protic acid such as trifluoroacetic acid or
HCl.
[1139] Step G: Reaction of the amine INT-NA5 with a dual functional
reagent such as 1,4-diisocyanatobutane yields the dimer product
from which protecting groups are removed through treatment with
appropriate reagents (such as 3M sodium hydroxide in methanol) to
provide the final dimer product.
Example 125:
N-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden--
1-yl]oxy)phenyl]sulfonyl)-1-[16-(4-[([4-([(1S,2S)-6-chloro-4-cyano-2-(pipe-
razin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoyl]piperi-
din-1-yl)-5,12-dioxo-4,6,11,13-tetraazahexadecyl]piperidine-4-carboxamide
##STR00236##
[1140] Representative Scheme for Synthesis of Piperazine Dimer
Products:
Example 126:
4-([(1S,2S)-6-Chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([1S,2S)-6-chloro-4-cyano-2-(1,4-diazepa-
n-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]--
7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulf-
onamide
##STR00237##
[1142] Step A: As described previously in this work, epoxide
INT-17B is reacted with Boc-homopiperazine in CH.sub.3CN at
elevated temperature. The resulting mixture is concentrated under
vacuum and purified on a silica gel column to provide the
aminoindanol INT-I8AA.
[1143] Step B: Aminoindanol INT-I8AA (1 equiv) and the thiophenol
are mixed in tetrahydrofuran (0.2M), heating to 40.degree. C. To
this slurry is added PPh.sub.3 (2 equiv) and DIAD (1.5 equiv). Upon
completion of the reaction (LCMS or TLC), the resulting mixture is
concentrated under vacuum and purified on a silica gel column to
provide ether INT-18AB.
[1144] Step C: Aminoindanol INT-18AB (1 equiv), Zn(CN).sub.2 (0.60
equiv), Pd(PPh.sub.3).sub.4 (0.10 equiv), and NMP (0.4M) are
combined at 95.degree. C. Upon completion, the reaction slurry is
cooled and extracted with 3.times. ethyl acetate. The combined
organic layers are washed with 3.times. brine, dried over anhydrous
sodium sulfate, filtered, and concentrated. The residue is purified
on a silica gel column providing the 4-cyano substituted
aminoindanol INT-I8AC.
[1145] Step D: Thioether INT-I8AC (1 equiv) and acetic acid and
water (9:1) are combined in a flask followed by the addition of
N-chlorosuccinimide (NCS, 5 equiv) in several batches. Upon
completion, the resulting slurry is concentrated under vacuum and
diluted with H.sub.2O. The resulting solution is extracted with of
ethyl acetate and the organic layers combined and washed with
3.times.H.sub.2O and 1.times. brine. The mixture is dried over
anhydrous sodium sulfate, filtered, and concentrated under vacuum.
The residue is purified on a silica gel column to provide the
sulfonyl chloride INT-I8AD.
[1146] Step E: Amine dimer INT-SD4 is slurried in CH.sub.3CN and
water (added as necessary for solubility) followed by the addition
of sulfonyl chloride INT-I8AD and diisopropylethylamine. The
reaction mixture is agitated until completion (as determined by TLC
or LCMS) and concentrated under vacuum. The residue is diluted in
CH.sub.2Cl.sub.2 and washed with 2.times.1M NaHSO.sub.4 and brine,
dried over anhydrous sodium sulfate, filtered, and concentrated
under vacuum. The residue is purified on a silica gel column
providing the Boc-protected dimer product. Subsequently, the
material is treated with trifluoracetic acid in CH.sub.2Cl.sub.2 to
remove the protecting groups and the resulting mixture purified by
reverse phase preparative HPLC.
[1147] The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge Shield RP18 OBD Column, 5 um,
19*150 mm; mobile phase, water (0.05% TFA) and ACN (13.0% ACN up to
36.0% in 8 min); Detector, UV 254 nm. This resulted in 188 mg (69%)
of the title compound as a white solid. MS (m/z): 1345.65
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.94 (d,
J=8.6 Hz, 2H), 7.80 (d, J=1.9 Hz, 1H), 7.51 (d, J=1.7 Hz, 1H), 7.39
(d, J=8.8 Hz, 2H), 6.09 (d, J=5.9 Hz, 1H), 4.00 (q, J=7.4 Hz, 2H),
3.78 (t, 4.9 Hz, 2H), 3.56 (t, J=5.3 Hz, 2H), 3.50-3.36 (m, 2H),
3.33-3.23 (m, 2H), 3.20-3.05 (m, 5H), 2.95 (t, J=6.0 Hz, 2H), 2.37
(s, 1H), 2.04 (dd, J=10.1, 4.0 Hz, 3H), 1.52 (s, 2H).
Example 127:
4-([(1S,2S)-6-Chloro-4-cyano-2-(1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-
-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-(1S,2S)-6-chloro-4-cyano-2-(1,4-diazepan-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7-
,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfo-
namide; bis(trifluoroacetic acid)
##STR00238##
[1149] The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19 mm*250 mm, 5 .mu.m; mobile phase, water (0.05% TFA) and ACN
(24.0% ACN up to 42.0% in 9 min); Detector, UV 254 nm. This
resulted in 128.3 mg (70%) of the title compound as a white solid.
MS (m/z): 1348 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz)
.delta. 7.89 (d, J=8.8 Hz, 2H), 7.75 (d, J=1.9 Hz, 1H), 7.46 (s,
1H), 7.34 (d, J=8.8 Hz, 2H), 6.03 (d, J=5.8 Hz, 1H), 4.87-4.77 (m,
1H), 4.00-3.89 (m, 2H), 3.73 (t, J=4.9 Hz, 2H), 3.52 (t, J=5.2 Hz,
2H), 3.43-3.31 (m, 3H), 3.28-3.01 (m, 6H), 2.89 (t, J=6.0 Hz, 2H),
2.04-1.94 (m, 3H), 1.47 (s, 2H).
Example 128:
4-([(1S,2S)-6-Chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-
-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
in-3-yl]benzenesulfonamide
##STR00239##
[1150] Example 129:
4-([(1S,2S)-6-Chloro-4-cyano-2-(4-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(4-
-methyl-1,4-diazepan-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
in-3-yl)benzenesulfonamide
##STR00240##
[1151] Example 130:
4-([(1S,2S)-2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cya-
no-2,3-dihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-2-1(1-
S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H--
inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6-
,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;
bis(trifluoroacetic acid)
##STR00241##
[1153] The crude product was purified by Preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
10 .mu.m, 19*250 mm; mobile phase, water (0.05% TFA) and ACN (23.0%
ACN up to 41.0% in 8 min); Detector, UV 254 nm. This resulted in
209 mg (51%) of the title compound as a white solid. MS (m/z): 1343
[M+H].sup.+. .sup.1H NMR (Methanol-d.sup.4' 400 MHz) .delta.
7.96-7.88 (m, 4H), 7.76 (d, J=1.9 Hz, 2H), 7.40-7.32 (m, 6H), 6.05
(d, J=6.9 Hz, 2H), 4.27 (s, 2H), 3.99 (s, 4H), 3.91-3.80 (m, 4H),
3.75 (t, J=5.0 Hz, 6H), 3.64-3.40 (m, 14H), 3.21 (dd, J=11.5, 2.4
Hz, 6H), 3.15-3.01 (m, 10H), 2.95-2.87 (m, 2H), 2.47-2.07 (m, 4H),
2.01 (s, 2H), 1.85 (d, J=11.6 Hz, 2H), 1.49 (s, 4H).
Example 131:
4-([(1S,2S)-2-[(1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cya-
no-2,3-dihydro-1H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-2-[(1-
S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-6-chloro-4-cyano-2,3-dihydro-1H--
inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6-
,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide;
bis(trifluoroacetic acid)
##STR00242##
[1155] The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
10 .mu.m, 19 mm.times.250 mm; mobile phase, water (0.05% TFA) and
ACN (23.0% ACN up to 41.0% in 8 min); Detector, UV 254 nm. This
resulted in 288.8 mg (63%) of the title compound as a white solid.
MS (m/z): 1343 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.96-7.88 (m, 4H), 7.77 (d, J=1.8 Hz, 2H), 7.40-7.32 (m,
6H), 6.06 (d, J=6.9 Hz, 2H), 4.30-4.25 (m, 2H), 3.99 (s, 2H),
3.93-3.81 (m, 5H), 3.75 (1, J=5.0 Hz, 7H), 3.65-3.36 (m, 16H), 3.21
(dd, J=11.6, 2.4 Hz, 4H), 3.15-3.01 (m, 10H), 2.97-2.89 (m, 2H),
2.49-2.06 (m, 4H), 2.00 (s, 2H), 1.86 (d, J=11.3 Hz, 2H), 1.49 (s,
4H).
Example 132:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([1S,2S)-6-chloro-4-cyano-2-[(R-
)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido-
)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidi-
n-3-yl]benzenesulfinamide; bis(trifluoroacetic acid)
##STR00243##
[1157] The crude product was purified by Preparative HPLC with the
following conditions: Column, XBridge Shield RP18 OBD Column, 5 um,
19*150 mm; mobile phase, water (0.05% TFA) and ACN (12% ACN up to
38% in 8 min); Detector, UV 220 nm. This resulted in 180.1 mg (59%)
of the title compound as a white solid. MS (m/z): 1347.7
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz) .delta. 7.93-7.83
(m, 4H), 7.75 (d, J=1.9 Hz, 2H), 7.43 (d, J=1.8 Hz, 2H), 7.38-7.29
(m, 4H), 6.12-6.03 (m, 2H), 3.96 (s, 2H), 3.74 (q, J=6.6, 5.1 Hz,
10H), 3.51 (t, J=5.2 Hz, 4H), 3.43-3.27 (m, 16H), 3.19-2.97 (m,
15H), 2.63 (t, J=10.8 Hz, 2H), 2.41-2.27 (m, 3H), 2.00 (s, 1H),
1.47 (s, 4H), 1.27 (d, J=6.6 Hz, 6H).
Example 133:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-(1S,2S)-6-chloro-4-cyano-2-[(R)-
-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-
pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-
-3-yl]benzenesulfonamide; bis(trifluoroacetic acid)
##STR00244##
[1159] The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge Preparative OBD C18 Column,
19*250 mm, 5 .mu.m; mobile phase, water (0.0.5% TFA) and ACN (25%
ACN up to 40% in 9 min); Detector, UV 220 nm. This resulted in
218.9 mg (54%) of the title compound as a white solid. MS (m/z):
1348 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz) .delta. 7.88
(d, J=8.8 Hz, 4H), 7.75 (d, J=1.9 Hz, 2H), 7.47-7.40 (m, 2H),
7.38-7.29 (m, 4H), 6.08 (d, J=6.0 Hz, 2H), 3.74 (q, J=6.8, 5.2 Hz,
8H), 3.51 (t, J=5.2 Hz, 7H), 3.43-3.27 (m, 10H), 3.19-2.97 (m,
21H), 2.63 (t, J=11.2 Hz, 2H), 2.34 (dd, J=12.6, 10.2 Hz, 2H), 2.00
(s, OH), 1.47 (s, 4H), 1.27 (d, J=6.6 Hz, 6H).
Example 134:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(-
S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
in-3-yl]benzenesulfonamide; bis(trifluoroacetic acid)
##STR00245##
[1161] The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge Shield RP18 OBD Column, 5
.mu.m, 19*150 mm; mobile phase, water (0.05% TFA) and ACN (12.0%
ACN up to 38.0% in 8 min); Detector, UV 220 nm. This resulted in
257.5 mg (51%) of the title compound as a white solid. MS (m/z):
1346 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.97-7.89 (m, 4H), 7.80 (d, J=1.8 Hz, 2H), 7.53-7.48 (m, 2H),
7.42-7.34 (m, 4H), 6.10 (d, J=5.9 Hz, 2H), 4.01 (s, 2H), 3.86-3.71
(m, 10H), 3.56 (t, J=5.3 Hz, 5H), 3.50-3.40 (m, 15H), 3.24-3.05 (m,
14H), 2.67-2.56 (m, 2H), 2.49 (dd, J=12.8, 10.2 Hz, 2H), 2.36 (s,
2H), 2.02 (s, 2H), 1.52 (s, 4H), 1.29 (d, J=6.6 Hz, 6H).
Example 135:
4-([1S,2S)-6-Chloro-4-cyano-2-[(S)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-
-inden-1
yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(S-
)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido-
)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidi-
n-3-yl]benzenesulfonamide; bis(trifluoroacetic acid
##STR00246##
[1163] The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
19*250 mm, 5 .mu.m; mobile phase, water (0.05% TFA) and ACN (25.0%
ACN up to 43.0% in 9 min); Detector, UV 254 nm. This resulted in
226.5 mg (44%) of the title compound as a white solid. MS (m/z):
1346 [M+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.97-7.89 (m, 4H), 7.80 (d, J=1.9 Hz, 2H), 7.53-7.48 (m, 2H),
7.42-7.34 (m, 4H), 6.10 (d, J=5.9 Hz, 2H), 4.01 (s, 2H), 3.86-3.74
(m, 10H), 3.56 (t, J=5.3 Hz, 4H), 3.44-3.34 (m, 16H), 3.24-3.06 (m,
14H), 2.68-2.56 (m, 2H), 2.54-2.43 (m, 2H), 2.36 (s, 2H), 2.01 (s,
2H), 1.51 (d, J=5.9 Hz, 4H), 1.29 (d, J=6.6 Hz, 6H).
Example 136:
4-([(1S,2S)-6-Chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cy-
ano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)p-
henyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraaz-
aicosyl)pyrrolidin-3-yl]benzenesulfonamide; bis(trifluoroacetic
acid
##STR00247##
[1165] The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge C18 OBD Preparative Column,
10 .mu.m, 19*250 mm; mobile phase, water (0.05% TFA) and ACN (25%
ACN up to 43% in 8 min); Detector, UV 254 nm. This resulted in 254
mg (84%) of the title compound as a white solid. MS (m/z): 1376
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz) .delta. 7.88 (d,
J=8.7 Hz, 4H), 7.76 (d, J=1.9 Hz, 2H), 7.45 (s, 2H), 7.33 (d, J=8.9
Hz, 4H), 6.07 (d, J=6.0 Hz, 2H), 3.96 (s, 3H), 3.74 (dt, J=9.6, 5.6
Hz, 10H), 3.51 (t, J=5.2 Hz, 4H), 3.41-3.28 (m, 14H), 3.20-3.07 (m,
12H), 2.30 (dt, J=28.3, 11.9 Hz, 5H), 1.99 (s, 3H), 1.47 (s, 4H),
1.25 (dd, J=9.3, 6.6 Hz, 13H).
Example 137:
4-([(1S,2S)-6-Chloro-4-cyano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-d-
ihydro-1H-inden-1-yl]oxy)-N--[(R)-1-(20-[(R)-3-([4-([(1S,2S)-6-chloro-4-cy-
ano-2-1(3S,5R)-3,5-dimethylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)p-
henyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraaz-
aicosyl)pyrrolidin-3-yl]benzenesulfonamide; bis(trifluoroacetic
acid)
##STR00248##
[1167] The crude product was purified by preparative HPLC with the
following conditions: Column, XBridge Shield RP18 OBD Column, 5 um,
19*150 mm, mobile phase, water (0.05% TFA) and ACN (13% ACN up to
40% in 8 min); Detector, UV 220 nm. This resulted in 171 mg (42%)
of the title compound as a white solid. MS (m/z): 1375.6
[M+H].sup.+. .sup.1H NMR (Methanol-d4, 300 MHz) .delta. 7.88 (d,
J=8.7 Hz, 4H), 7.76 (d, J=1.8 Hz, 2H), 7.46 (d, J=1.8 Hz, 2H),
7.38-7.29 (m, 4H), 6.07 (d, J=5.9 Hz, 2H), 3.96 (s, 2H), 3.74 (dt,
J=9.9, 5.6 Hz, 10H), 3.51 (t, J=5.2 Hz, 5H), 3.41-3.28 (m, 13H),
3.20-3.06 (m, 13H), 2.30 (dt, J=27.3, 11.9 Hz, 6H), 1.97 (s, 2H),
1.48 (d, J=5.3 Hz, 4H), 1.25 (dd, J=9.7, 6.6 Hz, 13H).
Example 138:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxopiperidin-1-yl]--
7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxopiperidin-3-yl]benzen-
esulfonamide
##STR00249##
[1168] Example 139:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[1-(20-[3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-di-
hydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)-2-oxoazepan-1-yl]-7,14-dioxo-3-
,18-dioxa-6,8,13,15-tetraazaicosyl)-2-oxoazepan-3-yl]benzenesulfonamide
##STR00250##
[1169] Scheme for the Synthesis of Cyclohexyl Core Dimer
Products:
Example 140:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[2-(2-[2-(3-[(1s,4s)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano--
2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy-
]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfinam-
ide
##STR00251##
[1171] Step 1: The amine INT-M5E is treated with disuccinimidyl
carbonate (DSC) or similar activating agent (others including
1,1'-carbonyldiimidazole, p-nitrophenylchloroformate, etc) in DMF,
followed by addition of the desired diamine, with
(1s,4s)-cyclohexane-1,4-diamine shown.
Bis(2,5-dioxopyrrolidin-1-yl)carbonate (85 mg, 0.33 mmol, 1.1 eq)
and tert-butyl 4-((1S,2
S)-2-(4-(N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-4-chloro--
6-cyano-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate (200 mg,
0.3 mmol) were stirred in DMF (1 mL) for 1.5 hours before a
solution of (1s,4s)-cyclohexane-1,4-diamine (15.5 mg, 0.135 mmol,
0.45 eq) in DMF (0.2 mL) was added. The mixture was stirred for 2 h
at 60.degree. C. LCMS showed significant amount of monourea
side-product, example 155. The DMF was removed under vacuum,
residue dissolved in 4:1 MeCN: H2O, filtered, and purified by
prep-HPLC with the following conditions: Column, Atlantis Prep T3
OBD, 50*250 mm, 10 um; mobile phase, water (0.1% TFA) and CH3CN
(25.0% CH3CN up to 80.0% in 60 min); Detector, UV 214 nm. Product
eluted .about.62% MeCN. Boc-protected cyclohexyl diamine product:
143 mg (61%); LCMS: ret time 3.3 min. MS (m/z): [M/2+H]+ 747.4. The
product was deprotected in the following step.
[1172] Step 2: The product was deprotected under acidic conditions
yielding Example 140. LCMS: ret time 2.40 min, [M/2+H].sup.+ 647.3.
.sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.86 (d, J=9.0 Hz, 4H),
7.76 (d, J=1.9 Hz, 2H), 7.45 (d, J=1.2 Hz, 2H), 7.31 (d, J=9.0 Hz,
4H), 6.06 (d, J=6.2 Hz, 2H), 3.79-3.67 (m, 1H), 3.62-3.44 (m, 22H),
3.33 (s, 3H), 3.22 (t, J=5.1 Hz, 8H), 3.05 (t, J=5.5 Hz, 4H), 2.85
(d, J=14.3 Hz, 5H), 1.70-1.46 (m, 4H)
Example 141:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[2-(2-[2-(3-[(1r,4r)-4-(3-[2-(2-[2-([4-([(1S,2S)-6-chloro-4-cyano--
2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)ethoxy-
]ethoxy)ethyl]ureido)cyclohexyl]ureido)ethoxy]ethoxy)ethyl]benzenesulfonam-
ide
##STR00252##
[1173] The title compound was prepared from
(1r,4r)-cyclohexane-1,4-diamine and INT-M5E through the route to
prepare Example 140. LCMS: ret time 2.37 min. MS (m/z):
[M/2+H].sup.+ 647.3. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.91-7.82 (m, 4H), 7.76 (d, J=1.9 Hz, 2H), 7.46 (d, J=1.2 Hz, 2H),
7.38-7.23 (m, 4H), 6.07 (d, J=6.1 Hz, 2H), 3.80-3.66 (m, 2H),
3.61-3.44 (m, 18H), 3.36 (dd, J=16.7, 8.0 Hz, 4H), 3.24 (dt,
J=15.3, 5.4 Hz, 13H), 3.12 (dd, J=16.6, 8.1 Hz, 2H), 3.05 (t, J=5.5
Hz, 4H), 2.86 (qd, J=13.0, 7.9 Hz, 8H), 1.88 (d, J=6.3 Hz, 4H),
1.21 (dd, J=10.9, 9.2 Hz, 4H).
Example 142:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(R)-1-(18-[(R)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-y-
l)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13,-
18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonamid-
e
##STR00253##
[1175] The title compound is prepared through the sequence employed
in preparation of Example 116, but beginning with
Boc-4-aminobutyric acid and 1-Boc-(R)-3-aminopyrrolidine.
Example 143:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N--[(S)-1-(18-[(1S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1--
yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-6,13-
,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidin-3-yl]benzenesulfonami-
de
##STR00254##
[1177] The title compound is prepared through the sequence employed
in preparation of Example 116, but beginning with
Boc-4-aminobutyric acid and 1-Boc-(S)-3-aminopyrrolidine.
Example 144:
(S)--N-([4-([1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-in-
den-1-yl]oxy)phenyl]sulfonyl)-1-(20-[(S)-3-[([4-([(1S,2S)-6-chloro-4-cyano-
-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamoy-
l]pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolid-
ine-3-carboxamide
##STR00255##
[1179] The title compound was prepared through the procedure
provided for Example 124 beginning with N-Boc-L-beta-proline. MS
(m/z): 687.3 [M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 8.12-7.98 (m, 4H), 7.81-7.77 (m, 2H), 7.48-7.44 (m, 2H),
7.41-7.28 (m, 4H), 6.12-6.06 (m, 2H), 3.76 (s, 9H), 3.59-3.50 (m,
6H), 3.25 (s, 14H), 3.19-3.07 (m, 9H), 2.96-2.74 (m, 9H), 1.57-1.43
(m, 4H).
Example 145:
(R)--N-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-i-
nden-1-yl]oxy)phenyl]sulfonyl)-1-(20-[(R)-3-[([4-([(1S,2S)-6-chloro-4-cyan-
o-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonyl)carbamo-
yl]pyrrolidin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrroli-
dine-3-carboxamide
##STR00256##
[1181] The title compound is prepared through the procedure
provided for Example 124 beginning with N-Boc-D-beta-proline.
Scheme for the Synthesis of Monomer Products:
##STR00257##
[1183] "Monomer" final products are described previously in this
work or obtained through deprotection (as necessary) of analogs
such as the INT-M2 series of compounds. Additionally, "monomers"
are obtained through the steps listed in the above scheme,
beginning with sulfonyl chloride A, prepared through oxidative
chlorination as previously described in this work. These materials
A are reacted with any commercial or synthetic amine (primary or
secondary) compounds, including those with protecting groups PG, in
the presence of bases like triethylamine, pyridine, or metal
carbonates. The product sulfonamides B are deprotected as necessary
to produce "monomer" products of structure C.
[1184] The following Example of products can also be prepared using
the synthetic routes described herein:
Example 146:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)benzenesulfonamide
##STR00258##
[1185] Example 147:
N-(2-[2-(2-Aminoethoxy)ethoxy]ethyl)-4-([(1S,2S)-6-chloro-4-cyano-2-(pipe-
razin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide
##STR00259##
[1186] Example 148:
N-[1-(4-Aminobutanoyl)piperidin-4-yl]-4-([(1S,2S)-6-chloro-4-cyano-2-(pip-
erazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)benzenesulfonamide
##STR00260##
[1187] Example 149:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-(3-oxo-7,10-dioxa-2,4-diazadodecan-12-yl)benzenesulfinamide
##STR00261##
[1188] Example 150:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-(1-[4-(3-methylureido)butanoyl]piperidin-4-yl)benzenesulfonamide
##STR00262##
[1189] Example 151:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan-2-yl]benzenesulfonamide
##STR00263##
[1190] Example 152:
4-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden--
1-yl]oxy)phenyl]sulfonamido)-N-[(2S,3R,4S,5R)-1,3,4,5,6-pentahydroxyhexan--
2-yl]piperidine-1-carboxamide
##STR00264##
[1191] Other Synthetic Schemes
##STR00265##
[1193] According to the General Scheme for the synthesis of
compounds of structure (III), the elaborated structures such as
INT-MON1, "monomers", are dimerized to the symmetric urea (Ill)
through reaction with 1,1'-carbonyldiimidazole or
p-nitrophenylchloroformate or the like. Through this step,
compounds such as Example 153-155 are prepared.
Example 153:
4-(3-[14-([4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-
-inden-1-yl]oxy)phenyl]sulfonamido)-4-oxobutyl]ureido)-N-([4-([(1S,2S)-6-c-
hloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulf-
onyl)butanamide
##STR00266##
[1194] Example 154:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[1-(4-[3-(4-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2-
,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidin-1-yl]-4-oxobutyl-
)ureido]butanoyl)piperidin-4-yl]benzenesulfonamide
##STR00267##
[1195] Example 155:
4-([(1S,2S)-6-Chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[19-([4-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10-oxo-3,6,14,17-tetraoxa-9,11-diaza-
nonadecyl]benzenesulfonamide
##STR00268##
[1196] Step A: Bis(2,5-dioxopyrrolidin-1-yl)carbonate (85 mg, 0.33
mmol, 1.1 eq) and tert-butyl 4-((1S,2
S)-2-(4-(N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-4-chloro--
6-cyano-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate (200 mg,
0.3 mmol) were stirred in DMF (1 mL) for 1.5 hours before a
solution of (1s,4s)-cyclohexane-1,4-diamine (15.5 mg, 0.135 mmol,
0.45 eq) in DMF (0.2 mL) was added. The mixture was stirred for 2 h
at 60.degree. C. LCMS showed significant amount of monourea
side-product, example 155. The DMF was removed under vacuum,
residue dissolved in 4:1 MeCN: H2O, filtered, and purified by
prep-HPLC with the following conditions: Column, Atlantis Prep T3
OBD, 50*250 mm, 10 um; mobile phase, water (0.1% TFA) and CH3CN
(25.0% CH3CN up to 80.0% in 60 min); Detector, UV 214 nm. Product
eluted .about.62% MeCN. Cyclohexyl diamine product: 143 mg (61%);
LCMS: ret time 3.3 min. MS (m/z): [M/2+H]+ 747.4. Symmetric urea
product: 47 mg (22%); LCMS: ret time 3.4 min MS (m/z): [M/2+H]+
677.3. The products were each deprotected in the following step.
Step B: Representative procedure (Example 155): TFA (150 .mu.L,
1.95 mmol, 69 eq) was added to a solution of tert-butyl
4-((1S,2S)-1-(4-(N-(19-((4-(((1S,2S)-2-(4-(tert-butoxycarbonyl)piperazin--
1-yl)-6-chloro-4-cyano-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)sulfonamido)-1-
0-oxo-3,6,14,17-tetraoxa-9,11-diazanonadecyl)sulfamoyl)
phenoxy)-6-chloro-4-cyano-2,3-dihydro-1H-inden-2-yl)piperazine-1-carboxyl-
ate (45 mg, 0.028 mmol) in DCM (1.0 mL). The mixture was stirred
for 4 hours (complete by LCMS). The volatiles were removed under
vacuum and the residue dissolved in 4:1 MeCN:H2O and purified by
prep-HPLC with the following conditions: Column, Atlantis Prep T3
OBD, 50*250 mm, 10 um; mobile phase, water (0.1% TFA) and CH3CN
(25.0% CH.sub.3CN up to 60.0% in 50 min); Detector, UV 214 nm.
Product eluted at 50% MeCN, 25 mg (55%) was collected Example 155
as a white solid. LCMS: ret time 2.40 min. MS: [M/2+H].sup.+ 577.3.
.sup.1H NMR (Methanol-d4, 400 MHz) .delta. 7.86 (d, J=9.0 Hz, 4H),
7.76 (d, J=1.9 Hz, 2H), 7.47-7.44 (m, 2H), 7.31 (d, J=9.0 Hz, 4H),
6.08-6.04 (m, 2H), 3.78-3.67 (m, 1H), 3.61-3.43 (m, 21H), 3.40-3.32
(m, 2H), 3.27 (s, 4H), 3.22 (t, J=5.2 Hz, 10H), 3.16-3.08 (m, 1H),
3.05 (s, 5H), 2.93-2.77 (m, 8H).
Example 156:
4-([(1S,2S)-6-Chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[26-([4-([(1S,2S)-6-chloro-4-amido-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,-
16,18-tetraazahexacosyl]benzenesulfinamide
##STR00269##
[1198] The title compound is prepared through controlled hydrolysis
of Example 41, via the use of either protic acids including
sulfuric acid or hydrogen chloride or aqueous bases such as sodium
hydroxide.
Example 157:
4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl-
]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro--
1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11,-
16,18-tetraazahexacosyl]benzenesulfonamide
##STR00270##
[1200] The title compound is prepared through the same procedures
as yield Example 41, beginning with the
4-methyl-2-bromobenzaldehyde or similar appropriate starting
material.
Scheme for the Synthesis of Bicyclic Analogs:
##STR00271##
[1202] According to the General Scheme for the Synthesis of
Bicyclic Analogs, compounds of structure (IV) are prepared from
starting materials such as phenol A. With or without protection of
the phenolic oxygen, compounds B are prepared via alkylation or
acylation with a suitable reagent such as alkyl halides, carboxylic
acids, isocyanates, etc using bases or coupling agents known to
those in the art. Subsequently the linker of compound B, containing
a reactive or masked substituent Y, is reacted with a bisfunctional
reagent such as 1,4-diisocyanatobutane or the like to generate a
dimer C. Compounds of structure (IV) are generated by coupling of C
with D under Mitsunobu conditions with diazocarboxylate reagents
(DEAD, DIAD, etc) and triphenylphosphine or through
mesylation/displacement in the presence of base.
Example 158:
1,1'-(Butane-1,4-diyl)bis[3-(4-[6-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-o-
xobutyl)urea]
##STR00272##
[1203] Example 159:
1,1'-(Butane-1,4-diyl)bis[3-(4-[7-([(1S,2S)-6-chloro-4-cyano-2-(piperazin-
-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3,4-dihydroisoquinolin-2(1H)-yl]-4-o-
xobutyl)urea]
##STR00273##
[1204] Example 160:
N,N'-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[6-([(1-
S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-
,4-dihydroisoquinoline-2(1H)-carboxamide]
##STR00274##
[1205] Example 161:
N,N'-(6,14-Dioxo-10-oxa-5,7,13,15-tetraazanonadecane-1,19-diyl)bis[7-([(1-
S,2S)-6-chloro-4-cyano-2-(piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-3-
,4-dihydroisoquinoline-2(1H)-carboxamide]
##STR00275##
[1206] Example 162:
1,1'-(Butane-1,4-diyl)bis(3-[2-(2-[6-([(1S,2S)-6-chloro-4-cyano-2-(pipera-
zin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl-
]urea)
##STR00276##
[1207] Example 163:
1,1'-(Butane-1,4-diyl)bis(3-[2-(2-[5-([(1S,2S)-6-chloro-4-cyano-2-(pipera-
zin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)-1-oxoisoindolin-2-yl]ethoxy)ethyl-
]urea)
##STR00277##
[1208] Example 164:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-((-
R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidi-
n-3-yl]benzenesulfonamide
##STR00278##
[1209] Example 165:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(R)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(-
R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamid-
o)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolidi-
n-3-yl]benzenesulfonamide
##STR00279##
[1210] Example 166:
4-[(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-
-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-((R)-3-methy-
lpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidi-
n-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl)benze-
nesulfonamide
##STR00280##
[1211] Example 167:
N.sup.1,N.sup.14-Bis(2-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-met-
hylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrol-
idin-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide
##STR00281##
[1212] Example 168:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-methy-
lpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperidi-
n-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]benz-
enesulfonamide
##STR00282##
[1213] Example 169: 4-([(1S,2S)-4,6-Dichloro-2-1.
(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)-N--[(S)-1-(20--
[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-KR)-3-methylpiperazin-1-yl]-2,3-dihydr-
o-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-1-yl]-7,14-dioxo-3,18-di-
oxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]benzenesulfonamide
##STR00283##
[1214] Example 170:
N.sup.1,N.sup.14-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylp-
iperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-
-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide
##STR00284##
[1215] Example 171:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N--[(S)-1-(18-[(S)-3-([4-([(1S,2S)-6-chloro-4-cyano-2-[(-
R)-3-methylpiperazin-1-yl]-2,3-dihydro-lii-inden-1-yl]oxy)phenyl]sulfonami-
do)pyrrolidin-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)pyrrolid-
in-3-yl]benzenesulfonamide
##STR00285##
[1217] Step A:
4-(((1S,2S)-6-Chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)pip-
erazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-N--((S)-pyrrolidin-3-yl)benzen-
esulfonamide (prepared by procedures analogous to the INT-SECS, 200
mg, 0.33 mmol), 4-((tert-butoxycarbonyl)amino)butanoic acid (100
mg, 0.49 mmol, 1.5 equiv), HATU (247 mg, 0.65 mmol, 2 equiv), and
crushed molecular sieves (3 .ANG.) were suspended in
dimethylformamide (1.0 mL), then diisopropylethylamine (226 .mu.L,
1.3 mmol, 4 equiv) was added at room temperature. The mixture was
stirred for 30 min at room temperature at which point the reaction
was complete by LC/MS. The reaction mixture was concentrated under
vacuum and the residue was purified by silica gel chromatography
with DCM:MeOH 0 to 8%. Product eluted .about.6% MeOH; 250 mg (97%)
was collected as tan solid. LC/MS: retention time 4.06 minutes. MS
(m/z): [M+H].sup.+ 797.2.
Step B: TEA (190 .mu.L, 2.5 mmol, 8.0 equiv) was added to a
solution of tert-butyl
(4-((S)-3-(4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluor-
oacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenylsulfonamido)py-
rrolidin-1-yl)-4-oxobutyl)carbamate (250 mg, 0.31 mmol) in DCM (1.0
mL). The reaction mixture was stirred for 16 h at rt, then
concentrated under vacuum (azeotroping TEA with DCE) providing
crude product (theoretical 0.31 mmol) as a white foam, which was
used for the next step without purification. LCMS: retention time
3.22 minutes. MS (m/z): [M+H].sup.+ 697.2. Step C:
1,4-Diisocyanatobutane (18.6 mg, 0.13 mmol, 0.43 equiv) was added
to a solution of
2N--(S)-1-(4-aminobutanoyl)pyrrolidin-3-yl)-4-(((1S,2S)-6-chloro-4-cyano--
2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-in-
den-1-yl)oxy)benzenesulfonamide (216 mg, 0.31 mmol) in DMF (1.0 mL)
and Et.sub.3N (213 .mu.L, 1.54 mmol, 5 equiv). The reaction mixture
was stirred for 4 h at room temperature, diluted with
H.sub.2O/MeCN, and purified by prep-HPLC with the following
conditions: Column, Atlantis Prep T3 OBD, 19*150 mm, 10 um; mobile
phase, water (0.1% TFA) and CH.sub.3CN (20.0% CH.sub.3CN up to
80.0% in 40 min); Detector, UV 214 nm. Product eluted .about.77%
MeCN. This procedure provided 170.1 mg (83%) of the title compound
as a white solid. LC/MS: retention time 4.31 minutes. MS (m/z):
[M/2+H].sup.+ 767.3. Step D: 3M aq NaOH (185 .mu.L, 0.55 mmol, 5.0
eq) was added to a solution of
(S,S,R)--N,N'-((3S,3'S)-1,1'-(6,13-dioxo-5,7,12,14-tetraazaoctadecane-1,1-
8-dioyl)bis(pyrrolidine-3,1-diyl))bis(4-(((1S,2S)-6-chloro-4-cyano-2-((R)--
3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-y-
l)oxy)benzenesulfonamide) (170 mg, 0.11 mmol) in THF/methanol
(0.9:0.1 mL). The reaction mixture was stirred for 4 h at
rt--complete by LC/MS. The reaction mixture was diluted in
H.sub.2O/MeCN and purified by prep-HPLC with the following
conditions: Column, Atlantis Prep T3 OBD, 19*150 mm, 10 .mu.m;
mobile phase, water (0.1% TFA) and CH.sub.3CN (10.0% CH.sub.3CN up
to 60.0% in 40 min); Detector, UV 214 nm. Product eluted .about.48%
MeCN. This procedure provided 124 mg (72%) of the title compound as
a white solid. LC/MS: retention time 2.9 minutes. MS (m/z):
[M/2+H].sup.+ 671.3. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.92-7.83 (m, 4H), 7.76 (s, 2H), 7.49-7.45 (m, 2H), 7.37-7.25 (m,
4H), 6.09-6.05 (m, 2H), 3.86-3.69 (m, 2H), 3.34 (dd, J=14.5, 6.4
Hz, 19H), 3.11 (t, J=8.6 Hz, 22H), 2.69-2.55 (m, 1H), 2.41-2.04 (m,
1H), 1.98-1.62 (m, 1H), 1.47 (s, 4H), 1.28 (dd, J=6.5, 3.7 Hz,
711).
Example 172:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[1-(18-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-meth-
ylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperid-
in-1-yl]-6,13,18-trioxo-5,7,12,14-tetraazaoctadecanoyl)piperidin-4-yl]benz-
enesulfonamide
##STR00286##
[1218] Step A:
4-(((1S,2S)-6-Chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)pip-
erazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)-N-(piperidin-4-yl)benzenesulfo-
namide (prepared by procedures analogous to INT-SLC5, 170 mg, 0.27
mmol), 4-((tert-butoxycarbonyl)amino)butanoic acid (83 mg, 0.40
mmol, 1.5 equiv), HATU (206 mg, 0.54 mmol, 2 equiv) and crushed
molecular sieves (3 .ANG.) were suspended in dimethylformamide (1.0
mL), then diisopropylethylamine (190 .mu.L, 1.1 mmol, 4 equiv) was
added at room temperature. The reaction mixture was stirred for 1 h
at room temperature--complete by LC/MS. The reaction mixture was
concentrated under vacuum and the residue was purified by silica
gel chromatography with DCM:MeOH 0 to 8%. Product eluted .about.6%
MeOH; 210 mg (96%) was collected as a tan solid. LC/MS: retention
time 4.11 minutes. MS (m/z): [M+H].sup.+ 811.2. Step B: TFA (160
.mu.L, 2.06 mmol, 8.0 equiv) was added to a solution of tert-butyl
(4-(4-(4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroace-
tyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenylsulfonamido)piperi-
din-1-yl)-4-oxobutyl)carbamate (210 mg, 0.26 mmol) in DCM (1.0 mL).
The reaction mixture was stirred for 18 h at rt, then concentrated
under vacuum (azeotroping TFA with DCE) providing crude product
(theoretical 0.26 mmol) as a white foam, which was used for the
next step without purification. LCMS: retention time 3.24 minutes.
MS (m/z): [M+H].sup.+ 711.2. Step C: 1,4-Diisocyanatobutane (15.1
mg, 0.11 mmol, 0.43 equiv) was added to a solution of
N-(1-(4-aminobutanoyl)piperidin-4-yl)-4-(((1S,2S)-6-chloro-4-cyano-2-((R)-
-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1--
yl)oxy)benzenesulfonamide (180 mg, 0.25 mmol) in DMF (0.8 mL) and
Et.sub.3N (175 .mu.L, 1.26 mmol, 5 equiv). The reaction mixture was
stirred for 4 h at room temperature diluted with H.sub.2O/MeCN and
purified by prep-HPLC with the following conditions: Column,
Atlantis Prep T3 OBD, 19*150 mm, 10 um; mobile phase, water (0.1%
TFA) and CH.sub.3CN (20.0% CH.sub.3CN up to 80.0% in 40 min);
Detector, UV 214 nm. Product eluted .about.77% MeCN. This procedure
provided 145 mg (86%) of the title compound as a white solid.
LC/MS: retention time 4.37 minutes. MS (m/z): [M/2+H].sup.+
781.3.
[1219] Step D: 3M aq NaOH (185 .mu.L, 0.55 mmol, 6.0 eq) was added
to a solution of
(S,S,R)--N,N'-(1,1'-(6,13-dioxo-5,7,12,14-tetraazaoctadecane-1,18-dioyl)b-
is(piperidine-4,1-diyl))bis(4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-
-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl)oxy)benz-
enesulfonamide) (145 mg, 0.9 mmol) in THF/methanol (0.9:0.1 mL).
The reaction mixture was stirred for 1 h at rt--complete by LC/MS.
The reaction mixture was diluted in H.sub.2O/MeCN and purified by
prep-HPLC with the following conditions: Column, Atlantis Prep T3
OBD, 19*150 mm, 10 um; mobile phase, water (0.1% TFA) and
CH.sub.3CN (10.0% CH.sub.3CN up to 60.0% in 40 min); Detector, UV
214 nm. Product eluted .about.48% MeCN. This procedure provided
108.8 mg (73%) of the title compound as a white solid. LC/MS:
retention time 2.93 minutes. MS (m/z): (M/2+H].sup.+ 685.3. .sup.1H
NMR (Methanol-d4, 400 MHz) .delta. 7.88 (d, J=8.9 Hz, 4H), 7.76 (d,
J=1.9 Hz, 2H), 7.44 (s, 2H), 7.31 (d, J=8.9 Hz, 4H), 6.06 (s, 2H),
4.24-4.16 (m, 1H), 3.84-3.70 (m, 3H), 3.41-3.30 (m, 17H), 3.24-3.01
(m, 15H), 2.40-2.30 (m, 5H), 1.85-1.76 (m, 1H), 1.71 (d, J=7.2 Hz,
4H), 1.46 (s, 5H), 1.28 (d, J=6.6 Hz, 7H).
Example 173:
4-([(1S,2S)-6-Chloro-4-cyano-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1-
H-inden-1-yl]oxy)-N-[1-(20-[4-([4-([(1S,2S)-6-chloro-4-cyano-2-[(R)-3-meth-
ylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)piperid-
in-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)piperidin-4-yl]ben-
zenesulfonamide
##STR00287##
[1221] The title compound was prepared following the procedure from
Example 123. The residue purified by Column, Atlantis Prep T3 OBD,
19*150 mm, 10 um; mobile phase, water (0.1% TFA) and CH.sub.3CN
(10.0% CH.sub.3CN up to 60.0% in 40 min); Detector, UV 214 nm.
Product eluted--43% MeCN. This procedure provided 28 mg (41%) of
the title compound as a white solid. LCMS: ret. time 1.89 min. MS
(m/z): [M/2+H].sup.+ 687.3. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.89 (d, J=9.0 Hz, 4H), 7.78-7.75 (m, 2H), 7.45-7.42 (m,
2H), 7.37-7.23 (m, 4H), 6.11-6.02 (m, 2H), 3.80-3.67 (m, 8H),
3.61-3.47 (m, 10H), 3.32 (dd, J=10.3, 7.5 Hz, 18H), 3.12 (d, J=8.8
Hz, 18H), 2.69-2.57 (m, 1H), 2.37-2.28 (m, 1H), 2.08-1.94 (m, 6H),
1.88-1.74 (m, 2H), 1.53-1.39 (m, 4H), 1.28 (d, J=6.6 Hz, 6H).
Example 174:
4-([(1S,2S)-4,6-Dichloro-2-[(R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-in-
den-1-yl]oxy)-N--[(S)-1-(20-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-met-
hylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrol-
idin-1-yl]-7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaicosyl)pyrrolidin-3-yl]-
benzenesulfonamide
##STR00288##
[1222] Step A: (S)-tert-Butyl
3-(4-hydroxyphenylsulfonamido)pyrrolidine-1-carboxylate (0.47 g,
1.37 mmol, 1.1 eq),
1-((R)-4-((1R,2R)-4,6-dichloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-met-
hylpiperazin-1-yl)-2,2,2-trifluoroethanone (0.5 g, 1.25 mmol), and
Ph.sub.3P (0.49 g, 1.87 mmol, 1.5 eq) were dissolved in THF (3 mL),
the mixture heated at 40.degree. C. for 15 minutes under N.sub.2,
then a solution of diisopropyl azodicarboxylate (0.39 mL, 2.0 mmol,
1.6 eq) in THE (1.2 mL) was added dropwise within 15 minutes. The
reaction mixture was stirred for 10 min (LCMS showed no starting
aminoalcohol). The reaction mixture was concentrated under vacuum
and purified by silica gel chromatography with hexane:EtOAc (0 to
60%) providing 840 mg (93%) of product as a white foam. LCMS: ret
time 3.96 min. MS (m/z): [M+H].sup.+ 721.1. Step B: TFA (1.0 mL,
12.9 mmol, 11.7 eq) was added to a solution of (S)-tert-butyl
(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-
-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonamido)pyrrolidine-1-carbo-
xylate (800 mg, 1.1 mmol) in DCM (5.0 mL). The reaction mixture was
stirred for 16 h, the DCM removed by evaporation, and the residue
was purified by prep-HPLC with the following conditions: Column,
Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile phase, water (0.1%
TFA) and CH.sub.3CN (30.0% CH.sub.3CN up to 70.0% in 50 min);
Detector, UV 214 nm. Product eluted .about.65% MeCN. Collected
fractions were concentrated under vacuum, neutralized with solid
NaHCO.sub.3 (pH 9), and extracted with 9:1 CHCl.sub.3:IPA
(3.times.40 mL). Combined organics were washed with brine (40 mL),
dried over Na.sub.2SO.sub.4, filtered, and concentrated to afford
500 mg (73%) of product as a white solid. LCMS: ret time 2.95 min.
MS (m/z): [M+H].sup.+ 621.2. Step C:
2-(2-((tert-Butoxycarbonyl)amino)ethoxy)ethyl
4-methylbenzenesulfonate (126 mg, 0.35 mmol, 1.1 eq),
4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperaz-
in-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)-N--((S)-pyrrolidin-3-yl)benzenesul-
fonamide (200 mg, 0.32 mmol) and K.sub.2CO.sub.3 (89 mg, 0.64 mmol,
2 eq) were mixed in MeCN (2.0 mL) and the mixture stirred at
55.degree. C. for 16 h giving approx. 50% conversion (LCMS). DMF
(0.5 mL) was added and the slurry was stirred for another 24 h at
60.degree. C. giving complete conversion. The reaction mixture was
filtered, the filtrates concentrated, and the residue purified by
silica gel column with DCM: MeOH (0 to 10%). The product 144 mg
(56%) was collected as a white foam. LCMS: ret time 3.3 min. MS
(m/z): [M+H].sup.+ 808.25. Step D: TFA (150 .mu.L, 1.95 mmol, 11
eq) was added to a solution of tert-butyl
(2-(2-((S)-3-(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoro-
acetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonamido)pyr-
rolidin-1-yl)ethoxy)ethyl)carbamate (145 mg, 0.18 mmol) in DCM (2
mL). The reaction mixture was stirred for 15 h then concentrated
under vacuum. The residue was dissolved in water (5 mL) and
neutralized with solid NaHCO.sub.3 (pH .about.8). The aqueous layer
was extracted with EtOAc (3.times.10 mL). The organic layer was
dried over Na.sub.2SO.sub.4, filtered, and concentrated to afford
120 mg (95%) of desired product. LCMS: ret time 2.43 min. MS (m/z):
[M+H].sup.+ 708.2. Step E: A solution of 1,4-diisocyanatobutane (10
mg, 0.071 mmol, 0.42 eq) in DMF (0.1 mL) was added to a solution of
N--((S)-1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)-4-(((1S,2S)-4,6-dichlo-
ro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-
-inden-2-yl)oxy)benzenesulfonamide (120 mg, 0.17 mmol) in DMF (0.4
mL). The reaction mixture was stirred at rt for 2 h, concentrated
under vacuum, and the residue purified by silica gel column DCM:
85DCM/15MeOH/5Et.sub.3N (0 to 10%). Product eluted .about.85% of
polar solvent. 150 mg (theoretical 110 mg, not completely dry) of
product was collected as a white foam. LCMS: ret time 3.56 min. MS
(m/z): [M/2+H].sup.+ 778.3. Step F: 3M aq NaOH (400 .mu.L, 1.2
mmol, 17 eq) was added to a solution of
(S,S,R)--N,N'-((3S,3'S')-1,1'-(7,14-dioxo-3,18-dioxa-6,8,13,15-tetraazaic-
osane-1,20-diyl)bis(pyrrolidine-3,1-diyl))bis(4-(((1S,2S)-4,6-dichloro-1-(-
(R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-
-2-yl)oxy)benzenesulfonamide) (110 mg, 0.071 mmol) in MeOH (1
mL):THF (0.5 mL). The addition was portionwise (130+130+240 .mu.L)
within 2 h, with LCMS monitoring of the reaction progress. After
2.5 h, the reaction was complete by LCMS. The reaction was quenched
with 4N HCl (pH .about.2), the volatiles removed under vacuum, and
the residue purified by prep-HPLC with the following conditions:
Column, Atlantis Prep T3 OBD, 50*250 mm, 10 urn; mobile phase,
water (0.1% TFA) and CH.sub.3CN (20.0% CH.sub.3CN up to 60.0% in 50
min); Detector, UV 214 nm. 127.7 mg (88%) was collected as a white
solid. 124.7 mg registered as NTX-0010630 tare: 4.9286. LCMS: ret
time 1.89 min. MS (m/z): [M/2+H].sup.+ 682.3. .sup.1H NMR
(Methanol-d4, 400 MHz) .delta. 7.87 (s, 4H), 7.43-7.41 (m, 2H),
7.33 (d, J=9.0 Hz, 5H), 7.11-7.09 (m, 2H), 6.07-6.04 (m, 2H),
3.77-3.70 (m, 8H), 3.70-3.62 (m, 3H), 3.55-3.49 (m, 6H), 3.26-3.06
(m, 7H), 2.64 (s, 1H), 2.37-2.28 (m, 1H), 1.50-1.44 (m, 3H), 1.28
(d, J=6.6 Hz, 6H).
Example 175:
N.sup.1,N.sup.14-Bis(2-[(S)-3-([4-([(1S,2S)-4,6-dichloro-2-[(R)-3-methylp-
iperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy)phenyl]sulfonamido)pyrrolidin-
-1-yl]-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecanediamide
##STR00289##
[1223] Step A: 2-(2-((tert-Butoxycarbonyl)amino)acetamido)acetic
acid (84 mg, 0.36 mmol, 1.5 eq),
4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperaz-
in-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)-N--((S)-pyrrolidin-3-yl)benzenesul-
fonamide (150 mg, 0.24 mmol), and HATU (183 mg, 0.48 mmol, 2 eq)
were mixed in DMF (1 mL). Diisopropylethylamine (170 .mu.L, 0.96
mmol, 4 eq) was added and the mixture stirred for 15
minutes--complete by LCMS. The reaction mixture was concentrated
under vacuum and the residue purified by silica gel column with
DCM:MeOH (0 to 10%); 220 mg (>100%, not dry) of product was
collected as a slightly yellowish solid. LCMS: ret time 3.50 min.
MS (m/z): [M+H]+ 835.2. Step B: TFA (300 .mu.L, 3.9 mmol, 16 eq)
was added to a solution of tert-butyl
(2-((2-((S)-3-(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-trifluor-
oacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonamido)py-
rrolidin-1-yl)-2-oxoethyl)amino)-2-oxoethyl)carbamate (theoretical
200 mg, 0.24 mmol) in DCM (2 mL). The reaction mixture was stirred
at rt for 1 h --complete by LCMS. The volatiles were removed by
evaporation and the residue dissolved in water (20 mL) and
neutralized with solid NaHCO.sub.3 (pH 9). The solution was
extracted with EtOAc (2.times.20 mL), then with 9:1 CHCl.sub.3:IPA
(2.times.20 mL) [compound mostly went to EtOAc]. The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated to afford 173 mg (98%) of product as a tan foam. LCMS:
ret time 2.89. MS (m/z): [M+H].sup.+ 735.2. Step C: A solution of
1,4-diisocyanatobutane (14.5 mg, 0.10 mmol, 0.45 eq) in DMF (0.14
mL) was added to a solution of
2-amino-N-(2-((S)-3-(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-(2,2,2-tr-
ifluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonam-
ido)pyrrolidin-1-yl)-2-oxoethyl)acetamide (170 mg, 0.23 mmol) in
DMF (0.5 mL). The reaction mixture was stirred for 0.5 h--complete
by LCMS. The reaction mixture was concentrated under vacuum and the
residue purified by silica gel chromatography with DCM:
8.5DCM/1.5MeOH/0.5Et.sub.3N (0 to 65%). The product eluted at 60%
of polar solvent, 200 mg (theoretical 165 mg) collected as a white
foam. LC/MS: ret time 3.28 minutes. MS (m/z): [M/2H].sup.+ 782.3.
Step D: 3M aq NaOH (100 .mu.L, 0.3 mmol, 3 eq) was added to a
solution of
N.sup.1,N.sup.14-bis(2-((S)-3-(4-(((1S,2S)-4,6-dichloro-1-((R)-3-methyl-4-
-(2,2,2-tri
fluoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenylsulfonam-
ido)pyrrolidin-1-yl)-2-oxoethyl)-4,11-dioxo-3,5,10,12-tetraazatetradecane--
1,14-diamide (165 mg, 0.1 mmol) in THF:MeOH 0.6:0.07 mL. After 1 h,
added additional NaOH (300 .mu.L) and MeOH (200 .mu.L) in two
portions over the next 2 hours. After 1 h the reaction was
complete. The reaction was quenched with 4N HCl (pH .about.2), the
volatiles removed under vacuum, and the residue purified by
prep-HPLC with the following conditions: Column, Atlantis Prep T3
OBD, 50*250 mm, 10 um; mobile phase, water (0.1% TFA) and
CH.sub.3CN (20.0% CH.sub.3CN up to 60.0% in 50 min); Detector, UV
214 nm. 92 mg (48%) was collected as a white solid. 90.6 mg
registered as NTX-0010628 tare: 4.9269. LCMS: ret time 2.5 min. MS
(m/z): [M/2+H].sup.+ 709.3. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.91-7.80 (m, 4H), 7.43-7.37 (m, 2H), 7.30 (s, 4H),
7.16-7.10 (m, 2H), 6.07-6.00 (m, 2H), 3.94-3.89 (m, 3H), 3.79 (d,
J=4.9 Hz, 5H), 3.59-3.50 (m, 4H), 3.13 (s, 14H), 1.53-1.45 (m, 4H),
1.25 (d, J=6.6 Hz, 6H).
Example 176:
4-([(1S,2S)-4-Cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-Ill-inden-1-y-
l]oxy)-N-[26-([4-([(1S,2S)-4-cyano-6-methyl-2-(piperazin-1-yl)-2,3-dihydro-
-1H-inden-1-yl]oxy)phenyl]sulfonamido)-10,17-dioxo-3,6,21,24-tetraoxa-9,11-
,16,18-tetraazahexacosyl]benzenesulfonamide
##STR00290## ##STR00291##
[1224] Step A: 3-(2-Bromo-4-methylphenyl)propanoic acid (2.4 g, 9.9
mmol) was dissolved in DCM (12 mL) and DMF (0.1 mL, 1.3 mmol, 0.13
eq). Oxalyl chloride (1.7 mL, 19.7 mmol, 2 eq) was added dropwise
over 7 minutes. The reaction mixture was stirred at rt under
N.sub.2 for 1.5 h (LCMS showed no starting material). The reaction
mixture was concentrated under vacuum to 1/3 of original volume and
added to a precooled suspension of AlCl.sub.3 (1.7 g, 12.8 mmol,
1.3 eq) in DCM (10 mL) over 5 minutes, keeping internal temperature
<5.degree. C. The reaction mixture was stirred at 3-5.degree. C.
for 20 minutes before the ice bath was removed and mixture stirred
for another 20 minutes--complete by LCMS. The reaction mixture was
quenched by slow addition of cold 3M aq HCl (20 mL) under cooling.
The solution was extracted with DCM (3.times.25 mL). The combined
organic layers were washed with brine (2.times.25 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The
residual solid was suspended in hexane and collected by
filtration--product 2.0 g (90%), white solid; LCMS, NMR are good.
The filtrates were purified by silica gel chromatography
Hexane:EtOAc (0 to 15%) to afford 0.1 g of product. LCMS: ret time
2.75 minutes. MS (m/z): [M+H].sup.+ 225.0. Step B: To
4-bromo-6-methyl-2,3-dihydro-1H-inden-1-one (2.1 g, 9.3 mmol) in
methanol (23 mL) was added NaBH.sub.4 (320 mg, 8.45 mmol, 0.9 eq),
becoming homogenous with addition. After 10 min, the reaction was
complete (LCMS) and the solvent was evaporated. The residue was
slurried in 40 mL of water and extracted with EtOAc (3.times.35
mL). The combined organic layers were washed with brine (2.times.30
mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated to 2.1
g (99%) of white solid. LCMS and NMR are good. The crude was used
directly in the next step. LCMS: ret. time 2.49 minutes. MS (m/z):
[M-H.sub.2O+H].sup.+209.0. Step C:
4-Bromo-6-methyl-2,3-dihydro-1H-inden-1-ol (2.1 g, 9.2 mmol)
suspended in toluene (10 mL), pTsOH.H.sub.2O (175 mg, 0.92 mmol,
0.1 eq) was added at room temperature and mixture heated to
90.degree. C. (internal). The reaction mixture was stirred at
90.degree. C. for 20 min--complete by LCMS. Upon cooling EtOAc (30
mL) was added and the resulting solution washed with brine
(2.times.15 mL). The organic phase was dried over Na.sub.2SO.sub.4,
filtered, and concentrated under vacuum to afford 1.8 g of crude
product as a yellowish oil. NMR and LCMS showed mixture of 2
compounds which were separated by silica gel chromatography with
hexane (2 long columns). Desired product--indene, eluted first,
providing 600 mg (31%) as a colorless liquid. Ret time 3.6 minutes,
no ionization, NMR confirmed structure. Step D:
7-Bromo-5-methyl-1H-indene (0.6 g, 2.86 mmol) was dissolved in DCM
(18 mL) and treated with a solution of pyridine 1-oxide (1.35 g,
14.3 mmol, 5 eq) in DCM (10 mL), followed by (S,S)-Jacobsen
catalyst (Sigma-Aldrich 404454, CAS 135620-04-1). The mixture was
cooled to 0.degree. C. and stirred for 15 minutes. mCPBA (0.98 g,
5.72 mmol, 2 eq) was added in 3 portions over 10 minutes. The
reaction mixture was stirred at 0.degree. C. for another hour
(complete by TLC). The reaction mixture was quenched with 3M aq
NaOH (8 mL), the organic layer separated, and the aqueous layer
extracted with hexane (2.times.20 mL). The combined organic layers
were washed with water (20 mL) and brine (20 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum. The
residue was purified by silica gel chromatography with hexane:DCM
(0 to 40%) to afford 320 mg (50%) of scalemic epoxide, used for the
next step without resolution. Step E:
5-Bromo-3-methyl-6,6a-dihydro-1aH-indeno[1,2-b]oxirene (300 mg,
1.33 mmol) [scalemic material from epoxidation step] and
(R)-tert-butyl 2-methylpiperazine-1-carboxylate (318 mg, 1.59 mmol,
1.2 eq) were mixed in MeCN (4 mL) and heated at 65.degree. C. for
16 h. The reaction mixture was concentrated under vacuum and the
residue purified by silica gel chromatography with hexane:EtOAc (0
to 40%): 260 mg (46%) of product was collected as a tan foam. NMR
showed presence of other diastereomer (.about.10%). LCMS: ret time
2.36 min. MS (m/z): [M+H].sup.+ 425.1. Step F: (R)-tert-Butyl
4-((1R,2R)-4-bromo-2-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-yl)-2-methyl-
piperazine-1-carboxylate (0.2 g, 0.47 mmol),
2,2,2-trifluoro-N-(2-(2-(2-(4-hydroxyphenylsulfonamido)ethoxy)ethoxy)ethy-
l)acetamide (0.2 g, 0.51 mmol, 1.1 eq) and Ph.sub.3P (0.18 g, 0.7
mmol, 1.5 eq) were dissolved in THF (1.2 mL) and the mixture heated
at 40.degree. C. for 15 minutes under N.sub.2. A solution of
diisopropyl azodicarboxylate (0.15 mL, 0.75 mmol, 1.6 eq) in THF
(0.4 mL) was added dropwise within 5 minutes. The reaction mixture
was stirred for 20 more minutes--complete by LCMS. The reaction
mixture was concentrated under vacuum and the residue was purified
by silica gel chromatography with hexane:EtOAc (0 to 70%) to afford
0.35 g (92%) of product as a white foam. NMR and LCMS showed
impurity of other diastereomer which came from the prev. step. LCMS
major diastereomer: ret time 3.44 min. MS (m/z): [M+H].sup.+ 807.2.
Step G: (R)-tert-Butyl
4-((1S,2S)-4-bromo-6-methyl-1-(4-(N-(2-(2-(2-(2,2,2-trifluoroacetamido)et-
hoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-2,3-dihydro-1H-inden-2-yl)-2-methylpi-
perazine-1-carboxylate (0.35 g, 0.43 mmol) and Zn(CN).sub.2 (30.4
mg, 0.26 mmol, 0.6 eq) were dissolved in NMP (1.5 mL), N2 bubbled
through solution, then (Ph.sub.3P).sub.4Pd (50 mg, 0.04 mmol, 0.1
eq) was added. The reaction mixture was stirred under N.sub.2 at
100.degree. C. for 3 h. The reaction mixture was diluted in water
(10 mL) and the suspension was extracted with EtOAc (3.times.15
mL). The combined organics were washed with brine (3.times.7 mL),
dried with Na.sub.2SO.sub.4, concentrated under vacuum, and the
residue purified by silica gel chromatography with hexane:EtOAc (0
to 100%), 0.25 g (77%) of product was collected as a white foam.
LCMS: major diastereomer 3.13 minutes. MS (m/z): [M+H].sup.+ 754.3.
Step H: 3M aq NaOH (300 .mu.L, 0.9 mmol, 2.7 eq) was added to a
solution of (R)-tert-butyl
4-((1S,2S)-4-cyano-6-methyl-1-(4-(N-(2-(2-(2-(2,2,2-tri
fluoroacetamido)ethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-2,3-dihydro-1H-ind-
en-2-yl)-2-methylpiperazine-1-carboxy late (250 mg, 0.33 mmol) in
MeOH (1.2 mL):THF (0.3 mL). The reaction mixture was stirred for
1.5 h at rt--complete by LCMS. The reaction mixture was
concentrated under vacuum and the residue dissolved in
MeCN/H.sub.2O and purified by prep-HPLC with the following
conditions: Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile
phase, water (0.1% TFA) and CH.sub.3CN (25.0% CH.sub.3CN isochratic
for 10 min then up to 60.0% in 20 min); Detector, UV 214 nm. 245 mg
(96%) was collected as a white solid. LCMS: ret time 2.43 min. MS
(m/z): [M+H].sup.+ 658.3. Step I: Triethylamine (100 .mu.L, 0.72
mmol, 4.3 eq) was added to a solution of (R)-tert-butyl
4-((1S,2S)-1-(4-(N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)sulfamoyl)phenoxy)-4-
-cyano-6-methyl-2,3-dihydro-1H-inden-2-yl)-2-methylpiperazine-1-carboxylat-
e 2,2,2-tri fluoroacetate (130 mg, 0.17 mmol, 1 eq) in DMF (0.5
mL). A solution of 1,4-diisocyanatobutane (9.5 mg, 0.067 mmol, 0.4
eq) in DMF (0.1 mL) was added. The reaction mixture was stirred for
20 min at rt--complete by LCMS. The reaction mixture was
concentrated under vacuum and the residue purified by silica gel
chromatography DCM:85DCM/15MeOH/5Et.sub.3N (0 to 90%). 150 mg of
product was collected (not completely dry) as a white solid. LCMS:
ret time 3.64 minutes. MS (m/z): [M/2+H].sup.+ 728.4. Step J:
(2R,2'R)-di-tert-Butyl
4,4'-((1S,1'S,2S,2'S)-(((((26-(hydrosulfonylamino)-10,17-dioxo-3,6,21,24--
tetraoxa-9,11,16,18-tetraazahexacosyl)amino)sulfonyl)bis(4,1-phenylene))bi-
s(oxy))bis(6-cyano-4-methyl-2,3-dihydro-1H-indene-2,1-diyl))bis(2-methylpi-
perazine-1-carboxylate) (100 mg, 0.68 mmol) was dissolved in DCM
(0.5 mL) then TFA (200.mu., 2.61 mmol, 38 eq) was added. The
reaction mixture was stirred for 2 h--complete by LCMS. The
reaction mixture was concentrated and the residue purified by
prep-HPLC with the following conditions: Column, Atlantis Prep T3
OBD, 50*250 mm, 10 um; mobile phase, water (0.1% TFA) and
CH.sub.3CN (20.0-60.0% CH.sub.3CN); Detector, UV 214 nm. 84 mg
(72%) was collected as a white solid. LCMS: ret time 2.36 min. MS
(m/z): [M+H].sup.+ 628.3. .sup.1H NMR (Methanol-d4, 400 MHz)
.delta. 7.85 (d, J=9.0 Hz, 4H), 7.51 (s, 2H), 7.30 (t, J=5.9 Hz,
7H), 6.05-6.00 (m, 2H), 3.72-3.64 (m, 1H), 3.55 (dd, J=6.2, 1.6 Hz,
9H), 3.49 (td, J=5.5, 2.8 Hz, 9H), 3.39-3.30 (m, 5H), 3.20-3.00 (m,
19H), 2.68-2.58 (m, 1H), 2.31 (s, 9H), 1.45 (s, 4H), 1.28 (d, J=6.6
Hz, 6H).
Example 177:
3-(2-{2-[(3S)-3-(4-[[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-
-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2,3,5,6-.sup.2H.sub.4)benzenesulfonami-
do)pyrrolidin-1-yl]ethoxy}ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-[[(1S,2S)-6-chlor-
o-4-cyano-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}(2-
,3,5,6-.sup.2H.sub.4)benzenesulfonamido)pyrrolidin-1-yl]ethoxy}ethyl)carba-
moyl]amino}(1,1,2,2,3,3,4,4-.sup.2H.sub.8)butyl)urea
##STR00292## ##STR00293##
[1225] Step A: 4-Bromophenol-2,3,5,6-th (300 mg, 1.69 mmol, 1 eq)
was dissolved in acetonitrile (5 mL). Powdered potassium carbonate
(0.39 g, 2.8 mmol, 1.6 eq) was added while stirring, followed by
dropwise addition of benzyl bromide (0.24 mL, 2.0 mmol, 1.2 eq).
The mixture was vigorously stirred under nitrogen over weekend
(after 6 h.about.90% conversion). The reaction mixture was filtered
and filtrates concentrated under vacuum to afford crude product as
a white solid, used for in next step without purification. LCMS:
ret.time 3.52 min, no ionization. Step B: Crude
1-(benzyloxy)-4-bromobenzene-2,3,5,6-d.sub.4 (450 mg, 1.69 mmol, 1
eq), Pd.sub.2(dba).sub.3 (38.4 mg, 0.042 mmol, 0.025 eq), and
xantphos (48.6 mg, 0.084 mmol, 0.05 eq) were dissolved in dioxane
(6.7 mL) and iPr.sub.2EtN (0.58 mL, 3.38 mmol, 2 eq). The solution
was degassed with N2, the vial sealed, and BnSH (0.2 mL, 1.69 mmol,
1 eq) added. The reaction mixture was stirred at 90.degree. C. for
5 h, concentrated under vacuum, and the residue purified by silica
gel column with hexane:EtOAc (0 to 10%) to afford 310 mg (60%) of
product as a white solid. LCMS: ret time 3.84 min. MS (m/z):
[M+H].sup.+ 311.5. Step C:
Benzyl(4-(benzyloxy)phenyl-2,3,5,6-d.sub.4)sulfone (310 mg, 1 mmol,
1 eq) was suspended in AcOH/H.sub.2O (7.5:2.5 mL). NCS (399 mg, 3
mmol, 3 eq) was added and reaction mixture stirred at rt for 2
h--complete by LCMS. The reaction mixture was diluted in EtOAc (50
mL) and washed with sat NaHCO.sub.3 (2.times.15 mL), brine (20 mL).
The organic phase was dried over Na.sub.2SO.sub.4, filtered, and
concentrated to afford crude product (286 mg, theoretical) as a
white solid. The material was used for the next step without
purification. LCMS: ret time 3.34 min, no ionization. Step D: To a
solution of crude 4-(benzyloxy)benzenesulfonyl
chloride-2,3,5,6-d.sub.4 (theoretical 0.29 g, 1.0 mmol) in DCM (2
mL) was added solution of (S)-tert-butyl
3-aminopyrrolidine-1-carboxylate (0.23 g, 1.2 mmol, 1.2 equiv) in
DCM (1 mL) then Et.sub.3N (0.17 mL, 1.2 mmol, 1.2 eq) was added.
The reaction mixture was stirred at rt for 20 minutes--complete by
LC/MS. The reaction mixture was concentrated under vacuum and the
residue purified by silica gel chromatography with hexane:EtOAc (0
to 50%) to afford 320 mg (73%) of product as a white solid. LCMS:
retention time 3.14 minutes. MS (m/z): [M+Na].sup.+ 459.1. Step E:
tert-Butyl
(S)-3-((4-(benzyloxy)phenyl)sulfonamido-2,3,5,6-d.sub.4)pyrrolidine-1-car-
boxylate (320 mg, 0.73 mmol) and Pd (10% on carbon, 50% wet, 100
mg, 0.05 mmol) were mixed in MeOH (3.7 mL). Vac/H.sub.2 cycles were
performed and the reaction slurry was stirred under H.sub.2 at room
temperature for 2.5 h--complete by LCMS. The reaction mixture was
filtered through a pad of Celite 545, and eluted with EtOAc. The
filtrate was concentrated to afford 250 mg (99%) of product as a
white foam. LCMS: ret time 2.09 min. MS (m/z): [M+Na].sup.+ 369.1.
Step F:
1-((R)-4-((1R,2R)-4-Bromo-6-chloro-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-
-methylpiperazin-1-yl)-2,2,2-trifluoroethanone (289 mg, 0.66 mmol,
1 eq),
boc-(S)-3-((4-hydroxyphenyl)sulfonamido-2,3,5,6-d.sub.4)pyrrolidine
(250 mg, 0.72 mmol, 1.1 eq) and triphenylphosphine (257 mg, 0.98
mmol, 1.5 eq) were mixed in THF (2.0 mL) and stirred at 40.degree.
C. for 15 minutes under N.sub.2. A solution of DIAD (0.2 mL, 1.07
mmol, 1.6 eq) in THF (0.7 mL) was added dropwise within 5 minutes.
The reaction mixture was stirred for 10 min--complete by LCMS. The
reaction mixture was concentrated under vacuum and the residue
purified by silica gel chromatography with hexane:EtOAc (0 to 50%)
affording 290 mg (58%) of product as a white foam. LCMS: ret time
4.05 min. MS (m/z): [M+H].sup.+ 769.15. Step G: The bromide (270
mg, 0.35 mmol, 1 eq), Zn(CN).sub.2 (23 mg, 0.19 mmol, 0.55 eq), Zn
(.about.4 mg), Pd.sub.2(dba).sub.3 (96 mg, 0.1 mmol, 0.3 eq), and
dppf (116 mg, 0.21 mmol, 0.6 eq) were dissolved in 3:1
dioxane:H.sub.2O (3.5 mL) and the reaction mixture stirred at
80.degree. C. under N.sub.2 for 2.5 h --complete by LCMS. The
reaction mixture was diluted in EtOAc (40 mL) and washed with brine
(15 mL). The organic phase was dried over Na.sub.2SO.sub.4,
filtered, concentrated, and the residue purified by silica gel
column with hexane:EtOAc (0 to 60%) affording 205 mg (82%) of
product as an orange foam. Step H: TFA (0.2 mL, 2.61 mmol, 9.3
equiv) was added to a solution of (S)-tert-butyl
3-(4-(((1S,2S)-4-chloro-6-cyano-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)-
piperazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)phenyl-da-sulfonamido)pyrrol-
idine-1-carboxylate (0.2 g, 0.28 mmol) in DCM (1.4 mL), The
reaction mixture was stirred at rt for 16 h--complete by LCMS. The
reaction mixture was concentrated under vacuum and the residue
purified by prep-HPLC with the following conditions: Column,
Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile phase, water (0.1%
TFA) and CH.sub.3CN (30.0% CH.sub.3CN up to 70.0% in 50 min);
Detector, UV 214 nm. Product eluted .about.58% MeCN. MeCN removed
under vacuum, the aq phase neutralized with solid NaHCO.sub.3 and
extracted with EtOAc (3.times.25 mL). Organic phases dried over
Na.sub.2SO.sub.4, filtered and concentrated to afford 136 mg (80%)
of product. LCMS: ret time 2.61 min. MS (m/z): [M++H].sup.+ 616.2.
Step I: 2-(2-((tert-Butoxycarbonyl)amino)ethoxy)ethyl
4-methylbenzenesulfonate (102 mg, 0.29 mmol, 1.3 eq),
4-(((1S,2S)-4-chloro-6-cyano-1-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)pip-
erazin-1-yl)-2,3-dihydro-1H-inden-2-yl)oxy)-N--((S)-pyrrolidin-3-yl)benzen-
e-d.sub.4-sulfonamide (136 mg, 0.22 mmol), and K.sub.2CO.sub.3 (61
mg, 0.44 mmol, 2 eq) were mixed in MeCN (1.7 mL) and stirred at
50.degree. C. for 20 h--complete consumption of amine by LCMS. The
reaction mixture was diluted with EtOAc, filtered, and concentrated
under vacuum. The residue was purified by silica gel chromatography
with hexane:EtOAc (50 to 80%) then with DCM:MeOH (0 to 6%)
providing 128 mg (73%) of product as a white solid. LCMS: ret time
3.0 min. MS (m/z): [M+H].sup.+ 803.3. Step J: TFA (100 .mu.L, 1.27
mmol, 8 eq) was added to a solution of tert-butyl
(2-(2-((S)-3-((4-(((1S,2S)-6-chloro-4-cyano-2-((R)-3-methyl-4-(2,2,2-trif-
luoroacetyl)piperazin-1-yl)-2,3-dihydro-1H-inden-1-yl]oxy)phenyl)sulfonami-
do-2,3,5,6-d.sub.4)pyrrolidin-1-yl)ethoxy)ethyl)carbamate (128 mg,
0.16 mmol) in DCM (1 mL). The reaction mixture was stirred at rt
for 5 h--complete by LCMS. The reaction mixture was concentrated.
The residue was dissolved in water (3 mL), neutralized with solid
NaHCO.sub.3, and extracted with 9:1 CHCl.sub.3:IPA.(3.times.5 mL).
The combined organics were washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated under vacuum to afford
108 mg (97%) of product as a white foam. LCMS: retention time 2.27
minutes. MS (m/z): [M+H].sup.+ 703.3. Step K: Butane-1,4-diamine
dihydrochloride (300 mg, 1.86 mmol) and CDI (930 mg, 5.7 mmol, 3
eq) were dissolved in MeCN (3.5 mL, 0.5M) and suspension was cooled
to 0.degree. C., then diisopropylethylamine (0.97 mL, 5.6 mmol, 3
eq) was added. The reaction mixture was allowed to warm to rt and
stirred for 1.5 h. The reaction mixture was quenched with H.sub.2O
(2 mL) and filtered, the solids washed with 4:1 MeCN:H.sub.2O (3
mL) then with MeCN (4.times.2 mL), dried under vacuum to provide
400 mg (78%) of product as a white solid.
N--((S)-1-(2-(2-aminoethoxy)ethyl)pyrrolidin-3-yl)-4-(((1S,2S)-6-chloro-4-
-cyano-2-((R)-3-methyl-4-(2,2,2-trifluoroacetyl)piperazin-1-yl)-2,3-dihydr-
o-1H-inden-1-yl)oxy)benzene-d4-sulfonamide (100 mg, 0.14 mmol, 2.2
eq) and
N,N'-(butane-d.sub.8-1,4-diyl)bis(1H-imidazole-1-carboxamide) (18.3
mg, 0.065 mmol) were mixed in THF (0.6 mL) and stirred at
60.degree. C. for 1.5 h--complete by LCMS. The reaction mixture was
concentrated under vacuum and the residue purified by silica gel
column DCM: 85/15/5 DCM/MeOH/Et.sub.3N (0 to 70%) to afford product
as a tan foam. LCMS: ret time 3.13 min. MS (m/z): [M/2+H].sup.+
777.3. Step L: Sodium hydroxide (3M NaOH(aq), 100 .mu.L, 0.3 mmol,
4.7 eq) was added to a solution of protected dimer (100 mg, 0.065
mmol) in THF:MeOH (0.38:0.26 mL). The reaction mixture was stirred
for 1 h (LCMS showed only sm). Additional 3M aq NaOH (200 .mu.L,
0.6 mmol, 9.4 eq) was added to the reaction mixture in 2 portions
within 1 hour at which point the reaction complete by LCMS. The
reaction mixture was neutralized with 4N HCl (0.3 mL, 1.2 mmol, 1.3
eq relative to NaO H), the volatiles removed under vacuum, and the
residue purified by prep-HPLC with the following conditions:
Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile phase, water
(0.1% TEA) and CH.sub.3CN (25.0% CH.sub.3CN up to 60.0% in 50 min);
Detector, UV 214 nm. Lyophilization provided 64 mg (73%) of the
title compound as a white solid. LCMS: ret time 1.95 min. MS (m/z):
681.3 [M/2+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.77 (d, J=1.9 Hz, 2H), 7.44 (d, J=0.9 Hz, 2H), 6.08 (d, J=5.9 Hz,
2H), 3.74 (t, J=4.9 Hz, 13H), 3.52 (t, J=5.4 Hz, 6H), 3.23-2.97 (m,
9H), 2.63 (t, J=12.0 Hz, 1H), 2.34 (t, J=9.8 Hz, 2H), 1.28 (d,
J=6.6 Hz, 6H).
Example 178:
3-(2-{2-[(3S)-3-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methylpiperazin-1-yl-
]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidin-1-yl]ethoxy}-
ethyl)-1-(4-{[(2-{2-[(3S)-3-(4-{[(1S,2S)-6-chloro-4-cyano-2-[(3R)-3-methyl-
piperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}benzenesulfonamido)pyrrolidi-
n-1-yl]ethoxy}ethyl)carbamoyl]amino}(1,1,2,2,3,3,4,4-.sup.2H.sub.8)butyl)u-
rea
##STR00294##
[1227] The title compound was prepared from INT-M5E utilizing the
same procedures in Example 177. LCMS: ret time 1.9 min. MS (m/z)
[M/3+H].sup.+ 452.1. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.89 (d, J=8.9 Hz, 4H), 7.79-7.76 (m, 2H), 7.47-7.41 (m, 2H), 7.35
(d, J=9.0 Hz, 5H), 6.11-6.04 (m, 2H), 4.04-3.87 (m, 1H), 3.74 (d,
J=4.9 Hz, 9H), 3.52 (s, 4H), 3.14 (s, 15H), 2.68-2.58 (m, 2H),
2.39-2.27 (m, 3H), 2.06-1.88 (m, 2H), 1.28 (d, 6.6 Hz, 7H).
Example 179:
(1S,2S)-1-(4-{[(3S)-[2-(2-{[(4-{[2-{2-[(3S)-3-(4-.ident.[(1S,2S)-4-carbox-
y-6-chloro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-inden-1-yl]oxy}b-
enzenesulfonamido)-1-hydroxy-1.lamda..sup.4-pyrrolidin-1-yl]ethoxy}ethyl)c-
arbamoyl]amino}butyl)carbamoyl]amino}ethoxy)
ethyl]-1-hydroxy-1.lamda..sup.4-pyrrolidin-3-yl]sulfamoyl}phenoxy)-6-chlo-
ro-2-[(3R)-3-methylpiperazin-1-yl]-2,3-dihydro-1H-indene-4-carboxylic
acid
##STR00295##
[1229] Hydrogen peroxide (3%, 0.1 mL, 87.9 mmol, 2.4 eq) was added
to Example 132 (50 mg, 37.1 mmol), followed by water (0.2 mL). The
suspension was sonicated for 1 hour. The reaction mixture diluted
with 1M HCl, filtered, and purified by prep-HPLC with the following
conditions: Column, Atlantis Prep T3 OBD, 50*250 mm, 10 um; mobile
phase, water (0.1% TFA) and CH.sub.3CN (25.0% CH.sub.3CN up to
50.0% in 50 min); Detector, UV 214 nm. Lyophilization provided the
title diacid di-N-oxide (NMR, HPLC). MS (m/z): 708.2 [M/2+H].sup.+,
472.5 [M/3+H].sup.+. .sup.1H NMR (Methanol-d4, 400 MHz) .delta.
7.87-7.72 (m, 3H), 7.59 (s, 2H), 7.25 (dd, J=14.4, 5.5 Hz, 6H),
5.93 (d, J=5.6 Hz, 2H), 4.16 (s, 1H), 4.00-3.75 (m, 14H), 3.02 (s,
12H), 2.54 (s, 1H), 2.40 (s, 1H), 2.23 (s, 1H), 1.39 (s, 3H),
1.25-1.13 (m, 6H).
Example 180: Cell-Bused Assay of NHE-3 Activity (Pre-Incubation
Inhibition)
[1230] Rat and human NHL-3-mediated Na.sup.+-dependent H.sup.+
antiport was measured using a modification of the pH sensitive dye
method originally reported by Paradiso (Proc. Natl. Acad. Sci. USA.
(1984) 81(23): 7436-7440). PS120 fibroblasts stably expressing
human NHE3 and NHERF2 were obtained from Mark Donowitz (Baltimore,
Md.). Opossum kidney (OK) cells were obtained from the ATCC and
propagated per their instructions. The rat NHE-3 gene (GenBank
M85300) was introduced into OK cells via electroporation, and cells
were seeded into 96 well plates and grown overnight. Medium was
aspirated from the wells then incubated for 30 min at 37.degree. C.
with NH.sub.4Cl-HEPES buffer (20 mM NH.sub.4Cl, 80 mM NaCl, 50 mM
HEPES, 5 mM KCl, 2 mM CaCl.sub.2), 1 mM MgCl.sub.2, pH 7.4)
containing 5 .mu.M BCECF-AM. Cells were washed once with Ammonium
free, Na.sup.+-free HEPES (100 mM choline, 50 mM HEPES, 10 mM
glucose, 5 mM KCl, 2 mM CaCl.sub.2), 1 mM MgCl.sub.2, pH 7.4) and
incubated in the same buffer for 10 minutes at room temperature to
lower intracellular pH with 0-30 .mu.M test compound. After
incubation, NHE-3-mediated recovery of neutral intracellular pH was
initiated by addition of Na-HEPES buffer containing 0.4 uM ethyl
isopropyl amiloride (EIPA, a selective antagonist of NHE-1 activity
that does not inhibit NHE-3). Changes in intracellular pH were
monitored using a FLIPR Tetra.RTM. (Molecular Devices, Sunnyvale,
Calif.) by excitation at LA 439 to 505 nm, and measuring BCECF
fluorescence at .lamda..sub.em 538 nm. The initial rate of the
fluorescence ratio change was used as a measure of NHE-mediated
Na.sup.+/H.sup.+ activity, and reported as the change in
fluorescence ratio per minute. Initial rates were plotted as the
average of 2 or more replicates, and pIC.sub.50 values were
estimated using GraphPad Prism.
TABLE-US-00003 TABLE 2 Data for example in human Preincubation
assay: Result pIC.sub.50 Range % inhibition range A NHE3 pIC.sub.50
< 6 NHE3 <40% B NHE3 pIC.sub.50 6-7 40-70% C NHE3 pIC.sub.50
> 7 >70% human Preincubation Example pIC50 % Inhibition 1 C C
2 C C 3 C C 4 C B 5 C B 6 A A 7 C C 8 A A 9 C A 10 C B 11 C C 12 C
A 13 A A 14 A B 15 B C 16 C B 17 C C 18 C B 19 A A 20 A A 21 C A 22
C C 23 C C 24 C C 25 C C 26 C C 27 C C 28 C C 29 C C 30 C C 31 C C
32 C C 33 C C 34 C C 35 C C 36 C C 37 C B 38 A A 39 C A 40 A A 41 C
C 42 C C 43 C C 44 C C 45 C C 46 C C 47 C C 48 B B 49 B C 50 C B 51
C B 52 C C 53 C C 54 C C 55 C C 56 C C 57 C C 58 C C 59 C C 60 C C
61 C C 62 C C 63 C B 64 A A 65 A A 66 A A 67 B C 68 C C 69 C C 70 C
C 71 A B 72 C C 73 B C 74 A C 75 B B 76 C C 77 A C 78 C C 79 C C 80
B B 81 C C 82 C B 83 C C 84 C C 85 C C 86 C C 87 C C 88 C C 89 C C
90 C C 91 C C 92 C C 93 C C 94 C C 95 C C 96 C C 97 C C 98 C C 99 C
C 100 C C 101 C C 102 C C 103 C C 104 C C 105 C C 106 C C 107 C C
108 C C 109 C C 110 C C 111 C C 112 C C 113 C C 114 C C 115 C C 120
C C 121 C B 122 C C 123 C C 124 C C 126 C C 127 C C 128 A A 129 A A
130 C B 131 C C 132 C C 133 C C 134 C C 135 C C 136 C C 137 C C 142
C C 143 C C 146 C C 154 C C
Example 181: Cell-Based Assay of NHE-3 Activity (Persistent
Inhibition)
[1231] The ability of compounds to inhibit human and rat
NHE-3-mediated Na'-dependent H.sup.+ antiport after application and
washout was measured using a modification of the pH sensitive dye
method described above. PS120 fibroblasts stably expressing human
NHE3 and NHERF2 were obtained from Mark Donowitz (Baltimore, Md.).
Opossum kidney (OK) cells were obtained from the ATCC and
propagated per their instructions. The rat NHE-3 gene was
introduced into OK cells via electroporation, and cells were seeded
into 96 well plates and grown overnight. Medium was aspirated from
the wells, cells were washed once with NaCl-HEPES buffer (100 mM
NaCl, 50 mM HEPES, 10 mM glucose, 5 mM KCl, 2 mM CaCl.sub.2), 1 mM
MgCl.sub.2, pH 7.4), then overlayed with NaCl-HEPES buffer
containing 0-30 .mu.M test compound. After a 60 min incubation at
room temperature, the test drug containing buffer was aspirated
from the cells. Following aspiration, cells were washed once with
NaCl-HEPES buffer without drug, then incubated for 30 min at
37.degree. C. with NH.sub.4Cl-HEPES buffer (20 mM NH.sub.4Cl, 80 mM
NaCl, 50 mM HEPES, 5 mM KCl, 2 mM CaCl.sub.2), 1 mM MgCl.sub.2, pH
7.4) containing 5 .mu.M BCECF-AM. Cells were washed once with
Ammonium free, Na.sup.+-free HEPES (100 mM choline, 50 mM HEPES, 10
mM glucose, 5 mM KCl, 2 mM CaCl.sub.2), 1 mM MgCl.sub.2, pH 7.4)
and incubated in the same buffer for 10 minutes at room temperature
to lower intracellular pH. NHE-3-mediated recovery of neutral
intracellular pH was initiated (10 min after compound washout) by
addition of Na-HEPES buffer. For the rat NHE3 assay, the Na-HEPES
buffer contained 0.4 .mu.M ethyl isopropyl amiloride (EIPA, a
selective antagonist of NILE-1 activity that does not inhibit
NHE-3). Changes in intracellular pH were monitored using a FLIPR
Tetra.RTM. (Molecular Devices, Sunnyvale, Calif.) by excitation at
.lamda..sub.ex 439 to 505 nm, and measuring BCECF fluorescence at
.lamda..sub.em 538 nm. The initial rate of the fluorescence ratio
change was used as a measure of NHE-mediated Na.sup.+/H.sup.+
activity, and reported as the change in fluorescence ratio per
minute. Initial rates were plotted as the average of 2 or more
replicates, and pIC.sub.50 values were estimated using GraphPad
Prism.
TABLE-US-00004 TABLE 3 Data for example in human Persistence assay:
% inhibition Result pIC.sub.50 Range range A NHE3 pIC.sub.50 < 6
NHE3 < 40% B NHE3 pIC.sub.50 6-7 40-70% C NHE3 pIC.sub.50 > 7
>70% human Persistence Example pIC50 % inhibition 1 C B 2 C C 3
C C 4 C B 5 C C 6 A A 7 C C 8 A A 9 B B 10 C C 11 C C 12 B B 13 A A
14 A A 15 A A 16 C B 17 C C 18 C B 19 A A 20 A A 21 A C 22 C C 23 C
C 24 C C 25 C C 26 C C 27 C C 28 C C 29 C C 30 C C 31 C C 32 C C 33
C C 34 C C 35 C C 36 C C 37 C B 38 A A 39 C A 40 A A 41 C C 42 C C
43 C C 44 B C 45 C C 46 C C 47 C C 48 B C 49 C C 50 C B 51 C B 52 C
C 53 C C 54 C B 55 C C 56 C C 57 C C 58 C C 59 C C 60 C C 61 C C 62
A A 63 B B 64 A A 65 A A 66 A A 67 B B 68 C C 69 B C 70 C C 71 A B
72 B C 73 A B 74 A A 75 A A 76 A A 77 A A 78 C C 79 B C 80 B B 81 B
C 82 B C 83 B C 84 C C 85 C C 86 C C 87 C C 88 C C 89 C C 90 B C 91
C C 92 C C 93 C C 94 C C 95 C C 96 C C 97 C C 98 C C 99 B C 100 C C
101 C B 102 C C 103 C C 104 C C 105 C C 106 C C 107 C C 108 C C 109
C C 110 C C 111 C C 112 C C 113 C C 114 C C 115 C C 120 C C 121 C A
122 C C 123 C C 124 B C 126 C B 127 C A 128 C A 129 C A 130 B C 131
B C 132 C C 133 C C 134 C C 135 C C 136 C C 137 C C 142 C C 143 C C
146 C A 154 C C
Example 182: Sustained Inhibition of Apical Acid Secretion in Human
Organoid Monolayer Cell Cultures
[1232] Basal media (BM) consisted of advanced DMEM/F12 containing
10 mM HEPES (Invitrogen, 15630-080), 1:100 Glutamax (Invitrogen,
35050-061), and 1:100 penicillin/streptomycin (Invitrogen,
15140-122). Supplemented basal media (SBM) contained 1:100 N2
(Invitrogen, 17502-048), 1:50 B27 (Invitrogen, 12587-010), 1 mM
N-acetylcysteine (Sigma, A9165), and 10 nM [Leu15]-gastrin I
(Sigma, G9145). Growth factors used included 50 ng per mL mouse EGF
(Peprotech, 315-09), 100 ng per mL mouse noggin (Peprotech,
250-38), 500 ng per mL human R-spondin 1 (R&D, 4645-RS), 100 ng
per mL mouse Wnt-3a (R&D, 1324-WN), 20 .mu.M Y-27632 (Tocris,
1254), 10 mM nicotinamide (Sigma, N0636), 500 nM A83-01 (Tocris,
2939), 10 .mu.M SB202190 (Tocris, 1264). Transwells were 0.4 .mu.m
pore polyester membrane 24-well Transwell inserts (Corning).
Cultures were incubated at 37.degree. C. in 5% C07.
[1233] Human ileum organoids were cultured in WENRNAS (Wnt, EGF,
noggin, R-spondin 1, Nicotinamide, A83-01, SB202190) and typically
grown for 7-12 days before being used to plate monolayer cultures.
On day 0, organoid cultures embedded in Matrigel were treated with
TrypLE Express to break organoids into small pieces and/or single
cells. The cells were resuspended to 0.5.times.10.sup.6 cells/mL in
SBM containing WENRAY (Wnt, EGF, noggin, R-spondin 1, A83-01,
Y-27632). Following this step, 200 .mu.L of cell suspension was
plated into the apical side of a 24-well Transwell (100,000
cells/well) and 600 .mu.L of SBM with WENRAY was added to the
basolateral side. Ileum cells were differentiated with ENRA (EGF,
noggin, R-spondin 1, A83-01) on day 3. The color of apical
compartment turns from pink or orange to yellow due to the increase
in NHE3 expression after differentiation.
[1234] Each human ileum monolayer culture well was washed twice
with fresh SBM on the apical side on day 6 before compound dosing.
All compound stocks were 10 mM dissolved in DMSO. Each compound
stock was individually mixed with fresh SBM to reach final compound
concentration 1 .mu.M and dosed only on the apical side of the
monolayer (total volume 200 .mu.l). DMSO at the equivalent
concentration was used as the vehicle control. Duplicate wells were
dosed for each compound. On day 8, apical media pH was measured by
pH electrode, to determine the ability of example compounds to
produce sustained inhibition of NHE3 activity in a human monolayer
culture system by preventing proton secretion into the apical
compartment. Each of the duplicate apical pH values for each
example compound was compared to the average of the DMSO wells and
expressed as a percent inhibition of apical acid secretion.
TABLE-US-00005 TABLE 4 % Inhibition Result (GI Segment) A <50% B
50-70%.sup. C >70% % inhibition % inhibition Example (ileum)
(duodenum) 17 B B 23 B B 24 A B 26 B B 28 B B 29 C C 31 C C 32 C C
33 C C 34 B B 35 C C 36 C C 41 B C 42 C C 43 B C 45 B C 49 C C 52 C
C 55 A B 78 C C 91 B C 105 C C 106 C C 107 C C 109 C C 110 C C 115
C C 122 C C 123 C C 126 A A
Example 183: Increased Trans-Epithelial Resistance in Human
Organoid Monolayer Cell Cultures
[1235] Basal media (BM) consisted of advanced DMEM/F12 containing
10 mM HEPES (Invitrogen, 15630-080), 1:100 Glutamax (Invitrogen,
35050-061), and 1:100 penicillin/streptomycin (Invitrogen,
15140-122). Supplemented basal media (SBM) contained 1:100 N2
(Invitrogen, 17502-048), 1:50 B27 (Invitrogen, 12587-010), 1 mM
N-acetylcysteine (Sigma, A9165), and 10 nM [Leu15]-gastrin I
(Sigma, G9145). Growth factors used included 50 ng per mL mouse EGF
(Peprotech, 315-09), 100 ng per mL mouse noggin (Peprotech,
250-38), 500 ng per mL human R-spondin 1 (R&D, 4645-RS), 100 ng
per mL mouse Wnt-3a (R&D, 1324-WN), 20 .mu.M Y-27632 (Tocris,
1254), 10 mM nicotinamide (Sigma, N0636), 500 nM A83-01 (Tocris,
2939), 10 .mu.M SB202190 (Tocris, 1264). Transwells were 0.4 .mu.m
pore polyester membrane 24-well Transwell inserts (Corning).
Cultures were incubated at 37.degree. C. in 5% CO.sub.2.
[1236] Human duodenum organoids were cultured in WENRNAS (Wnt, EGF,
noggin, R-spondin1, Nicotinamide, A83-01, SB202190) and typically
grown for 7-12 days before being used to plate monolayer cultures.
On day 0, organoid cultures embedded in Matrigel were treated with
TrypLE Express to break organoids into small pieces and/or single
cells. The cells were resuspended to 0.5.times.10.sup.6 cells/mL in
SBM containing WENRAY (Wnt, EGF, noggin, R-spondin1, A83-01,
Y-27632). Following this step, 200 .mu.L of cell suspension was
plated into the apical side of a 24-well Transwell (100,000
cells/well) and 600 .mu.L of SBM with WENRAY was added to the
basolateral side. Duodenum cells were differentiated with ENA (EGF,
noggin, A83-01) on day 3. The color of apical compartment turns
from pink or orange to yellow due to the increase in NHE3
expression after differentiation.
[1237] Each human duodenum monolayer culture well was washed twice
with fresh SBM on the apical side on day 6 or day 7 before dosing.
All compound stocks were 10 mM dissolved in DMSO. Each compound
stock was individually mixed with fresh SBM to reach final compound
concentration 1 .mu.M and dosed only on the apical side of the
monolayer (total volume 200 .mu.l). DMSO at the equivalent
concentration was used as the vehicle control. Duplicate wells were
dosed for each compound. Transepithelial electrical resistance
(TEER) was used as a quantitative technique to measure of tight
junction permeability. TEER values were recorded (MERS00002,
Millipore) before dosing and 30 mins and 1 hr after dosing for all
wells. Each of the duplicate TEER values following treatment were
corrected for the individual well baseline TEER. Baseline corrected
TEER for each example compound was compared to the average of the
DMSO wells and expressed as a percent TEER of vehicle control.
TABLE-US-00006 TABLE 5 TEER Result (% of vehicle) A <100% B
100-130% C >130% TEER at 30 minutes TEER at 60 minutes Example
(% of Vehicle) (% of Vehicle) 17 B B 24 B B 30 B B 31 B C 32 B C 33
B C 41 B B 42 B C 43 B B 91 B B 105 C C 106 C C 107 C B 110 C B 115
B B 126 B B
Example 184: Inhibition of Intestinal Sodium Absorption in Mice
[1238] Urinary and fecal sodium excretions were measured to assess
the ability of selected example compounds to inhibit the absorption
of sodium from the intestinal lumen. In addition, an assessment of
the absence or presence of diarrhea in response to compound
treatment was made. Approximately eight-week old, male, CD-1 mice
were purchased from Envigo (Livermore, Calif.), were housed 6 per
cage and acclimated for at least 48 hours before study initiation.
Animals were fed Harlan Teklad Global TD.160470 rodent chow
(Maddison, Wis.), standard laboratory rodent chow Harlan Teklad
Global 2018 with the addition of 0.4% inorganic phosphorous.
Animals had ad libitum access to food and water for the duration of
the study and were maintained in a temperature and humidity
controlled room on a standard light/dark cycle of 6 AM to 6 PM. To
initiate the study, mice were weighed and then individually placed
in metabolic cages. Following a 3-day acclimation period to the
metabolic cage, a 24-hr baseline collection of urine and feces was
performed. Mice (n=8/group) were then dosed by oral gavage with
test compound (15 mg/kg) or vehicle (3 mM HCl, 0.01% Tween80) at a
dose volume of 5 mL/kg, twice daily at 6 AM and 3 PM for 3
consecutive days. Each day, measurements of body weight, 24-hour
food intake, water intake, urine volume and wet fecal weight were
recorded, along with any observation of diarrhea. Fecal samples
were dried using a lyophilizer for at least 3 days, following which
dry weight was recorded and fecal fluid content was calculated
based on the difference between the wet and dry stool weights.
Fecal fluid content on day 3 of compound treatment was calculated
as a change from the vehicle group mean. For urine samples, the
volumes were determined gravimetrically. Feces and urine were
analyzed for sodium content by microwave plasma-atomic emission
spectroscopy or ion chromatography, respectively. Urine samples
were analyzed on an ion chromatography system (Thermo Fisher
ICS-3000 or ICS-5000+) coupled with conductivity detectors.
Chromatographic separation of cations was performed using an IonPac
CS12A (Thermo Fisher) 2.times.250 mm analytical column with an
isocratic elution using 25 mM methanesulfonic acid. Concentrations
were interpolated from a a standard curve (prepared in 10 mM HCl)
for sodium ion based on retention time and peak area. Fecal sample
analysis by Microwave Plasma Atomic Emission Spectrometry (MP-AES).
Dry fecal samples were ground into a fine powder on a homogenizer
and the ground samples (400-600 mg aliquots weighed) were digested
with nitric acid by microwave method (Mars 6). These digested
samples were diluted with 1% Nitric acid and analyzed on Agilent
4100 MP-AES. Concentrations were calculated relative to a standard
curve (prepared in 1% Nitric acid) for sodium based on the signal
intensity. Sodium was detected at a wavelength of 588.995 nm.
Twenty-four-hour urinary sodium excretion (mg/24-hours) was
calculated by multiplying urinary sodium concentration by 24-hour
urine volume. Twenty-four-hour fecal sodium excretion (mg/24-hours)
was calculated by multiplying fecal sodium concentration by 24-hour
dry fecal weight. The urinary and fecal sodium excretion on day 3
of compound treatment were normalized to dietary sodium intake and
expressed as a percentage of the vehicle mean.
TABLE-US-00007 TABLE 6 Urinary Na Fecal Na Fecal fluid Excretion
Excretion content (% of (% of (= from Result vehicle) vehicle)
vehicle) A >70% <150% <5 B 50-70%.sup. 150-200% 5-10 C
<50% >200% >10 Urinary Na Fecal Na Fecal fluid Excretion
Excretion content (% of (% of (A from Diarrhea Example vehicle)
vehicle) vehicle) (.+-.) 17 B B B -- 23 B B B -- 24 B C A -- 26 B B
B -- 27 B C C -- 28 A B B -- 29 B B A -- 30 B C C -- 31 B C B -- 32
B B A -- 33 C C C -- 34 B B B -- 35 A B A -- 36 B B B -- 41 C C B
-- 42 C B B -- 43 C C C -- 45 A A A -- 49 A A A -- 52 B C B -- 53 A
A B -- 55 A B B -- 78 A A A -- 88 B B B --
Example 185: Inhibition of Intestinal Sodium Absorption in Rats
[1239] Urinary sodium excretion and fecal form were measured to
assess the ability of selected example compounds to inhibit the
absorption of sodium from the intestinal lumen. Eight-week old,
male, Sprague Dawley rats were purchased from Envigo (Livermore,
Calif.), were housed 2 per cage and acclimated for at least 48
hours before study initiation. Animals were fed Harlan Teklad
Global TD.160470 rodent chow (Maddison, Wis.), standard laboratory
rodent chow Harlan Teklad Global 2018 with the addition of 0.4%
inorganic phosphorous. Animals had ad libitum access to food and
water for the duration of the study and were maintained in a
temperature and humidity controlled room on a standard light/dark
cycle of 6 AM to 6 PM. On the day of study initiation, rats
(n=5/group) were dosed by oral gavage with test compound or vehicle
(3 mM HCl, 0.01% Tween80) at a dose volume of 5 mL/kg. Immediately
after dose administration animals were placed in individual
metabolic cages. At 13-hours post-dose, urine samples were
collected and fecal form was assessed. In addition, the weight of
food consumed over the 13-hour period was measured and recorded.
Fecal forms were scored according to a common scale associated with
increasing fecal water to the wettest observation in the cage's
collection funnel (1, normal pellet; 2, pellet adhering to sides of
collection funnel due to moisture; 3, loss of normal pellet shape;
4, complete loss of shape with a blotting pattern; 5, liquid fecal
streams evident). Fecal form score (FFS) was calculated for each
group as the median of each individual rat's FFS within the group
and reported in Table 7. Fecal samples were dried using a
lyophilizer for at least 3 days, following which dry weight was
recorded and fecal fluid content was calculated based on the
difference between the wet and dry stool weights. Fecal fluid
content was calculated as a change from the vehicle group mean. For
urine samples, the volumes were determined gravimetrically. Urine
samples were analyzed on an ion chromatography system (Thermo
Fisher ICS-3000 or ICS-5000+) coupled with conductivity detectors.
Chromatographic separation of cations was performed using an IonPac
CS12A (Thermo Fisher) 2.times.250 mm analytical column with an
isocratic elution using 25 mM methanesulfonic acid. Concentrations
were interpolated from a standard curve (prepared in 10 mM HCl) for
sodium based on retention time and peak area. Thirteen-s-hour
urinary sodium excretion (mg/13-hours) was calculated by
multiplying urinary sodium concentration by 13-hour urine volume.
The urinary sodium excretion of compound treatment was normalized
to dietary sodium intake and expressed as a percentage of the
vehicle mean.
TABLE-US-00008 TABLE 7 Urinary Na Result (% of Vehicle, out/in) A
>70% B 40-70%.sup. C <40% Urinary Na Dose (% of Vehicle, FFS
Example (mg/kg) out/in) (1-5) 41 0.003 A 2 41 0.01 A 2 41 0.03 B 2
41 0.1 C 5 115 0.003 A 1 115 0.01 A 2 115 0.03 A 2 115 0.1 C 2 107
0.03 B 3 107 0.1 B 3 107 0.3 C 3 120 0.03 A 2 120 0.1 B 3 120 0.3 C
4 132 0.03 A 3 132 0.1 B 3 132 0.3 C 5 123 0.03 A 3 123 0.1 B 3 123
0.3 C 3 122 0.03 A 2 122 0.1 A 2 122 0.3 B 3 133 0.03 A 3 133 0.1 C
3 133 0.3 C 3 143 0.03 B 3 143 0.1 C 3 143 0.3 C 4
Example 186: Inhibition of Intestinal Sodium and Phosphorous
Absorption in the Rat Balance Model
[1240] Urinary and fecal sodium excretion, along with urinary
phosphorous excretion are measured to assess the ability of
selected example compounds to inhibit the absorption of sodium and
phosphorous from the intestinal lumen. In addition, an assessment
of fecal form in response to compound treatment is made.
Approximately eight-week old, male, Sprague Dawley rats are
purchased from Envigo (Livermore, Calif.), housed 2 per cage and
acclimated for at least 48 hours before study initiation. Animals
are fed Harlan Teklad Global TD.160470 rodent chow (Maddison,
Wis.), standard laboratory rodent chow Harlan Teklad Global 2018
with the addition of 0.4% inorganic phosphorous. Animals have ad
libitum access to food and water for the duration of the study and
are maintained in a temperature and humidity controlled room on a
reversed light/dark cycle of 6 PM to 6 AM. To initiate the study,
rats are weighed and individually placed in metabolic cages.
Following a 2-day acclimation period to the metabolic cage, a 24-hr
baseline collection of urine and feces is performed. Rats
(n=6/group) are then dosed by oral gavage with test compound or
vehicle (3 mM HCl, 0.01% Tween80) at a dose volume of 5 mL/kg,
twice daily at 6 AM and 3 PM for 3 consecutive days. Each day,
measurements of body weight, 24-hour food intake, water intake,
urine volume and wet fecal weight are recorded, along with any
observation of diarrhea. Fecal samples are dried using a
lyophilizer for at least 3 days, following which dry weight is
recorded and fecal fluid content is calculated based on the
difference between the wet and dry stool weights. Fecal fluid
content on day 3 of compound treatment is calculated as a change
from the vehicle group mean. For urine samples, the volumes are
determined gravimetrically. Feces and urine are analyzed for sodium
and phosphorous content by microwave plasma-atomic emission
spectroscopy or ion chromatography, respectively. Urine samples are
analyzed on an ion chromatography system (Thermo Fisher ICS-3000 or
ICS-5000+) coupled with conductivity detectors. Chromatographic
separation of cations is performed using an Ion Pac CS12A (Thermo
Fisher) 2.times.250 mm analytical column with an isocratic elution
using 25 mM methanesulfonic acid. Chromatographic separation of
anions is performed using an IonPac AS18 (Thermo Fisher)
2.times.250 mm analytical column with an isocratic elution using 35
mM potassium hydroxide. Concentrations are interpolated from a
standard curve (prepared in 10 mM HCl) for each ion based on
retention time and peak area. Fecal sample analysis by Microwave
Plasma Atomic Emission Spectrometry (MP-AES). Dry fecal samples are
ground into a fine powder on a homogenizer and the ground samples
(400-600 mg aliquots weighed) are digested with nitric acid by
microwave method (Mars 6). These digested samples are diluted with
1% Nitric acid and analyzed on Agilent 4100 MP-AES. Concentrations
are interpolated from a standard curve (prepared in 1% Nitric acid)
for sodium based on the signal intensity. Sodium is detected at a
wavelength 01588.995 nm. Twenty-four-hour urinary sodium and
phosphorous excretion (mg/24-hours) is calculated by multiplying
urinary sodium or phosphorous concentration, respectively, by
24-hour urine volume. Twenty-four-hour fecal sodium excretion
(mg/24-hours) is calculated by multiplying fecal sodium
concentration by 24-hour dry fecal weight. The urinary and fecal
sodium excretion and urinary phosphorous excretion on day 3 of
compound treatment are normalized to dietary sodium or phosphorous
intake, respectively, and expressed as a percentage of the vehicle
mean.
Example 187: Restoration of Gastrointestinal Motility in Opioid
Induced Constipation
[1241] Gastrointestinal transit is measured in mice treated with
the peripherally acting .mu.-opioid agonist loperamide to assess
the ability of selected example compounds to restore
gastrointestinal motility in a model of opioid induced
constipation. Approximately eight-week old, female, CDI rats are
purchased from Envigo (Livermore, Calif.), are housed 4 per cage
and acclimated for at least 48 hours before study initiation.
Animals are fed standard laboratory rodent chow Harlan Teklad
Global 2018 (Maddison, Wis.). Animals have ad libitum access to
food and water for the duration of the acclimation period and are
maintained in a temperature and humidity controlled room on a
standard light/dark cycle of 6 AM to 6 PM. Following an overnight
fast, with free access to water, animals are dosed by oral gavage
with varying doses of test compound or vehicle (3 mM HCl, 0.01%
Tween80), at a dose volume of 5 mL/kg. Approximately Fifteen
minutes following oral dosing of test compound or vehicle, animals
are dosed by subcutaneous injection with loperamide (0.3 to 6
mg/kg) or vehicle (30:70 PG:0.9% NaCl) at a dose volume of 5 mL/kg.
Fifteen minutes later, animals are dosed orally with Evans Blue Dye
(6%) at a dose volume of 100 .mu.L. 30 minutes later, animals are
euthanized by carbon dioxide inhalation, and the length from the
pylorus to cecum (whole length of the small intestine) and the
length from the pylorus to the Evans Blue dye front are measured
and recorded. For an individual animal, the length travels by the
Evans Blue dye front is divided by the length of the whole small
intestine, measured from the pylorus to the cecum, and multiplied
by 100, to provide the distance of the small intestine travelled by
the dye as a percentage. In animals dosed orally with vehicle and
injected subcutaneously with vehicle (vehicle/vehicle), the Evans
Blue dye front travels approximately 70% of the length of the small
intestine in the 30-minute period. In animals dosed orally with
vehicle and injected subcutaneously with loperamide
(vehicle/loperamide), the Evans Blue dye front travels
approximately only 25% of the length of the small intestine in the
30-minute period, indicating decreased gastrointestinal motility in
response to loperamide. The effect of example compounds on GIT
motility in the presence of loperamide is calculated as the ability
to restore vehicle/vehicle transit distance from the
vehicle/loperamide transit, expressed as a percentage.
TABLE-US-00009 TABLE 8 % Restoration Result of Transit A <20% B
20-40%.sup. C >40% Dose % Restoration Example (mg/kg) of Transit
Standard 15 C 41 15 A 115 15 B 132 15 C 123 15 A Standard 15 C 43
15 A 43 1.5 B 43 5 A
Example 188: Restoration of Gastrointestinal Motility in Multiple
Sclerosis
[1242] Gastrointestinal transit time is measured to assess the
ability of selected example compounds to restore gastrointestinal
motility in a model of multiple sclerosis. Multiple sclerosis (MS)
patients often experience constipation and other gastrointestinal
manifestations related to disturbed gastrointestinal motility. The
Experimental Autoimmune Encephalomyelitis (EAE) mouse model is one
of the most frequently used animal models for studying multiple
sclerosis (MS), in which immunization against CNS-specific antigen
results in central nervous system inflammation. This model results
in a spectrum of acute, chronic, and relapsing disease that results
in varying degrees of progressive paralysis and gastrointestinal
dysmotility.
[1243] Animals are 8-16 weeks of age at study initiation, and are
fed standard laboratory rodent chow Harlan Teklad Global 2018
(Maddison, Wis.). Animals have ad libitum access to food and water
for the duration of the study and are maintained in a temperature
and humidity controlled room on a standard light/dark cycle of 6 AM
to 6 PM. EAE is induced in female mice by injection of a
combination of antigen (MOG35-55, S.C.) in complete Freund's
adjuvant (CFA), and pertussis toxin (PTX, IP). After somatic motor
symptoms develop, generally 10 or more days' post immunization, EAE
mice are dosed by oral gavage with test compound at varying doses
(0.01 to 30 mg/kg) or vehicle (3 mM HCl, 0.01% Tween80) at a dose
volume of 5 mL/kg. Test compound is administered for a single dose
or twice daily for multiple doses. Fecal output is monitored for a
standardized period of time (1-24 hours) and recorded as fecal
pellet number, fecal mass and fecal dry weight. Whole
gastrointestinal transit time is determined by oral gavage of
carmine red or Evans Blue and calculating the latency for dye to
appear in the feces. Small intestinal transit is measured by dosing
carmine red or Evans Blue by oral gavage and measuring the distance
of the leading edge of the dye from compared to the whole length of
the small intestine 15 minutes to two hours following oral dosing
of the dye. Colonic motility is assessed by measuring time to
extrusion of a single glass bead inserted a standardized distance
into the distal colon. The effect of example compounds on GIT
motility in EAE mice is calculated as the ability to restore
transit distance to those observed in control mice from those
observed in EAE treated with vehicle, expressed as a
percentage.
Example 189: Restoration of Gastrointestinal Motility in
Parkinson's Disease
[1244] Gastrointestinal transit time is measured to assess the
ability of selected example compounds to restore gastrointestinal
motility in a model of Parkinson's disease. Parkinson's disease
(PD) is a neurodegenerative disorder characterized by chronic and
progressive motor impairment. PD patients also experience
significant non-motor symptoms including constipation and other
gastrointestinal manifestations related to disturbed
gastrointestinal motility. The toxin,
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been widely
used to develop animal models for testing new therapies in the PD.
This model results in motor changes and pathology that resemble PD
and has also been reported to manifest gastrointestinal dysmotility
(Scientific Reports, 2016 6:30269)
[1245] Animals are 8-16 weeks of age at study initiation, and fed
standard laboratory rodent chow Harlan Teklad Global 2018
(Maddison, Wis.). Animals have ad libitum access to food and water
for the duration of the study and are maintained in a temperature
and humidity controlled room on a standard light/dark cycle of 6 AM
to 6 PM. PD is induced in mice by multiple, generally four,
intraperitoneal injections of MPTP. After MPTP is injected,
generally 4 to 20 days' post injection, PD mice are dosed by oral
gavage with test compound at varying doses (0.01 to 30 mg/kg) or
vehicle (3 mM 11C1, 0.01% Tween80) at a dose volume of 5 mL/kg.
Test compound is administered once or twice daily for multiple
doses. Fecal output is monitored for a standardized period of time
(1-24 hours) and recorded as fecal pellet number, fecal mass and
fecal dry weight. Whole gastrointestinal transit time is determined
by oral gavage of carmine red or Evans Blue and calculating the
latency for dye to appear in the feces. Small intestinal transit is
measured by dosing carmine red or Evans Blue by oral gavage and
measuring the distance of the leading edge of the dye from compared
to the whole length of the small intestine 15 minutes to two hours
following oral dosing of the dye. Colonic motility is assessed by
measuring time to extrusion of a single glass bead inserted a
standardized distance into the distal colon. The effect of example
compounds on GIT motility in PD mice is calculated as the ability
to restore transit distance to those observed in control mice from
those observed in PD mice treated with vehicle, expressed as a
percentage.
Example 190: Effect on Blood Pressure in a Models of Salt-Sensitive
Hypertension
[1246] Arterial blood pressure is measured to assess the ability of
selected example compounds to attenuate hypertension in a model of
salt-sensitive hypertension. Dahl Salt Sensitive (DSS) rats are a
well characterized model of salt-sensitive hypertension and
end-organ injury. Salt-sensitive hypertension is established in DSS
rats by increasing the NaCl content of the diet from 0.49% up to 4%
NaCl for a period of 1 to 4-weeks. DSS rats maintained on 0.49%
NaCl are used as a control group. Animals are 6-10 weeks of age at
study initiation, and have ad libitum access to food and water for
the duration of the study and are maintained in a temperature and
humidity controlled room on a 12-hr light/dark cycle. Rats
(n=6-8/group) are dosed by oral gavage with test compound (0.01-30
mg/kg) or vehicle (3 mM HCl, 0.01% Tween80) at a dose volume of 5
mL/kg, twice daily for 1 to 3 weeks, while maintained on a 4% NaCl
diet. Arterial blood pressure is measured weekly by tail cuff
plethysmography. A 24-hr urine collection is also collected weekly
by placing animals individually in metabolic cages.
Example 191: Effect on Cardiac Function in Models of Heart
Failure
[1247] Serial echocardiography is used to measure cardiac function
and morphology to assess the ability of selected example compounds
to improve cardiac function, structure and neuro-humoral activation
in a rat model of heart failure. Male Dahl Salt Sensitive (DSS)
rats or male Lewis rats are used to induce heart failure by
permanent left main coronary arterial ligation. Animals are 6-10
weeks of age at study initiation, and have ad libitum access to
food and water for the duration of the study and are maintained in
a temperature and humidity controlled room on a 12-hr light/dark
cycle. Rats (n=6-10/group) are dosed by oral gavage with test
compound (0.01 to 30 mg/kg) or vehicle (3 mM HCl, 0.01% Tween80) at
a dose volume of 5 mL/kg, twice daily for 1 to 8 weeks. Serial
echocardiography is performed weekly to assess time-dependent
cardiac remodelling (HWI, LVI, chamber size), time-dependent
cardiac performance (EF, dP/dt, LVEDP) changes and time-dependent
cardiac morphometry (HWI, LVI, LVEDV, LVESV) indices. Terminal
assessment of load-dependent and load-independent left ventricular
function are made using pressure-volume loop analysis.
Extracellular volume expansion is assessed by measuring volume
sensitive hormones ANP and BNP.
Example 192: Pain Relief in IBS-C--Reduction of Visceral
Hypersensitivity in Rats
[1248] The ability of selected example compounds to reduce the
hypersensitivty of the colon to balloon distension (CRD) in a rat
model of visceral hypersensitivy is measured by grading the rat's
abdominal withdrawal reflex (AWR) and by measuring
electromyographic (EMG) responses. Visceral hypersensitivity is
induced by injecting 10-day old male Sprague Dawley rat pups with a
0.2 mL infusion of 0.5% acetic acid solution in saline into the
colon 2 cm from the anus. Control rats receive an equal volume of
saline. Visceral hypersensitivity is then assessed in these rats as
adults, between 8 and 12 weeks of age. Rats (n=4-10/group) are
dosed by oral gavage with test compound (0.01 to 30 mg/kg) or
vehicle (3 mM HCl, 0.01% Tween80) at a dose volume of 5 mL/kg,
twice daily for up to 2 weeks prior to the assessment of visceral
hypersensitivity. Visceral hypersensitivity is measured by grading
the response to CRD Under mild sedation with 1% methohexital
sodium, a flexible balloon attached to Tygon tubing is inserted 8
cm into the descending colon and rectum via the anus and secured in
place by taping the tube to the tail. Approximately 30 minutes
later, CRD is performed by rapidly inflating the balloon to varying
pressures (10 to 80 mmHg) measured by a sphygmomanometer connected
to a pressure transducer for a 20 second period followed by a
2-minute rest period. Behavioral responses to CRD are measured by
grading the AWR by blinded observer and assigning an AWR score as
follows: 1, normal behavior without response; 2, contraction of
abdominal muscles; 3, lifting of abdominal wall; 4, body arching
and lifting of pelvic structures. EMG responses are measured
continuously in response to CRD via two electrodes implanted at
least one-week prior to in the external oblique muscle and
calculated as the area under the curve of the EMG in response to
CRD.
EQUIVALENTS
[1249] Those skilled in the art will recognize, or be able to
ascertain, using no more than routine experimentation, numerous
equivalents to the specific embodiments described specifically in
this disclosure. Such equivalents are intended to be encompassed in
the scope of the following claims.
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