U.S. patent application number 15/903928 was filed with the patent office on 2018-08-30 for modulators of the cystic fibrosis transmembrane conductance regulator protein and methods of use.
The applicant listed for this patent is AbbVie S.a.r.l., Galapagos NV. Invention is credited to Robert J. Altenbach, Andrew Bogdan, Nicolas Desroy, Gregory A. Gfesser, Stephen N. Greszler, Philip R. Kym, Bo Liu, Karine Fabienne Malagu, Nuria Merayo Merayo, Mathieu Rafael Pizzonero, Xenia B. Searle, Steven Emiel Van der Plas, Xueqing Wang, Ming C. Yeung, Gang Zhao.
Application Number | 20180244611 15/903928 |
Document ID | / |
Family ID | 61617055 |
Filed Date | 2018-08-30 |
United States Patent
Application |
20180244611 |
Kind Code |
A1 |
Altenbach; Robert J. ; et
al. |
August 30, 2018 |
Modulators of the Cystic Fibrosis Transmembrane Conductance
Regulator Protein and Methods of Use
Abstract
The present invention relates to compounds and their use in the
treatment of cystic fibrosis, methods for their production,
pharmaceutical compositions comprising the same, and methods of
treating cystic fibrosis by administering a compound of the
invention.
Inventors: |
Altenbach; Robert J.;
(Chicago, IL) ; Bogdan; Andrew; (Evanston, IL)
; Desroy; Nicolas; (Romainville, FR) ; Gfesser;
Gregory A.; (Lindenhurst, IL) ; Greszler; Stephen
N.; (Vernon Hills, IL) ; Kym; Philip R.;
(Libertyville, IL) ; Liu; Bo; (Waukegan, IL)
; Malagu; Karine Fabienne; (Saffron, GB) ; Merayo
Merayo; Nuria; (Romainville, FR) ; Pizzonero; Mathieu
Rafael; (Romainville, FR) ; Searle; Xenia B.;
(Grayslake, IL) ; Van der Plas; Steven Emiel;
(Mechelen, BE) ; Wang; Xueqing; (Northbrook,
IL) ; Yeung; Ming C.; (Grayslake, IL) ; Zhao;
Gang; (Northbrook, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie S.a.r.l.
Galapagos NV |
Luxembourg
Mechelen |
|
LU
BE |
|
|
Family ID: |
61617055 |
Appl. No.: |
15/903928 |
Filed: |
February 23, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62463019 |
Feb 24, 2017 |
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62583237 |
Nov 8, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 2601/02 20170501;
C07C 2601/14 20170501; C07D 311/04 20130101; C07C 2601/04 20170501;
C07D 317/68 20130101; C07D 405/12 20130101; A61P 11/00 20180101;
C07C 2602/06 20170501; C07D 307/81 20130101; C07D 319/22 20130101;
C07C 2602/08 20170501; C07D 307/16 20130101; C07C 2602/10 20170501;
C07C 311/51 20130101; C07D 407/12 20130101; C07D 311/76 20130101;
C07D 215/48 20130101; C07C 317/14 20130101; C07C 2601/08
20170501 |
International
Class: |
C07C 311/51 20060101
C07C311/51; C07D 215/48 20060101 C07D215/48; A61P 11/00 20060101
A61P011/00 |
Claims
1. A compound of Formula (I), or a pharmaceutically acceptable salt
thereof, ##STR00028## wherein A.sup.1 is selected from the group
consisting of ##STR00029## X.sup.1 is N or C(R.sup.2A); X.sup.2 is
N or C(R.sup.2B); X.sup.3 is N or C(R.sup.2C); X.sup.4 is N or
C(R.sup.2D); R.sup.1 is selected from the group consisting of
hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein the R.sup.1 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.7, OR.sup.7, SR.sup.7,
NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2, C(O)OH, OH, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.1 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; one of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8,
NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; or
two of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D on adjacent
carbons form a fused ring selected from the group consisting of
phenyl, 5-6 membered heteroaryl, C.sub.3-C.sub.7 cycloalkyl,
C.sub.4-C.sub.7 cycloalkenyl, and 4-7 membered heterocyclyl; and
the remaining are independently selected from the group consisting
of hydrogen, R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8,
C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2,
NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein the phenyl, 5-6
membered heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and
I; R.sup.3 is selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl are optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkoxy, phenyl, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.3 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; R.sup.4 is selected from the
group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein the
R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10, N(R.sup.10).sub.2,
NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; R.sup.5A,
R.sup.5B, R.sup.5C, and R.sup.5D are each independently selected
from the group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.5A, R.sup.5B,
R.sup.5C, and R.sup.5D C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are
optionally substituted with one or more substituents independently
selected from the group consisting of 6-10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D 6-10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C(O)OH,
NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; or R.sup.5A and
R.sup.5B, together with the carbon atom to which they are attached,
form a C.sub.3-C.sub.7 monocyclic cycloalkyl or a 4-7 membered
monocyclic heterocycle; wherein the C.sub.3-C.sub.7 monocyclic
cycloalkyl and the 4-7 membered monocyclic heterocycle are each
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; and
R.sup.5C and R.sup.5D are each independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.5C and R.sup.5D
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally substituted with
one or more substituents independently selected from the group
consisting of 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, 4-12
membered heterocyclyl, C.sub.1-C.sub.6 thioalkyl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; wherein the R.sup.5C and R.sup.5D 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2, F,
Cl, Br and I; or R.sup.5A and R.sup.5B are each independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A
and R.sup.5B C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A and R.sup.5B 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; and R.sup.5C and R.sup.5D, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; R.sup.6A, R.sup.6B, R.sup.6C, and
R.sup.6D are each independently hydrogen; R.sup.7, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I; R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.8 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.11, OR.sup.11,
C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; R.sup.9, at each occurrence, is independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.9
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, C(O)R.sup.13,NHR.sup.13, N(R.sup.13).sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.9
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.14, OR.sup.14, C(O)R.sup.14, OC(O)R.sup.14, C(O)OR.sup.14,
SO.sub.2R.sup.14, NHR.sup.14, N(R.sup.14).sub.2, NH.sub.2, C(O)OH,
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; R.sup.11, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl; wherein
each R.sup.11 C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I; R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I;
R.sup.13, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.13
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; wherein each R.sup.13 C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C
.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; and R.sup.14, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.14 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12 membered
heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; with the
proviso that R.sup.3 is not methyl; with the proviso that, when
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are each hydrogen,
R.sup.1 is not hydrogen; with the proviso that, when R.sup.3 is
naphthyl, R.sup.2C is not 4-(1-methylethyl)phenoxy; and with the
proviso that, when R.sup.1 is C.sub.1-alkyl, R.sup.3 is not
3-pyridinyl or 4-cyanobenzyl.
2. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein X.sup.1 is C(R.sup.2A); X.sup.2 is C(R.sup.2B);
X.sup.3 is C(R.sup.2C); and X.sup.4 is C(R.sup.2D).
3. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein A.sup.1 is ##STR00030##
4. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein A.sup.1 is ##STR00031##
5. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein A.sup.1 is ##STR00032##
6. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein one of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D
is hydrogen, and the remaining are independently selected from the
group consisting of hydrogen, R.sup.8, OR.sup.8, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br.
7. The compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein R.sup.1 is hydrogen or C.sub.1-C.sub.6 alkyl;
which is unsubstituted.
8. A compound, or a pharmaceutically acceptable salt thereof,
wherein the compound is selected from the group consisting of:
4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carbo-
xamide;
(1R)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide;
1-benzyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
(1R)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide;
1-benzyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronap-
hthalene-1-carboxamide;
1-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide;
(1R)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide;
(1S)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide;
4-chloro-N-(2,2-difluoro-2H-1,3-benzodioxole-4-sulfonyl)-1-ethyl-2,3-dihy-
dro-1H-indene-1-carboxamide;
7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide;
8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydrona-
phthalene-1-carboxamide;
4-chloro-1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N-(naphthalene-1-sulfon-
yl)-2,3-dihydro-1H-indene-1-carboxamide;
(1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
(1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide;
(6S)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno-
[4,5-d][1,3]dioxole-6-carboxamide;
(6R)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][-
1,3]dioxole-6-carboxamide;
(1S)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
(1R)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
N-(naphthalene-1-sulfonyl)-6,7,8,9-tetrahydro-2H-naphtho[1,2-d][1,3]dioxo-
le-6-carboxamide;
(1S)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
(1R)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
4-bromo-1-ethyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
4-chloro-1-(cyclopropylmethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H--
indene-1-carboxamide;
1-butyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
4-chloro-1-ethyl-N-(8-hydroxynaphthalene-1-sulfonyl)-2,3-dihydro-1-
H-indene-1-carboxamide;
8-bromo-5-ethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide;
8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide;
8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide;
4-chloro-N-(naphthalene-1-sulfonyl)-1-[6-(trifluoromethyl)pyridin-2-yl]me-
thyl-2,3-dihydro-1H-indene-1-carboxamide;
4-chloro-1-[(6-chloropyridin-3-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide;
4-chloro-1-[(6-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide;
4-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide;
4-chloro-N-(5-chloronaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1-
H-indene-1-carboxamide;
8-bromo-N-(naphthalene-1-sulfonyl)-5-[(propan-2-yl)oxy]-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide;
5-bromo-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide;
4-chloro-1-ethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide;
N-(1-benzothiophene-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-inde-
ne-1-carboxamide;
4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide;
8-bromo-5-(2-methoxyethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide;
(1S)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide;
(1R)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide;
(1S)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide;
(1R)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide;
5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide;
(1S)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
(1R)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
4-bromo-7-ethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
4-bromo-N-(naphthalene-1-sulfonyl)-7-[(propan-2-yl)oxy]-2,3-dihydr-
o-1H-indene-1-carboxamide;
4-bromo-7-(cyclopropylmethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H--
indene-1-carboxamide;
8-bromo-5-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide;
5-methoxy-8-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide;
4-bromo-7-(difluoromethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide;
4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide;
(1S)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide;
(1R)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide;
(1S)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphtha-
lene-1-carboxamide;
(1R)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphtha-
lene-1-carboxamide;
(1S)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide;
(1R)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide;
4-chloro-1-ethyl-N-(1-methyl-1H-indole-7-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
5-methoxy-8-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide;
8-methoxy-5-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide;
5-cyclobutyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide;
5-chloro-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide;
(1S)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
(1R)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
5,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide;
4-chloro-1-ethyl-N-(1-methyl-1H-indole-4-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
7-methoxy-4-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide;
4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-
-indene-1-carboxamide;
4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-bromo-N-(imidazo[1,2-a]pyridine-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-in-
dene-1-carboxamide;
2-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trie-
ne-7-carboxamide;
(1S)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide;
(1R)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide;
8-cyclobutyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide;
7-cyclobutyl-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
(1R)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
(1S)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
(1R)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
(1S)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
5-cyclopropyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaph-
thalene-1-carboxamide;
(1S)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide;
(1R)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide;
(1S)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
(1R)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
(1S)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-
-1H-indene-1-carboxamide;
(1R)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-
-1H-indene-1-carboxamide;
(1S)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1-
H-indene-1-carboxamide;
(1R)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1-
H-indene-1-carboxamide;
4-chloro-1-ethyl-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
4-bromo-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-
-indene-1-carboxamide;
4-bromo-7-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide;
4-bromo-7-methoxy-N-(2-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide;
2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-
-triene-7-carboxamide;
(1R)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
(1S)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
4-bromo-N-(5-hydroxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-inde-
ne-1-carboxamide;
(7S)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa--
1,3,5-triene-7-carboxamide;
(7R)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa--
1,3,5-triene-7-carboxamide;
(1R)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
(1S)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]-
pyridine-7-carboxamide;
4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopen-
ta[c]pyridine-7-carboxamide;
4-chloro-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c-
]pyridine-7-carboxamide;
4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoli-
ne-8-carboxamide;
2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-t-
riene-7-carboxamide;
(8S)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoqu-
inoline-8-carboxamide;
(8R)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoqu-
inoline-8-carboxamide;
(1S)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-d-
ihydro-1H-indene-1-carboxamide;
(1R)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-d-
ihydro-1H-indene-1-carboxamide;
4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dih-
ydro-1H-indene-1-carboxamide;
(8R)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydro-
isoquinoline-8-carboxamide;
(8S)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydro-
isoquinoline-8-carboxamide;
(1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide;
(1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide;
7-methoxy-N-(naphthalene-1-sulfonyl)-4-(prop-1-en-2-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
4-(2-hydroxypropan-2-yl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-
-1H-indene-1-carboxamide;
(1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide;
(1S)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro--
1H-indene-1-carboxamide;
(1R)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro--
1H-indene-1-carboxamide;
(1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide;
(1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide;
(1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide;
2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]o-
cta-1,3,5-triene-7-carboxamide;
4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide;
2-cyclobutyl-5-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)bicyclo[4.-
2.0]octa-1,3,5-triene-7-carboxamide;
4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-
-1H-indene-1-carboxamide;
2-cyclobutyl-5-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)bicyclo[4.2.-
0]octa-1,3,5-triene-7-carboxamide;
2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[-
4.2.0]octa-1,3,5-triene-7-carboxamide;
7-methoxy-N-(naphthalene-1-sulfonyl)-4-(oxolan-2-yl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
7-methoxy-4-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide;
7-methoxy-4-(2-methylpropyl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
(1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide;
(1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide;
(7S)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.-
2.0]octa-1,3,5-triene-7-carboxamide;
(7R)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.-
2.0]octa-1,3,5-triene-7-carboxamide;
(7S)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bic-
yclo[4.2.0]octa-1,3,5-triene-7-carboxamide;
(7R)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bic-
yclo[4.2.0]octa-1,3,5-triene-7-carboxamide;
(7S)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,-
3,5-triene-7-carboxamide;
(7R)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,-
3,5-triene-7-carboxamide;
7-methoxy-3,3-dimethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
(1R)-4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-di-
hydro-1H-indene-1-carboxamide;
7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide;
(1S)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
(1R)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
(7R)-2-cyclobutyl-5-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-
bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide;
N-(benzenesulfonyl)-4-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxamide-
;
4-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de;
(1S)-6-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide;
(1R)-6-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
4-chloro-N-(2-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de;
N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxa-
mide;
5-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide;
5,6-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide;
8-chloro-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide;
N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
6-fluoro-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide;
(1R)-5-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide;
(1S)--N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide;
6,7-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydrona-
phthalene-1-carboxamide;
4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-2-carboxam-
ide;
(1R)--N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide;
(1S)-6-methoxy-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide;
7-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
4,5-difluoro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de;
1,5-dimethyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide;
4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
N-(2-ethylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxami-
de;
4-chloro-N-(2-ethylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide;
4-chloro-N-(3-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide;
4-chloro-N-(4-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-chloro-N-(2-fluorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de;
(1S)-4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide;
N-(2-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide;
4-methoxy-N-(2-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
4-chloro-1-ethyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide;
4-bromo-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamid-
e;
4-(3,6-dihydro-2H-pyran-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide;
4-cyclobutyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
N-(2-methylbenzene-1-sulfonyl)-4-phenyl-2,3-dihydro-1H-indene-1-ca-
rboxamide;
4-methoxy-N-[2-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-
-1H-indene-1-carboxamide;
N-(2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide;
N-(2-bromobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carbo-
xamide;
N-(2-methylbenzene-1-sulfonyl)-4-[(propan-2-yl)oxy]-2,3-dihydro-1H-
-indene-1-carboxamide;
7-bromo-4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
4-(2-methoxypyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide;
5-methoxy-N-(quinoline-8-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carbox-
amide;
(1R)-5-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide;
(1S)-5-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
(1S)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyrrolidin-1-yl)methyl]-2,3-dihyd-
ro-1H-indene-1-carboxamide;
4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-2-carboxamide;
1-methyl-N-(naphthalene-1-sulfonyl)-6-(trifluoromethoxy)-2,3-dihydro-1H-i-
ndene-1-carboxamide;
8-bromo-5-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide;
5,6-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
amide;
N-(naphthalene-1-sulfonyl)-2,3,7,8,9,10-hexahydronaphtho[1,2-b][1,4-
]dioxine-7-carboxamide;
6,7-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide;
4-chloro-N-(2-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-chloro-1-ethyl-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
4-chloro-1-ethyl-N-[5-methyl-2-(propan-2-yl)benzene-1-sulfonyl]-2,3-dihyd-
ro-1H-indene-1-carboxamide;
4-chloro-N-[3-chloro-2-(methoxymethyl)benzene-1-sulfonyl]-1-ethyl-2,3-dih-
ydro-1H-indene-1-carboxamide;
4-chloro-1-ethyl-N-(2-fluorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-chloro-1-ethyl-N-(2-phenoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
4-chloro-1-ethyl-N-[2-(trifluoromethoxy)benzene-1-sulfonyl]-2,3-dihydro-1-
H-indene-1-carboxamide;
4-chloro-N-[2-(difluoromethoxy)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-
-indene-1-carboxamide;
4-chloro-N-(2,5-dimethylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide;
4-chloro-1-ethyl-N-[2-(2-methoxyethoxy)benzene-1-sulfonyl]-2,3-dihydro-1H-
-indene-1-carboxamide;
N-([1,1'-biphenyl]-2-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-chloro-1-ethyl-N-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
N-(benzenesulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbo-
xamide;
N-(2,1,3-benzothiadiazole-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-
-1H-indene-1-carboxamide;
N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
4-chloro-N-(naphthalene-1-sulfonyl)-1-[(oxolan-3-yl)methyl]-2,3-dihydro-1-
H-indene-1-carboxamide;
4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(1H-pyrazol-1-yl)ethyl]-2,3-dihy-
dro-1H-indene-1-carboxamide;
4-chloro-1-[(5-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide;
4-chloro-1-[(2-methoxypyridin-4-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide;
4-chloro-N-(naphthalene-1-sulfonyl)-1-{[3-(trifluoromethyl)pyridin-2-yl]m-
ethyl}-2,3-dihydro-1H-indene-1-carboxamide;
4-chloro-N-(2,3-dihydro-1,4-benzodioxine-5-sulfonyl)-1-ethyl-2,3-dihydro--
1H-indene-1-carboxamide;
4-bromo-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
N-(4-bromonaphthalene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene--
1-carboxamide;
4-chloro-1-ethyl-N-(4-fluoronaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide;
N-(5-bromonaphthalene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene--
1-carboxamide;
4-chloro-1-ethyl-N-(5,6,7,8-tetrahydronaphthalene-1-sulfonyl)-2,3-dihydro-
-1H-indene-1-carboxamide;
4-chloro-N-(3,4-dihydroquinoline-1(2H)-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide;
4-chloro-1-(hydroxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
4-cyclobutyl-N-(4-cyclobutylnaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1-
H-indene-1-carboxamide;
4-cyclobutyl-N-(5-cyclobutylnaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1-
H-indene-1-carboxamide;
8-bromo-5-(cyclohexylmethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide;
8-bromo-5-[(3-methoxyphenyl)methoxy]-N-(naphthalene-1-sulfonyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide;
8-bromo-5-[(3-methoxyphenyl)methoxy]-N-[(3-methoxyphenyl)methyl]-N-(napht-
halene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide;
ethyl({4-bromo-5-[(naphthalene-1-sulfonyl)carbamoyl]-5,6,7,8-tetrahydrona-
phthalen-1-yl}oxy)acetate;
8-bromo-5-(cyclopentyloxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide;
5-(benzyloxy)-8-bromo-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide;
N-benzyl-5-(benzyloxy)-8-bromo-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide;
8-bromo-N-(naphthalene-1-sulfonyl)-5-[(oxetan-3-yl)oxy]-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide;
8-bromo-N-(naphthalene-1-sulfonyl)-5-[(oxan-4-yl)oxy]-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide;
8-bromo-5-(2-hydroxy-2-methylpropoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide;
6,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[4-(trifluoromethoxy)phenyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[(E)-2-phenylethenyl]-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide;
8-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)-5-methoxy-N-(naphthalene-1-sulfo-
nyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide;
8-(2-fluoro-4-methylphenyl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)-8-(2-phenoxyphenyl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide;
N-(3-bromo-2-methylbenzene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-in-
dene-1-carboxamide;
4-chloro-1-ethyl-N-(3-fluoro-2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide;
4-chloro-1-ethyl-N-[2-(methoxymethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-i-
ndene-1-carboxamide;
4-chloro-N-(2,3-difluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide;
4-chloro-N-[2-(2,2-difluoroethoxy)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-
-1H-indene-1-carboxamide;
4-chloro-1-ethyl-N-(quinoxaline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
4-chloro-N-(3-chloro-2-fluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihyd-
ro-1H-indene-1-carboxamide;
4-chloro-N-(2,3-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide;
4-chloro-1-ethyl-N-(1-methyl-1H-indole-3-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
5-[2-(1,3-dioxan-2-yl)ethyl]-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide;
4-cyano-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide;
5-cyano-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydrona-
phthalene-1-carboxamide;
4-chloro-N-(3-cyclobutyl-2-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro--
1H-indene-1-carboxamide;
4-chloro-1-ethyl-N-(isoquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trie-
ne-7-carboxamide;
8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide;
4-bromo-7-methoxy-N-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
4-bromo-N-(8-fluoroquinoline-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene--
1-carboxamide;
7-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trie-
ne-7-carboxamide;
8-methoxy-N-(naphthalene-1-sulfonyl)-5-[3-(trifluoromethoxy)phenyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide;
8-methoxy-N-(naphthalene-1-sulfonyl)-5-[(E)-2-phenylethenyl]-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide;
5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide;
5-methoxy-8-(6-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide;
4-bromo-N-(2-ethoxyquinoline-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene--
1-carboxamide;
8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyrrolidin-1-yl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide;
4-chloro-1-ethyl-N-[2-methyl-3-(piperidin-1-yl)benzene-1-sulfonyl]-2,3-di-
hydro-1H-indene-1-carboxamide;
4-chloro-N-[3-(3,3-difluoroazetidin-1-yl)-2-methylbenzene-1-sulfonyl]-1-e-
thyl-2,3-dihydro-1H-indene-1-carboxamide;
4-chloro-N-[3-(3,3-difluoropyrrolidin-1-yl)-2-methylbenzene-1-sulfonyl]-1-
-ethyl-2,3-dihydro-1H-indene-1-carboxamide;
5-chloro-8-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[6-(trifluoromethyl)pyridin-3-yl]--
1,2,3,4-tetrahydronaphthalene-1-carboxamide;
8-(3,6-dihydro-2H-pyran-4-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide;
8-(6-cyclopropylpyridin-3-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide;
4-bromo-7-methoxy-N-[2-(propan-2-yl)quinoline-5-sulfonyl]-2,3-dihydro-1H--
indene-1-carboxamide;
4-bromo-7-methoxy-N-(5-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; methyl
7-methoxy-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-c-
arboxylate; methyl
5-[(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]naphthal-
ene-1-carboxylate;
5-chloro-8-[2-(morpholin-4-yl)ethoxy]-N-(naphthalene-1-sulfonyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide;
4-chloro-1-methyl-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide;
4-chloro-N-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-1H-
-indene-1-carboxamide;
4-chloro-N-(2-methoxyethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
4-chloro-N-(propane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
8-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-2--
carboxamide;
5-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide;
N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-2-carbox-
amide;
4-methoxy-N-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-1H-
-indene-1-carboxamide;
4-methoxy-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide;
4-methoxy-N-(5-methylpyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide;
4-methoxy-N-(oxane-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide;
4-methoxy-N-(3-methoxypropane-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide;
4-methoxy-N-(2-methoxyethanesulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide;
4-methoxy-N-(propane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide;
4-chloro-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide;
4-chloro-N-(5-methylpyridine-2-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
N-(4-hydroxybenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxa-
mide;
4-methoxy-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide;
N-(6-hydroxynaphthalene-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide;
4-methoxy-N-(4-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide;
N-(5-acetamido-1,3,4-thiadiazole-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-
-indene-1-carboxamide;
4-methoxy-N-[5-methyl-2-(propan-2-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-i-
ndene-1-carboxamide;
N-[4-(methanesulfonyl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-
-1-carboxamide;
4-methoxy-N-(3-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de;
N-(4-chloro-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-
-1-carboxamide;
N-(6-chloro-1,1-dioxo-1,2-dihydro-1.lamda..sup.6,2,4-benzothiadiazine-7-s-
ulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
4-methoxy-N-(2-methyl-5-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
N-(4-acetamido-2-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide;
N-(4-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide;
N-(4-chloro-2-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide;
4-methoxy-N-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
N-(3-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide;
4-methoxy-N-[4-(3-oxobutanamido)benzene-1-sulfonyl]-2,3-dihydro-1H-in-
dene-1-carboxamide;
N-(2,4-dichlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide;
N-(4-amino-2-chloro-5-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dih-
ydro-1H-indene-1-carboxamide;
N-(2-chloro-5-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide;
N-(2-chloro-5-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1--
carboxamide;
N-(4-acetamidobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carbo-
xamide;
N-(4-acetamido-2-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide;
N-(4-butanamidobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide;
N-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-4-methoxy-2,3-di-
hydro-1H-indene-1-carboxamide;
N-(2,4-dihydroxy-6-methylpyrimidine-5-sulfonyl)-4-methoxy-2,3-dihydro-1H--
indene-1-carboxamide;
N-(4-cyanobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxami-
de;
4-methoxy-N-(2-oxo-2H-1-benzopyran-6-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; ethyl
4-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate;
N-(2,4-dimethyl-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide;
N-{2-chloro-5-[(2,6-dimethylphenyl)carbamoyl]-4-hydroxybenzene-1-sulfonyl-
}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
N-[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonyl]-4-methoxy-2,3-d-
ihydro-1H-indene-1-carboxamide;
N-[3-({[(2S)-1-ethylpyrrolidin-2-yl]methyl}carbamoyl)-4-methoxybenzene-1--
sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
N-(6-ethoxy-1,3-benzothiazole-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-
-1-carboxamide;
N-(4-hexanoylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carbox-
amide;
N-[4-(4-{2-[(1S)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazin-1-
-yl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
propan-2-yl
2-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate;
N-{4-[(3-hydroxy-3-methylbutyl)amino]-3-nitrobenzene-1-sulfonyl}-4-methox-
y-2,3-dihydro-1H-indene-1-carboxamide;
N-[2-chloro-5-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)be-
nzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
N-{7-[(4-chlorophenyl)methyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1-
H-purine-8-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
N-(9-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purine-8-sulfony-
l)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
N-{4-[(dimethylamino)methyl]benzene-1-sulfonyl}-4-methoxy-2,3-dihydro-1H--
indene-1-carboxamide;
N-(2-cyano-3-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1--
carboxamide;
N-(4-hydroxy-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide;
N-(3-cyanobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxami-
de;
N-(5-bromopyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carbo-
xamide;
N-(6-hydroxypyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide;
N-(4-cyano-1,3-dimethyl-1H-pyrazole-5-sulfonyl)-4-methoxy-2,3-dihydro-1H--
indene-1-carboxamide; tert-butyl
5-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-1,3-dimethyl-1H-
-pyrazole-4-carboxylate;
N-[4-(hydroxymethyl)-1,3-dimethyl-1H-pyrazole-5-sulfonyl]-4-methoxy-2,3-d-
ihydro-1H-indene-1-carboxamide;
N-(3-chloro-2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide;
N-(2,6-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide;
4,5-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
N-(5-chloro-2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide;
N-(2,5-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide;
N-(2-chloro-5-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H--
indene-1-carboxamide;
N-(2,6-dichlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide;
N-(2,4-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide;
4-methoxy-N-[1-(2-methoxyethyl)-1H-pyrazole-4-sulfonyl]-2,3-dihydro-1H-in-
dene-1-carboxamide;
N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide;
N-(2,4-dimethyl-1,3-thiazole-5-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene--
1-carboxamide;
4-methoxy-N-(pyridine-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
2-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-N,N-dimethylpyr-
idine-3-carboxamide;
N-(2-cyanopyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide;
4-methoxy-N-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide-
;
4-(6-methoxypyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H--
indene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-[6-(piperidin-1-yl)pyridin-3-yl]-2,3-dih-
ydro-1H-indene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-
-2,3-dihydro-1H-indene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(2-methylpyridin-3-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
4-(6-fluoropyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
4-[6-(dimethylamino)pyridin-3-yl]-N-(2-methylbenzene-1-sulfonyl)-2,3-dihy-
dro-1H-indene-1-carboxamide;
4-(5-fluoropyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(5-methylpyridin-3-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
4-(2-fluoropyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
4-(3-fluoropyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(3-methylpyridin-4-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(2-methylpyridin-4-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-4-yl)-2,3-dihydro-1H-indene--
1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-5-yl)-2,3-dihydro-1H-indene--
1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(thiophen-3-yl)-2,3-dihydro-1H-indene-1--
carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-2,3-dih-
ydro-1H-indene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(3-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-
H-indene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-
H-indene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(5-methylfuran-2-yl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(2-methylfuran-3-yl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-di-
hydro-1H-indene-1-carboxamide;
N-(2-methylbenzene-1-sulfonyl)-4-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydro-1-
H-indene-1-carboxamide;
(1R)--N-(2-aminopyridine-3-sulfonyl)-5-methoxy-1,2,3,4-tetrahydronaphthal-
ene-1-carboxamide;
N-(6-aminopyridine-2-sulfonyl)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carbo-
xamide;
(1R)--N-(6-aminopyridine-2-sulfonyl)-5-methoxy-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide;
N-(6-aminopyridine-2-sulfonyl)-8-chloro-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide;
4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihy-
dro-1H-indene-1-carboxamide;
4-chloro-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-N-(naphthalene-1-sulf-
onyl)-2,3-dihydro-1H-indene-1-carboxamide;
4-chloro-N-(2,4-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide;
4-chloro-N-(2,4-dimethylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide;
4-chloro-N-(2,6-difluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide;
4-chloro-N-(2,5-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide;
4-chloro-N-(3-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-chloro-N-(2-chloro-5-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide;
4-chloro-1-ethyl-N-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2,3-dihydro-1-
H-indene-1-carboxamide;
4-chloro-N-(2-cyanobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-ca-
rboxamide;
4-chloro-N-(2,6-dimethoxybenzene-1-sulfonyl)-1-ethyl-2,3-dihydr-
o-1H-indene-1-carboxamide;
4-chloro-1-ethyl-N-[2-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-
-indene-1-carboxamide;
4-chloro-N-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1-ethyl-2,3-dihydro--
1H-indene-1-carboxamide;
4-chloro-N-(2-chloro-6-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide;
4-chloro-N-(4-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-chloro-1-ethyl-N-[2-methyl-6-(trifluoromethyl)benzene-1-sulfonyl]-2,3-d-
ihydro-1H-indene-1-carboxamide;
4-chloro-N-(2-cyano-3-fluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-in-
dene-1-carboxamide;
4-chloro-1-ethyl-N-(1-methylcyclopropane-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide;
N-([1,1'-biphenyl]-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-chloro-N-{4-[(dimethylamino)methyl]benzene-1-sulfonyl}-1-ethyl-2,3-dihy-
dro-1H-indene-1-carboxamide;
4-chloro-N-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-1-ethyl-2,3-dih-
ydro-1H-indene-1-carboxamide;
4-chloro-N-(2-chloropyridine-3-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1--
carboxamide;
4-chloro-1-ethyl-N-(quinoline-6-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide;
4-chloro-N-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-1-ethyl--
2,3-dihydro-1H-indene-1-carboxamide;
2-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-N,N-dime-
thylpyridine-3-carboxamide;
4-chloro-N-(cyclohexanesulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxam-
ide;
4-chloro-1-ethyl-N-{4-[4-(propan-2-yl)piperazin-1-yl]pyridine-3-sulfo-
nyl}-2,3-dihydro-1H-indene-1-carboxamide;
4-chloro-1-ethyl-N-{2-[2-(piperidin-1-yl)ethoxy]benzene-1-sulfonyl}-2,3-d-
ihydro-1H-indene-1-carboxamide;
4-chloro-1-ethyl-N-(4-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide;
4-chloro-1-ethyl-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide;
4-chloro-1-ethyl-N-(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindole-4-s-
ulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
4-chloro-1-ethyl-N-(4-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
4-chloro-1-ethyl-N-(4-phenoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide;
4-chloro-N-(3-cyanobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-ca-
rboxamide;
4-chloro-1-ethyl-N-(1H-pyrazole-3-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
3-{4-chloro-1-[naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-inden-1-y-
l}propanoic acid;
4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyridin-2-yl)methyl]-2,3-dihydro--
1H-indene-1-carboxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)-8[3-(trifluoromethoxy)phenyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide; methyl
2-chloro-6-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-
benzoate;
4-chloro-1-ethyl-N-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-
-1H-indene-1-carboxamide;
4-chloro-1-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
4-bromo-7-hydroxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide;
5-methoxy-8-(morpholin-4-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[4-(trifluoromethyl)phenyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide;
4-chloro-1-(cyanomethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide;
4-chloro-N-(3-chloro-2-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide;
8-chloro-1-cyano-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide;
4-bromo-7-methoxy-N-(2-methoxypyridine-3-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide;
N-(2-aminopyridine-3-sulfonyl)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1--
carboxamide;
N-(6-aminopyridine-2-sulfonyl)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1--
carboxamide;
4-bromo-N-(4-ethoxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide;
4-bromo-7-methoxy-N-(4-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
4-bromo-7-methoxy-N-([1,2,4]triazolo[4,3-a]pyridine-8-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide;
8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyrimidin-5-yl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide;
5-(6-cyclopropylpyridin-3-yl)-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide;
8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyridin-4-yl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide;
8-methoxy-5-(6-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide;
7-methoxy-4-(pyrimidin-5-yl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihy-
dro-1H-indene-1-carboxamide;
8-methoxy-5-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide;
8-methoxy-N-(naphthalene-1-sulfonyl)-5-[6-(trifluoromethyl)pyridin-3-yl]--
1,2,3,4-tetrahydronaphthalene-1-carboxamide;
4-chloro-1-ethyl-N-[2-methyl-3-(morpholin-4-yl)benzene-1-sulfonyl]-2,3-di-
hydro-1H-indene-1-carboxamide;
4-chloro-1-ethyl-N-{3-[(2-methoxyethyl)(methyl)amino]-2-methylbenzene-1-s-
ulfonyl}-2,3-dihydro-1H-indene-1-carboxamide;
5-methoxy-N-(naphthalene-1-sulfonyl)-8-(pyrrolidin-1-yl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide;
2,3-dimethoxy-N-(2-methylbenzene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trie-
ne-7-carboxamide;
N-(2-methylbenzene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxami-
de;
2,3-dimethoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trien-
e-7-carboxamide;
2-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-
-5-carboxamide;
2-chloro-6-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-
benzoic acid;
1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-
-7-carboxamide;
5-[(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]naphthal-
ene-1-carboxylic acid;
7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
7-methoxy-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-c-
arboxylic acid; methyl
7-methoxy-3-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-c-
arboxylate;
4-(hydroxymethyl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide;
7-methoxy-N.sup.4-methyl-N.sup.1-(naphthalene-1-sulfonyl)-2,3-dihydro-1H--
indene-1,4-dicarboxamide;
7-methoxy-N.sup.4,N.sup.4-dimethyl-N.sup.1-(naphthalene-1-sulfonyl)-2,3-d-
ihydro-1H-indene-1,4-dicarboxamide; and
7-methoxy-N-(naphthalene-1-sulfonyl)-4-[pyrrolidin-1-yl)methyl]-2,3-dihyd-
ro-1H-indene-1-carboxamide.
9.
(1S)-4-Chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide, or a pharmaceutically acceptable salt thereof.
10.
(1R)-4-Chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide, or a pharmaceutically acceptable salt thereof.
11.
(1S)-4-Bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide, or a pharmaceutically acceptable salt thereof.
12.
(1R)-4-Bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide, or a pharmaceutically acceptable salt thereof.
13.
(1S)-7-Methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide, or a pharmaceutically acceptable salt
thereof.
14.
(1R)-7-Methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide, or a pharmaceutically acceptable salt
thereof.
15. A pharmaceutical composition comprising a therapeutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt thereof, in combination with a pharmaceutically
acceptable carrier.
16. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, for use in medicine.
17. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, for use in the treatment of cystic fibrosis.
18. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof, one potentiator, and
one or more additional correctors.
19. A pharmaceutical composition comprising a compound of claim 1,
or a pharmaceutically acceptable salt thereof, and one or more
additional therapeutic agents.
20. The pharmaceutical composition of claim 19, wherein the
additional therapeutic agents are selected from the group
consisting of CFTR modulators and CFTR amplifiers.
21. The pharmaceutical composition of claim 19, wherein the
additional therapeutic agents are CFTR modulators.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/463,019, filed Feb. 24, 2017 and U.S.
Provisional Application No. 62/583,237, filed Nov. 8, 2017, both of
which are incorporated herein by reference for all purposes.
BACKGROUND OF THE INVENTION
Technical Field
[0002] This invention relates to compounds that are modulators of
the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
protein, useful in treating diseases and conditions mediated and
modulated by CFTR. This invention also relates to compositions
containing compounds of the invention, processes for their
preparation, and methods of treatment using them.
Description of Related Technology
[0003] ABC transporters are a family of homologous membrane
transporter proteins regulating the transport of a wide variety of
pharmacological agents (for example drugs, xenobiotics, anions,
etc.) that bind and use cellular adenosine triphosphate (ATP) for
their specific activities. Some of these transporters were found to
defend malignant cancer cells against chemotherapeutic agents,
acting as multidrug resistance proteins (like the MDR1-P
glycoprotein, or the multidrug resistance protein, MRP 1). So far,
48 ABC transporters, grouped into 7 families based on their
sequence identity and function, have been identified.
[0004] ABC transporters provide protection against harmful
environmental compounds by regulating a variety of important
physiological roles within the body, and therefore represent
important potential drug targets for the treatment of diseases
associated with transporter defects, outwards cell drug transport,
and other diseases in which modulation of ABC transporter activity
may be beneficial.
[0005] The cAMP/ATP-mediated anion channel, CFTR, is one member of
the ABC transporter family commonly associated with diseases, which
is expressed in a variety of cell types, including absorptive and
secretory epithelia cells, where it regulates anion flux across the
membrane, as well as the activity of other ion channels and
proteins. The activity of CFTR in epithelial cells is essential for
the maintenance of electrolyte transport throughout the body,
including respiratory and digestive tissue (Quinton, P. M., 1990.
Cystic fibrosis: a disease in electrolyte transport. FASEB J. 4,
2709-2717).
[0006] The gene encoding CFTR has been identified and sequenced
(Kerem, B., Rommens, J. M., Buchanan, J A, Markiewicz, D., Cox, T.
K., Chakravarti, A., Buchwald, M., Tsui, L. C., 1989.
Identification of the cystic fibrosis gene: genetic analysis.
Science 245, 1073-1080). CFTR comprises about 1480 amino acids that
encode a protein made up of a tandem repeat of transmembrane
domains, each containing six transmembrane helices and a nucleotide
binding domain. The pair of transmembrane domains is linked by a
large, polar, regulatory (R)-domain with multiple phosphorylation
sites that regulate channel activity and cellular trafficking.
[0007] Cystic fibrosis (CF) is caused by a defect in this gene
which induces mutations in CFTR. Cystic fibrosis is the most common
fatal genetic disease in humans, and affects 0.04% of white
individuals (Bobadilla, J. L., Macek, M., Jr, Fine, J. P., Farrell,
P. M., 2002. Cystic fibrosis: a worldwide analysis of CFTR
mutations--correlation with incidence data and application to
screening. Hum. Mutat. 19, 575-606. doi:10.1002/humu. 10041), for
example, in the United States, about one in every 2,500 infants is
affected, and up to 10 million people carry a single copy of the
defective gene without apparent ill effects; moreover subjects
bearing a single copy of the gene exhibit increased resistance to
cholera and to dehydration resulting from diarrhea. This effect
might explain the relatively high frequency of the CF gene within
the population.
[0008] In contrast, individuals with two copies of the CF
associated gene suffer from the debilitating and fatal effects of
CF, including chronic lung infections.
[0009] In cystic fibrosis patients, mutations in endogenous
respiratory epithelial CFTR fails to confer chloride and
bicarbonate permeability to epithelial cells in lung and other
tissues, thus leading to reduced apical anion secretion and
disruptions of the ion and fluid transport. This decrease in anion
transport causes an enhanced mucus and pathogenic agent
accumulation in the lung triggering microbial infections that
ultimately cause death in CF patients.
[0010] Beyond respiratory disease, CF patients also suffer from
gastrointestinal problems and pancreatic insufficiency that result
in death if left untreated. Furthermore, female subjects with
cystic fibrosis suffer from decreased fertility, whilst males with
cystic fibrosis are infertile.
[0011] A variety of disease causing mutations has been identified
through sequence analysis of the CFTR gene of CF chromosomes
(Kerem, B., Rommens, J. M., Buchanan, J A, Markiewicz, D., Cox, T.
K., Chakravarti, A., Buchwald, M., Tsui, L. C., 1989.
Identification of the cystic fibrosis gene: genetic analysis.
Science 245, 1073-1080). .DELTA.F508-CFTR, the most common CF
mutation (present in at least 1 allele in 90% of CF patients) and
occurring in approximately 70% of the cases of cystic fibrosis,
contains a single amino acid deletion of phenylalanine 508. This
deletion prevents the nascent protein from folding correctly, which
protein in turn cannot exit the endoplasmic reticulum (ER) and
traffic to the plasma membrane, and then is rapidly degraded. As a
result, the number of channels present in the membrane is far less
than in cells expressing wild-type CFTR. In addition to impaired
trafficking, the mutation results in defective channel gating.
Indeed, even if .DELTA.F508-CFTR is allowed to reach the cell
plasma membrane by low-temperature (27.degree. C.) rescue where it
can function as a cAMP-activated chloride channel, its activity is
decreased significantly compared with WT-CFTR (Pasyk, E. A.,
Foskett, J. K., 1995. Mutant (.delta.F508) Cystic Fibrosis
Transmembrane Conductance Regulator Cl.sup.- Channel Is Functional
When Retained in Endoplasmic Reticulum of Mammalian Cells. J. Biol.
Chem. 270, 12347-12350).
[0012] Other mutations with lower incidence have also been
identified that alter the channel regulation or the channel
conductance. In case of the channel regulation mutants, the mutated
protein is properly trafficked and localized to the plasma membrane
but either cannot be activated or cannot function as a chloride
channel (e.g. missense mutations located within the nucleotide
binding domains), examples of these mutations are G551D, G178R, and
G1349D. Mutations affecting chloride conductance have a CFTR
protein that is correctly trafficked to the cell membrane but that
generates reduced chloride flow (e.g. missense mutations located
within the membrane-spanning domain), examples of these mutations
are R117H and R334W.
[0013] In addition to cystic fibrosis, CFTR activity modulation may
be beneficial for other diseases not directly caused by mutations
in CFTR, such as, for example, chronic obstructive pulmonary
disease (COPD), dry eye disease, and Sjogren's syndrome.
[0014] COPD is characterized by a progressive and non-reversible
airflow limitation, which is due to mucus hypersecretion,
bronchiolitis, and emphysema. A potential treatment of mucus
hypersecretion and impaired mucociliary clearance that is common in
COPD could consist in using activators of mutant or wild-type CFTR.
In particular, the anion secretion increase across CFTR may
facilitate fluid transport into the airway surface liquid to
hydrate the mucus and optimize periciliary fluid viscosity. The
resulting enhanced mucociliary clearance would help in reducing the
symptoms associated with COPD.
[0015] Dry eye disease is characterized by a decrease in tear
production and abnormal tear film lipid, protein and mucin
profiles. Many factors may cause dry eye disease, some of which
include age, arthritis, Lasik eye surgery, chemical/thermal burns,
medications, allergies, and diseases, such as cystic fibrosis and
Sjogren's syndrome. Increasing anion secretion via CFTR could
enhance fluid transport from the corneal endothelial cells and
secretory glands surrounding the eye, and eventually improve
corneal hydration, thus helping to alleviate dry eye disease
associated symptoms. Sjogren's syndrome is an autoimmune disease
where the immune system harms moisture-producing glands throughout
the body, including the eye, mouth, skin, respiratory tissue,
liver, vagina, and gut. The ensuing symptoms, include, dry eye,
mouth, and vagina, as well as lung disease. Sjogren's syndrome is
also associated with rheumatoid arthritis, systemic lupus, systemic
sclerosis, and polymyositis/dermatomyositis. The cause of the
disease is believed to lie in defective protein trafficking, for
which treatment options are limited. As a consequence, modulation
of CFTR activity may help hydrating the various organs and help to
elevate the associated symptoms.
[0016] In addition to CF, the defective protein trafficking induced
by the .DELTA.F508-CFTR has been shown to be the underlying basis
for a wide range of other diseases, in particular diseases where
the defective functioning of the endoplasmic reticulum (ER) may
either prevent the CFTR protein to exit the cell, and/or the
misfolded protein is degraded (Morello, J.-P., Bouvier, M.,
Petaja-Repo, U. E., Bichet, D. G., 2000. Pharmacological
chaperones: a new twist on receptor folding. Trends Pharmacol. Sci.
21, 466-469. doi:10.1016/S0165-6147(00)01575-3; Shastry, B. S.,
2003. Neurodegenerative disorders of protein aggregation.
Neurochem. Int. 43, 1-7. doi:10.1016/S0197-0186(02)00196-1; Zhang,
W., Fujii, N., Naren, A. P., 2012. Recent advances and new
perspectives in targeting CFTR for therapy of cystic fibrosis and
enterotoxin-induced secretory diarrheas. Future Med. Chem. 4,
329-345. doi:10.4155/fmc.12.1).
[0017] A number of genetic diseases are associated with a defective
ER processing equivalent to the defect observed with CFTR in CF
such as glycanosis CDG type 1, hereditary emphysema
(.alpha.-1-antitrypsin (PiZ variant)), congenital hyperthyroidism,
osteogenesis imperfecta (Type I, II, or IV procollagen), hereditary
hypofibrinogenemia (fibrinogen), ACT deficiency
(.alpha.-1-antichymotrypsin), diabetes insipidus (DI), neurophyseal
DI (vasopvessin hormoneN2-receptor), neprogenic DI (aquaporin II),
Charcot-Marie Tooth syndrome (peripheral myelin protein 22),
Perlizaeus-Merzbacher disease, neurodegenerative diseases such as
Alzheimer's disease (APP and presenilins), Parkinson's disease,
amyotrophic lateral sclerosis, progressive supranuclear palsy,
Pick's disease, several polyglutamine neurological disorders such
as Huntington's disease, spinocerebullar ataxia type I, spinal and
bulbar muscular atrophy, dentatorubal pallidoluysian, and myotonic
dystrophy, as well as spongiform encephalopathies, such as
hereditary Creutzfeldt-Jakob disease (prion protein processing
defect), Fabry disease (lysosomal .alpha.-galactosidase A),
Straussler-Scheinker syndrome, chronic obstructive pulmonary
disease (COPD), dry eye disease, and Sjogren's syndrome.
[0018] In addition to up-regulation of the activity of CFTR, anion
secretion reduction by CFTR modulators may be beneficial for the
treatment of secretory diarrheas, in which epithelial water
transport is dramatically increased as a result of secretagogue
activated chloride transport. The mechanism involves elevation of
cAMP and stimulation of CFTR.
[0019] Regardless of the cause, excessive chloride transport is
seen in all diarrheas, and results in dehydration, acidosis,
impaired growth and death. Acute and chronic diarrheas remain a
major medical problem worldwide, and are a significant factor in
malnutrition, leading to death in children of less than five years
old (5,000,000 deaths/year). Furthermore, in patients with chronic
inflammatory bowel disease (IBD) and/or acquired immunodeficiency
syndrome (AIDS), diarrhea is a dangerous condition.
[0020] Accordingly, there is a need for novel compounds able to
modulate CFTR. In particular, the present invention discloses
compounds that may act as CFTR modulators for the treatment of
cystic fibrosis. The present invention also provides methods for
the preparation of these compounds, pharmaceutical compositions
comprising these compounds and methods for the treatment of cystic
fibrosis by administering the compounds of the invention.
SUMMARY
[0021] In one aspect, the invention provides for compounds of
Formula (I)
##STR00001##
wherein [0022] A.sup.1 is selected from the group consisting of
[0022] ##STR00002## [0023] X.sup.1 is N or C(R.sup.2A); [0024]
X.sup.2 is N or C(R.sup.2B); [0025] X.sup.3 is N or C(R.sup.2C);
[0026] X.sup.4 is N or C(R.sup.2D); [0027] R.sup.1 is selected from
the group consisting of hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.1 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, SR.sup.7, NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.1 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C(O)OH, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; [0028] one of R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D is hydrogen, and the remaining are independently selected
from the group consisting of hydrogen, R.sup.8, OR.sup.8,
C(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; or
[0029] two of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D on
adjacent carbons form a fused ring selected from the group
consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-C.sub.7
cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7 membered
heterocyclyl; and the remaining are independently selected from the
group consisting of hydrogen, R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I;
wherein the phenyl, 5-6 membered heteroaryl, C.sub.3-C.sub.7
cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; [0030] R.sup.3 is selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.3
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkoxy, phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.3 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; [0031] R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0032] R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D are
each independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A,
R.sup.5B, R.sup.5C, and R.sup.5D C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, 4-12 membered
heterocyclyl, C.sub.1-C.sub.6 thioalkyl, OH, oxo, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.5A, R.sup.5B, R.sup.5C, and
R.sup.5D 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0033] R.sup.5A and R.sup.5B, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; and [0034] R.sup.5C and R.sup.5D are
each independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5C
and R.sup.5D C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5C and R.sup.5D 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0035] R.sup.5A and R.sup.5B are each
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A
and R.sup.5B C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A and R.sup.5B 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; and [0036] R.sup.5C and R.sup.5D, together with
the carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; [0037] R.sup.6A, R.sup.6B, R.sup.6C, and
R.sup.6D are each independently hydrogen; [0038] R.sup.7, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I; [0039] R.sup.8,
at each occurrence, is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0040] R.sup.9, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.9
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, C(O)R.sup.13, NHR.sup.13, N(R.sup.13).sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.9
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.14, OR.sup.14, C(O)R.sup.14, OC(O)R.sup.14, C(O)OR.sup.14,
SO.sub.2R.sup.14, NHR.sup.14, N(R.sup.14).sub.2, NH.sub.2, C(O)OH,
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; [0041] R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, cycloalkenyl, and 4-12 membered
heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally
substituted with one or more substituents independently selected
from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and
I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered
heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; [0042]
R.sup.11, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl; wherein each R.sup.11 C.sub.1-C.sub.6 alkyl
and C.sub.1-C.sub.6 alkoxy is optionally substituted with one or
more substituents independently selected from the group consisting
of OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.11
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I;
[0043] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11
cycloalkyl, 4-12 membered heterocyclyl, C.sub.4-C.sub.11
cycloalkenyl, and 5-6 membered heteroaryl; wherein each R.sup.12
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy is optionally
substituted with one or more substituents independently selected
from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and
I; wherein each R.sup.12 C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I; [0044] R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.13 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO
.sub.2, F, Cl, Br and I; and [0045] R.sup.14, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl; wherein each R.sup.14 C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, 5-6 membered heteroaryl, 4-12 membered heterocyclyl, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; [0046] with the proviso that
R.sup.3 is not methyl; [0047] with the proviso that, when R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D are each hydrogen, R.sup.1 is not
hydrogen; [0048] with the proviso that, when R.sup.3 is naphthyl,
R.sup.2C is not 4-(1-methylethyl)phenoxy; and [0049] with the
proviso that, when R.sup.1 is C.sub.1-alkyl, R.sup.3 is not
3-pyridinyl or 4-cyanobenzyl.
[0050] Another aspect of the invention relates to pharmaceutical
compositions comprising a compound of the invention, and a
pharmaceutical carrier. Such compositions can be administered in
accordance with a method of the invention, typically as part of a
therapeutic regimen for treatment or prevention of conditions and
disorders related to Cystic Fibrosis Transmembrane Conductance
Regulator activity. In a particular aspect, the pharmaceutical
compositions may additionally comprise further therapeutically
active ingredients suitable for use in combination with the
compounds of the invention. In a more particular aspect, the
further therapeutically active ingredient is an agent for the
treatment of cystic fibrosis.
[0051] Moreover, the compounds of the invention, useful in the
pharmaceutical compositions and treatment methods disclosed herein,
are pharmaceutically acceptable as prepared and used.
[0052] Yet another aspect of the invention relates to a method for
treating, or preventing conditions and disorders related to Cystic
Fibrosis Transmembrane Conductance Regulator activity in mammals.
More particularly, the method is useful for treating or preventing
conditions and disorders related to cystic fibrosis, Sjogren's
syndrome, pancreatic insufficiency, chronic obstructive lung
disease, or chronic obstructive airway disease. Accordingly, the
compounds and compositions of the invention are useful as a
medicament for treating or preventing Cystic Fibrosis Transmembrane
Conductance Regulator modulated disease.
[0053] The compounds, compositions comprising the compounds,
methods for making the compounds, and methods for treating or
preventing conditions and disorders by administering the compounds
are further described herein.
[0054] In a particular aspect, the compounds of the invention are
provided for use in the treatment of cystic fibrosis. In a
particular aspect, the compounds of the invention are provided for
use in the treatment of cystic fibrosis caused by class I, II, III,
IV, V, and/or VI mutations.
[0055] The present invention also provides pharmaceutical
compositions comprising a compound of the invention, and a suitable
pharmaceutical carrier for use in medicine. In a particular aspect,
the pharmaceutical composition is for use in the treatment of
cystic fibrosis.
[0056] These and other objects of the invention are described in
the following paragraphs. These objects should not be deemed to
narrow the scope of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0057] Described herein are compounds of Formula (I)
##STR00003##
wherein A.sup.1, R.sup.3, and R.sup.4 are defined above in the
Summary and below in the Detailed Description. Further,
compositions comprising such compounds and methods for treating
conditions and disorders using such compounds and compositions are
also included.
[0058] Compounds included herein may contain one or more
variable(s) that occur more than one time in any substituent or in
the formulae herein. Definition of a variable on each occurrence is
independent of its definition at another occurrence. Further,
combinations of substituents are permissible only if such
combinations result in stable compounds. Stable compounds are
compounds which can be isolated from a reaction mixture.
[0059] Compounds included herein may contain one or more
variable(s) that occur more than one time in any substituent or in
the formulae herein. Definition of a variable on each occurrence is
independent of its definition at another occurrence. Further,
combinations of substituents are permissible only if such
combinations result in stable compounds. Stable compounds are
compounds which can be isolated from a reaction mixture.
Definitions
[0060] It is noted that, as used in this specification and the
intended claims, the singular form "a," "an," and "the" include
plural referents unless the context clearly dictates otherwise.
Thus, for example, reference to "a compound" includes a single
compound as well as one or more of the same or different compounds;
reference to "a pharmaceutically acceptable carrier" means a single
pharmaceutically acceptable carrier as well as one or more
pharmaceutically acceptable carriers, and the like.
[0061] As used in the specification and the appended claims, unless
specified to the contrary, the following terms have the meaning
indicated:
[0062] The term "alkenyl" as used herein, means a straight or
branched hydrocarbon chain containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond. The term
"C.sub.2-C.sub.6 alkenyl" means an alkenyl group containing 2-6
carbon atoms. Non-limiting examples of C.sub.2-C.sub.6 alkenyl
include buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl,
3-butenyl, 4-pentenyl, and 5-hexenyl.
[0063] The term "C.sub.1-C.sub.6 alkoxy" as used herein, means a
C.sub.1-C.sub.6 alkyl group, as defined herein, appended to the
parent molecular moiety through an oxygen atom. Non-limiting
examples of alkoxy include methoxy, ethoxy, propoxy, 2-propoxy,
butoxy, tert-butoxy, pentyloxy, and hexyloxy.
[0064] The term "alkyl" as used herein, means a saturated, straight
or branched hydrocarbon chain radical. In some instances, the
number of carbon atoms in an alkyl moiety is indicated by the
prefix "C.sub.x-C.sub.y", wherein x is the minimum and y is the
maximum number of carbon atoms in the substituent. Thus, for
example, "C.sub.1-C.sub.6 alkyl" means an alkyl substituent
containing from 1 to 6 carbon atoms and "C.sub.1-C.sub.3 alkyl"
means an alkyl substituent containing from 1 to 3 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl,
2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl,
1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl,
1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, and
1,2,2-trimethylpropyl. The terms "alkyl," "C.sub.1-C.sub.6 alkyl,"
"C.sub.1-C.sub.4 alkyl," and "C.sub.1-C.sub.3 alkyl" used herein
are unsubstituted, unless otherwise indicated.
[0065] The term "alkylene" or "alkylenyl" means a divalent radical
derived from a straight or branched, saturated hydrocarbon chain,
for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms
(C.sub.1-C.sub.6 alkylenyl) or of 1 to 4 carbon atoms or of 1 to 3
carbon atoms (C.sub.1-C.sub.3 alkylenyl) or of 2 to 6 carbon atoms
(C.sub.2-C.sub.6 alkylenyl). Examples of C.sub.1-C.sub.6 alkylenyl
include, but are not limited to, --CH.sub.2--,
--CH.sub.2CH.sub.2--,
--C(CH.sub.3).sub.2--CH.sub.2CH.sub.2CH.sub.2--,
--C(CH.sub.3).sub.2--CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and
--CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0066] The term "C.sub.2-C.sub.6 alkynyl" as used herein, means a
straight or branched chain hydrocarbon radical containing from 2 to
6 carbon atoms and containing at least one carbon-carbon triple
bond. Representative examples of C.sub.2-C.sub.6 alkynyl include,
but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,
3-butynyl, 2-pentynyl, and 1-butynyl.
[0067] The term "C.sub.3-C.sub.11 cycloalkyl" as used herein, means
a hydrocarbon ring radical containing 3-11 carbon atoms, zero
heteroatoms, and zero double bonds. The C.sub.3-C.sub.11 cycloalkyl
group may be a single-ring (monocyclic) or have two or more rings
(polycyclic or bicyclic). Monocyclic cycloalkyl groups typically
contain from 3 to 8 carbon ring atoms (C.sub.3-C.sub.11 monocyclic
cycloalkyl), and even more typically 3-6 carbon ring atoms
(C.sub.3-C.sub.6 monocyclic cycloalkyl). Examples of monocyclic
cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl
groups contain two or more rings, and bicyclic cycloalkyls contain
two rings. In certain embodiments, the polycyclic cycloalkyl groups
contain 2 or 3 rings. The rings within the polycyclic and the
bicyclic cycloalkyl groups may be in a bridged, fused, or spiro
orientation, or combinations thereof. In a spirocyclic cycloalkyl,
one atom is common to two different rings. Examples of a
spirocyclic cycloalkyl include spiro[2.5]octanyl and
spiro[4.5]decanyl. In a bridged cycloalkyl, the rings share at
least two non-adjacent atoms. Examples of bridged cycloalkyls
include, but are not limited to bicyclo[1.1.1]pentanyl,
bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.1.1]heptyl,
bicyclo[2.2.1]heptyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, and
bicyclo[4.2.1]nonyl, tricyclo[3.3.1.0.sup.3,7]nonyl
(octahydro-2,5-methanopentalenyl or noradamantyl),
tricyclo[3.3.1.1.sup.3,7]decyl (adamantyl), and
tricyclo[4.3.1.1.sup.3,8]undecyl (homoadamantyl). In a fused ring
cycloalkyl, the rings share one common bond. Examples of fused-ring
cycloalkyl include, but not limited to, decalin
(decahydronaphthyl), bicyclo[3.1.0]hexanyl, and
bicyclo[2.2.0]octyl.
[0068] The term "C.sub.3-C.sub.6 cycloalkyl" as used herein, means
a hydrocarbon ring radical containing 3-6 carbon atoms, zero
heteroatoms, and zero double bonds. The C.sub.3-C.sub.6 cycloalkyl
group may be a single-ring (monocyclic) or have two rings
(bicyclic).
[0069] The term "C.sub.4-C.sub.11 cycloalkenyl" as used herein,
means a non-aromatic hydrocarbon ring radical containing 4-11
carbon atoms, zero heteroatoms, and one or more double bonds. The
C.sub.4-C.sub.11 cycloalkenyl group may be a single-ring
(monocyclic) or have two or more rings (polycyclic or bicyclic).
Examples of monocyclic cycloalkenyl include cyclobutenyl,
cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl,
cyclooctenyl, and cyclooctadienyl. Examples of bicyclic
cycloalkenyl include bicyclo[2.2.1]hept-2-enyl.
[0070] The term "C.sub.4-C.sub.8 monocyclic cycloalkenyl" as used
herein, means cyclobutenyl, cyclopentenyl, cyclohexenyl,
cyclohexadienyl, cycloheptyl, cycloheptadienyl, cyclooctenyl, and
cyclooctadienyl.
[0071] The term "C.sub.4-C.sub.7 monocyclic cycloalkenyl" as used
herein, means cyclobutenyl, cyclopentenyl, cyclohexenyl,
cyclohexadienyl, and cycloheptyl.
[0072] The term "halo" or "halogen" as used herein, means Cl, Br,
I, and F.
[0073] The term "haloalkyl" as used herein, means an alkyl group,
as defined herein, in which one, two, three, four, five or six
hydrogen atoms are replaced by halogen. The term "C.sub.1-C.sub.6
haloalkyl" means a C.sub.1-C.sub.6 alkyl group, as defined herein,
in which one, two, three, four, five, or six hydrogen atoms are
replaced by halogen. The term "C.sub.1-C.sub.3 haloalkyl" means a
C.sub.1-C.sub.3 alkyl group, as defined herein, in which one, two,
three, four, or five hydrogen atoms are replaced by halogen.
Representative examples of haloalkyl include, but are not limited
to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl,
2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl,
pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and
trifluoropropyl.
[0074] The term "4-12 membered heterocyclyl" as used herein, means
a hydrocarbon ring radical of 4-12 carbon ring atoms wherein at
least one carbon atom is replaced by a heteroatom(s) independently
selected from the group consisting of O, N, and S. The 4-12
membered heterocycle ring may be a single ring (monocyclic) or have
two or more rings (bicyclic or polycyclic). In certain embodiments,
the monocyclic heterocycle is a four-, five-, six-, seven-, or
eight-membered hydrocarbon ring wherein at least one carbon ring
atom is replaced by a heteroatom(s) independently selected from the
group consisting of O, N, and S. In certain embodiments, the
monocyclic heterocycle is a 4-7 membered hydrocarbon ring wherein
at least one carbon ring atom is replaced by a heteroatom(s). A
four-membered monocyclic heterocycle contains zero or one double
bond, and one heteroatom selected from the group consisting of O,
N, and S. A five-membered monocyclic heterocycle contains zero or
one double bond and one, two, or three heteroatoms selected from
the group consisting of O, N, and S. Examples of five-membered
monocyclic heterocycles include those containing in the ring: 1 O;
1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O
and 2 N. Non limiting examples of 5-membered monocyclic
heterocyclic groups include 1,3-dioxolanyl, tetrahydrofuranyl,
dihydropyranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl,
oxazolidinyl, imidazolinyl, imidazolidinyl, isoxazolidinyl,
pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl,
3-pyrrolinyl, thiazolinyl, and thiazolidinyl. A six-membered
monocyclic heterocycle contains zero, one, or two double bonds and
one, two, or three heteroatoms selected from the group consisting
of O, N, and S. Examples of six-membered monocyclic heterocycles
include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N;
3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S
and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples of six-membered
monocyclic heterocycles include dihydropyranyl, 1,4-dioxanyl,
1,3-dioxanyl, 1,4-dithianyl, hexahydropyrimidine, morpholinyl,
1,4-dihydropyridinyl, piperazinyl, piperidinyl, tetrahydropyranyl,
1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl,
thiomorpholinyl, thioxanyl, and trithianyl. Seven- and
eight-membered monocyclic heterocycles contains zero, one, two, or
three double bonds and one, two, or three heteroatoms selected from
the group consisting of O, N, and S. Examples of monocyclic
heterocycles include, but are not limited to, azetidinyl, azepanyl,
aziridinyl, 1,4-diazepanyl, dihydropyranyl, 1,3-dioxanyl,
1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl,
imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl,
isoxazolidinyl, morpholinyl, oxazepanyl, oxadiazolinyl,
oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl,
piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl,
tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl,
thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
thiopyranyl, and trithianyl. Polycyclic heterocycle groups contain
two or more rings, and bicyclic heterocycles contain two rings. In
certain embodiments, the polycyclic heterocycle groups contain 2 or
3 rings. The rings within the polycyclic and the bicyclic
heterocycle groups may be in a bridged, fused, or spiro
orientation, or combinations thereof. In a spirocyclic heterocycle,
one atom is common to two different rings. Non limiting examples of
the spirocyclic heterocycle include 6-oxaspiro[2.5]octanyl,
2-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.5]octyl,
2-azaspiro[3.5]nonyl, 2-azaspiro[3.4]octyl, 3-azaspiro[5.5]undecyl,
5-azaspiro[3.4]octyl, 2-oxaspiro[3.3]heptyl,
2-oxa-6-azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.4]octyl,
6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl,
1-oxa-7-azaspiro[4.4]nonyl, 1-oxa-7-azaspiro[3.5]nonyl,
1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl,
1-oxa-4,9-diazaspiro[5.5]undecyl, 2-oxa-7-azaspiro[3.5]nonyl,
5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.5]nonyl,
7-oxa-2-azaspiro[3.5]nonyl, 8-oxa-2-azaspiro[4.5]decyl,
2,7-diazaspiro[4.4]nonyl, 1,4-dioxa-8-azaspiro[4.5]decyl,
1,3,8-triazaspiro[4.5]decyl. In a fused ring heterocycle, the rings
share one common bond. Examples of fused bicyclic heterocycles are
a 4-6 membered monocyclic heterocycle fused to a phenyl group, or a
4-6 membered monocyclic heterocycle fused to a C.sub.3-C.sub.6
monocyclic cycloalkyl, or a 4-6 membered monocyclic heterocycle
fused to a C.sub.4-C.sub.7 monocyclic cycloalkenyl, or a 4-6
membered monocyclic heterocycle fused to a 4-7 membered monocyclic
heterocycle. Examples of fused bicyclic heterocycles include, but
are not limited to, 1,2-dihydrophthalazinyl,
3,4-dihydro-2H-benzo[b][1,4]dioxepinyl, chromanyl, chromenyl,
isochromanyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, isoindolinyl,
2,3-dihydrobenzo[b]thienyl, hexahydro-1H-cyclopenta[c]furanyl,
3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexyl, benzopyranyl,
benzothiopyranyl, indolinyl, decahydropyrrolo[3,4-b]azepinyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl,
2,3-dihydro-1H-indolyl, 3,4-dihydroisoquinolin-2(1H)-yl,
2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl,
hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl,
hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl,
hexahydrocyclopenta[c]pyrrol-3a(1H)-yl,
hexahydro-1H-oxazolo[3,4-a]pyrazinyl,
octahydropyrrolo[3,4-b][1,4]oxazinyl,
octahydroimidazo[1,5-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl,
octahydro-1H-pyrrolo[3,2-c]pyridinyl, and
octahydropyrrolo[3,4-c]pyrrolyl. In a bridged heterocycle, the
rings share at least two non-adjacent atoms. Examples of such
bridged heterocycles include, but are not limited to,
8-oxabicyclo[3.2.1]octanyl, 7-oxabicyclo[2.2.1]heptanyl,
azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),
8-azabicyclo[3.2.1]oct-8-yl, octahydro-2,5-epoxypentalene,
8-oxa-3-azabicyclo[3.2.1]octyl,
hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane
(1-azatricyclo[3.3.1.1.sup.3,7]decane), and oxa-adamantane
(2-oxatricyclo[3.3.1.1.sup.3,7]decane). The nitrogen and sulfur
heteroatoms in the heterocycle rings may optionally be oxidized
(e.g. 1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl,
1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally
be quaternized. Non limiting examples of the polycyclic heterocycle
include 6,7-dihydro-[1,3]dioxolo[4,5-f]benzofuranyl.
[0075] The term "5-11 membered heteroaryl" as used herein, means a
monocyclic heteroaryl and a bicyclic heteroaryl. The "5-6 membered
heteroaryl" is a five- or six-membered ring. The five-membered ring
contains two double bonds. The five membered ring may contain one
heteroatom selected from O or S; or one, two, three, or four
nitrogen atoms and optionally one oxygen or one sulfur atom. The
six-membered ring contains three double bonds and one, two, three
or four nitrogen atoms. Examples of 5-6 membered monocyclic
heteroaryl include, but are not limited to, furanyl, imidazolyl,
isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridazinonyl,
pyridinonyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,
pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl,
thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists
of a monocyclic heteroaryl fused to a phenyl, or a monocyclic
heteroaryl fused to a C.sub.3-C.sub.6 monocyclic cycloalkyl, or a
monocyclic heteroaryl fused to C.sub.4-C.sub.7 monocyclic
cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic
heteroaryl, or a monocyclic heteroaryl fused to a 4-7 membered
monocyclic heterocycle. Representative examples of bicyclic
heteroaryl groups include, but are not limited to,
4H-furo[3,2-b]pyrrolyl, benzofuranyl, benzothienyl,
benzoisoxazolyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,
phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl,
6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl,
6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl,
indolyl, isoindolyl, isoquinolinyl, naphthyridinyl,
pyridoimidazolyl, quinolinyl,
4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl,
2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl,
thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and
5,6,7,8-tetrahydroquinolin-5-yl. The nitrogen atom in the
heteroaryl rings may optionally be oxidized and may optionally be
alkylated.
[0076] The term "6-10 membered aryl", as used herein, means a
hydrocarbon ring radical containing 6-10 carbon atoms, zero
heteroatoms, and one or more aromatic rings. The 6-10 membered aryl
group may be a single-ring (monocyclic) or have two rings
(bicyclic). The bicyclic aryl is naphthyl, or a phenyl fused to a
monocyclic cycloalkyl, or a phenyl fused to a monocyclic
cycloalkenyl. Representative examples of 6-10 membered aryl groups
include, but are not limited to, phenyl, indenyl,
tetrahydronaphthalenyl, dihydroindenyl (indanyl), naphthyl, and the
like.
[0077] The aryls, the cycloalkyls, the cycloalkenyls, the
heterocycles, and the heteroaryls, including the exemplary rings,
are optionally substituted unless otherwise indicated; and are
attached to the parent molecular moiety through any substitutable
atom contained within the ring system.
[0078] The term "heteroatom" as used herein, means a nitrogen,
oxygen, and sulfur.
[0079] The term "oxo" as used herein, means a=O group.
[0080] The term "radiolabel" means a compound of the invention in
which at least one of the atoms is a radioactive atom or a
radioactive isotope, wherein the radioactive atom or isotope
spontaneously emits gamma rays or energetic particles, for example
alpha particles or beta particles, or positrons. Examples of such
radioactive atoms include, but are not limited to, .sup.3H
(tritium), .sup.14C, .sup.11C, .sup.15O, .sup.18F, .sup.35S,
.sup.123I, and .sup.125I.
[0081] A moiety is described as "substituted" when a non-hydrogen
radical is in the place of hydrogen radical of any substitutable
atom of the moiety. Thus, for example, a substituted heterocycle
moiety is a heterocycle moiety in which at least one non-hydrogen
radical is in the place of a hydrogen radical on the heterocycle.
It should be recognized that if there are more than one
substitution on a moiety, each non-hydrogen radical may be
identical or different (unless otherwise stated).
[0082] If a moiety is described as being "optionally substituted,"
the moiety may be either (1) not substituted or (2) substituted. If
a moiety is described as being optionally substituted with up to a
particular number of non-hydrogen radicals, that moiety may be
either (1) not substituted; or (2) substituted by up to that
particular number of non-hydrogen radicals or by up to the maximum
number of substitutable positions on the moiety, whichever is less.
Thus, for example, if a moiety is described as a heteroaryl
optionally substituted with up to 3 non-hydrogen radicals, then any
heteroaryl with less than 3 substitutable positions would be
optionally substituted by up to only as many non-hydrogen radicals
as the heteroaryl has substitutable positions. To illustrate,
tetrazolyl (which has only one substitutable position) would be
optionally substituted with up to one non-hydrogen radical. To
illustrate further, if an amino nitrogen is described as being
optionally substituted with up to 2 non-hydrogen radicals, then a
primary amino nitrogen will be optionally substituted with up to 2
non-hydrogen radicals, whereas a secondary amino nitrogen will be
optionally substituted with up to only 1 non-hydrogen radical.
[0083] The terms "treat", "treating", and "treatment" refer to a
method of alleviating or abrogating a disease and/or its attendant
symptoms. In certain embodiments, "treat," "treating," and
"treatment" refer to ameliorating at least one physical parameter,
which may not be discernible by the subject. In yet another
embodiment, "treat", "treating", and "treatment" refer to
modulating the disease or disorder, either physically (for example,
stabilization of a discernible symptom), physiologically (for
example, stabilization of a physical parameter), or both. In a
further embodiment, "treat", "treating", and "treatment" refer to
slowing the progression of the disease or disorder.
[0084] The terms "prevent", "preventing", and "prevention" refer to
a method of preventing the onset of a disease and/or its attendant
symptoms or barring a subject from acquiring a disease. As used
herein, "prevent", "preventing" and "prevention" also include
delaying the onset of a disease and/or its attendant symptoms and
reducing a subject's risk of acquiring or developing a disease or
disorder.
[0085] The phrase "therapeutically effective amount" means an
amount of a compound, or a pharmaceutically acceptable salt
thereof, sufficient to prevent the development of or to alleviate
to some extent one or more of the symptoms of the condition or
disorder being treated when administered alone or in conjunction
with another therapeutic agent for treatment in a particular
subject or subject population. The "therapeutically effective
amount" may vary depending on the compound, the disease and its
severity, and the age, weight, health, etc., of the subject to be
treated. For example in a human or other mammal, a therapeutically
effective amount may be determined experimentally in a laboratory
or clinical setting, or may be the amount required by the
guidelines of the United States Food and Drug Administration, or
equivalent foreign agency, for the particular disease and subject
being treated.
[0086] The term "subject" is defined herein to refer to animals
such as mammals, including, but not limited to, primates (e.g.,
humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits,
rats, mice and the like. In one embodiment, the subject is a human.
The terms "human," "patient," and "subject" are used
interchangeably herein.
[0087] The term "one or more" refers to one to eight. In one
embodiment it refers to one to eight. In one embodiment it refers
to one to seven. In one embodiment it refers to one to six. In one
embodiment it refers to one to five. In one embodiment it refers to
one to four. In one embodiment it refers to one or three. In
another embodiment it refers to one to three. In a further
embodiment it refers to one to two. In yet other embodiment it
refers to two. In yet other further embodiment it refers to
one.
[0088] As used herein, "Class I mutation(s)" refers to mutations
which interfere with protein synthesis. They result in the
introduction of a premature signal of termination of translation
(stop codon) in the mRNA. The truncated CFTR proteins are unstable
and rapidly degraded, so, the net effect is that there is no
protein at the apical membrane. In particular, Class I mutation(s)
refers to p.Gly542X (G542X), W1282X, c.489+1G>T (621+1G>T),
or c.579+1G>T (711+1G>T) mutation. More particularly, Class I
mutation(s) refers to G542X; or W1282X mutations.
[0089] As used herein, "Class II mutation(s)" refers to mutations
which affect protein maturation. These lead to the production of a
CFTR protein that cannot be correctly folded and/or trafficked to
its site of function on the apical membrane. In particular, Class
II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or
p.Asn1303Lys (N1303K) mutations. More particularly, Class II
mutation(s) refers to F508del or N1303K mutations.
[0090] As used herein, "Class III mutation(s)" refers to mutations
which alter the regulation of the CFTR channel. The mutated CFTR
protein is properly trafficked and localized to the plasma membrane
but cannot be activated, or it cannot function as a chloride
channel. In particular, Class III mutation(s) refers to p.Gly551Asp
(G551D), G551S, R553G, G1349D, S1251N, G178R, S549N mutations. More
particularly, Class III mutation(s) refers to G551D, R553G, G1349D,
S1251N, G178R, or S549N mutations.
[0091] As used herein, "Class IV mutation(s)" refers to mutations
which affect chloride conductance. The CFTR protein is correctly
trafficked to the cell membrane but generates reduced chloride flow
or a "gating defect" (most are missense mutations located within
the membrane-spanning domain). In particular, Class IV mutation(s)
refers to p.Arg117His (R117H), R347P, or p.Arg334Trp (R334W)
mutations.
[0092] As used herein, "Class V mutation(s)" refers to mutations
which reduce the level of normally functioning CFTR at the apical
membrane or result in a "conductance defect" (for example partially
aberrant splicing mutations or inefficient trafficking missense
mutations). In particular, Class V mutation(s) refers to
c.1210-12T[5] (5T allele), c.S3140-26A>G (3272-26A>G),
c.3850-2477C>T (3849+10kb C>T) mutations.
[0093] As used herein, "Class VI mutation(s)" refers to mutations
which decrease the stability of the CFTR which is present or which
affect the regulation of other channels, resulting in inherent
instability of the CFTR protein. In effect, although functional,
the CFTR protein is unstable at the cell surface and it is rapidly
removed and degraded by cell machinery. In particular, Class VI
mutation(s) refers to Rescued F508del, 120del23, N287Y, 4326dellTC,
or 4279insA mutations. More particularly, Class VI mutation(s)
refers to Rescued F508del mutations.
Compounds
[0094] Compounds of the invention are described herein.
[0095] Particular values of variable groups are as follows. Such
values may be used where appropriate with any of the other values,
definitions, claims or embodiments defined hereinbefore or
hereinafter.
Formula (I)
[0096] One embodiment pertains to compounds of Formula (I), or a
pharmaceutically acceptable salt thereof,
##STR00004##
wherein [0097] A.sup.1 is selected from the group consisting of
[0097] ##STR00005## [0098] X.sup.1 is N or C(R.sup.2A); [0099]
X.sup.2 is N or C(R.sup.2B); [0100] X.sup.3 is N or C(R.sup.2C);
[0101] X.sup.4 is N or C(R.sup.2D); [0102] R.sup.1 is selected from
the group consisting of hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.1 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, SR.sup.7, NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.1 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C(O)OH, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; [0103] one of R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D is hydrogen, and the remaining are independently selected
from the group consisting of hydrogen, R.sup.8, OR.sup.8,
C(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; or
[0104] two of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D a on
adjacent carbons form a fused ring selected from the group
consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-C.sub.7
cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7 membered
heterocyclyl; and the remaining are independently selected from the
group consisting of hydrogen, R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I;
wherein the phenyl, 5-6 membered heteroaryl, C.sub.3-C.sub.7
cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; [0105] R.sup.3 is selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.3
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkoxy, phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.3 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; [0106] R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0107] R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D are
each independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A,
R.sup.5B, R.sup.5C, and R.sup.5D C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, 4-12 membered
heterocyclyl, C.sub.1-C.sub.6 thioalkyl, OH, oxo, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.5A, R.sup.5B, R.sup.5C, and
R.sup.5D 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0108] R.sup.5A and R.sup.5B, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; and [0109] R.sup.5C and R.sup.5D are
each independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5C
and R.sup.5D C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5C and R.sup.5D 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0110] R.sup.5A and R.sup.5B are each
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A
and R.sup.5B C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A and R.sup.5B 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; and [0111] R.sup.5C and R.sup.5D, together with
the carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; [0112] R.sup.6A, R.sup.6B, R.sup.6C, and
R.sup.6D are each independently hydrogen; [0113] R.sup.7, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I; [0114] R.sup.8,
at each occurrence, is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0115] R.sup.9, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.13, OR.sup.13, SR.sup.13, C(O)R.sup.13,
NHR.sup.13, N(R.sup.13).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br
and I; wherein each R.sup.9 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, OR.sup.14, C(O)R.sup.14,
OC(O)R.sup.14, C(O)OR.sup.14, SO.sub.2R.sup.14, NHR.sup.14,
N(R.sup.14).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0116] R.sup.10, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally
substituted with one or more substituents independently selected
from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and
I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br
and I; [0117] R.sup.11, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl; wherein
each R.sup.11 C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I; [0118] R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I;
[0119] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.13 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each
R.sup.13 C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of C
.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered
heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; and [0120]
R.sup.14, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.14
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12
membered heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I;
[0121] with the proviso that R.sup.3 is not methyl; [0122] with the
proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are
each hydrogen, R.sup.1 is not hydrogen; [0123] with the proviso
that, when R.sup.3 is naphthyl, R.sup.2C is not
4-(1-methylethyl)phenoxy; and [0124] with the proviso that, when
R.sup.1 is C.sub.1-alkyl, R.sup.3 is not 3-pyridinyl or
4-cyanobenzyl.
[0125] One embodiment pertains to a compound of formula (I)
wherein [0126] A.sup.1 is selected from the group consisting of
[0126] ##STR00006## [0127] R.sup.1 is selected from the group
consisting of hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.1 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, SR.sup.7, NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.1 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C(O)OH, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; [0128] one of R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D is hydrogen, and the remaining are independently selected
from the group consisting of hydrogen, R.sup.8, OR.sup.8,
C(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; or
[0129] two of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D on
adjacent carbons form a fused ring selected from the group
consisting of phenyl, 5-6 membered heteroaryl, C.sub.3-C.sub.7
cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7 membered
heterocyclyl; and the remaining are independently selected from the
group consisting of hydrogen, R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I;
wherein the phenyl, 5-6 membered heteroaryl, C.sub.3-C.sub.7
cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; [0130] R.sup.3 is selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.3
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkoxy, phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.3 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; [0131] R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0132] R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D are
each independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A,
R.sup.5B, R.sup.5C, and R.sup.5D C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, 4-12 membered
heterocyclyl, C.sub.1-C.sub.6 thioalkyl, OH, oxo, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.5A, R.sup.5B, R.sup.5C, and
R.sup.5D 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0133] R.sup.5A and R.sup.5B, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; and [0134] R.sup.5C and R.sup.5D are
each independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5C
and R.sup.5D C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5C and R.sup.5D 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0135] R.sup.5A and R.sup.5B are each
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A
and R.sup.5B C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A and R.sup.5B 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; and [0136] R.sup.5C and R.sup.5D, together with
the carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; [0137] R.sup.6A, R.sup.6B, R.sup.6C, and
R.sup.6D are each independently hydrogen; [0138] R.sup.7, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I; [0139] R.sup.8,
at each occurrence, is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0140] R.sup.9, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.13, OR.sup.13, SR.sup.13, C(O)R.sup.13,
NHR.sup.13, N(R.sup.13).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br
and I; wherein each R.sup.9 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, OR.sup.14, C(O)R.sup.14,
OC(O)R.sup.14, C(O)OR.sup.14, SO.sub.2R.sup.14, NHR.sup.14,
N(R.sup.14).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0141] R.sup.10, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally
substituted with one or more substituents independently selected
from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and
I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br
and I; [0142] R.sup.11, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl; wherein
each R.sup.11 C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each [0143] R.sup.11 C.sub.6-C.sub.10 membered
aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I; [0144] R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I;
[0145] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.13 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each
R.sup.13 C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered
heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; and [0146]
R.sup.14, at each occurrence, is independently selected from the
group consisting of C
.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.14 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12 membered
heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; [0147] with
the proviso that R.sup.3 is not methyl; [0148] with the proviso
that, when R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are each
hydrogen, R.sup.1 is not hydrogen; [0149] with the proviso that,
when R.sup.3 is naphthyl, R.sup.2C is not 4-(1-methylethyl)phenoxy;
and [0150] with the proviso that, when R.sup.1 is C.sub.1-alkyl,
R.sup.3 is not 3-pyridinyl or 4-cyanobenzyl.
[0151] In one embodiment of Formula (I), A.sup.1 is selected from
the group consisting of
##STR00007##
In another embodiment of Formula (I), A.sup.1 is
##STR00008##
In another embodiment of Formula (I), A.sup.1 is
##STR00009##
In another embodiment of Formula (I), A.sup.1 is
##STR00010##
In another embodiment of Formula (I), A.sup.1 is
##STR00011##
In another embodiment of Formula (I), A.sup.1 is
##STR00012##
[0152] In one embodiment of Formula (I), X.sup.1 is N or
C(R.sup.2A). In another embodiment of Formula (I), X.sup.1 is N. In
another embodiment of Formula (I), X.sup.1 is C(R.sup.2A).
[0153] In one embodiment of Formula (I), X.sup.2 is N or
C(R.sup.2B). In another embodiment of Formula (I), X.sup.2 is N. In
another embodiment of Formula (I), X.sup.2 is C(R.sup.2B).
[0154] In one embodiment of Formula (I), X.sup.3 is N or
C(R.sup.2C). In another embodiment of Formula (I), X.sup.3 is N. In
another embodiment of Formula (I), X.sup.3 is C(R.sup.2C).
[0155] In one embodiment of Formula (I), X.sup.4 is N or
C(R.sup.2D). In another embodiment of Formula (I), X.sup.4 is N. In
another embodiment of Formula (I), X.sup.4 is C(R.sup.2D).
[0156] In one embodiment of Formula (I), X.sup.1 is C(R.sup.2A);
X.sup.2 is C(R.sup.2B); X.sup.3 is C(R.sup.2C); and X.sup.4 is
C(R.sup.2D).
[0157] In one embodiment of Formula (1), A.sup.1 is selected from
the group consisting of
##STR00013##
In another embodiment of Formula (I), A.sup.1 is
##STR00014##
In another embodiment of Formula (I), A.sup.1 is
##STR00015##
In another embodiment of Formula (I), A.sup.1 is
##STR00016##
In another embodiment of Formula (I), A.sup.1 is
##STR00017##
In another embodiment of Formula (I), A.sup.1 is
##STR00018##
[0158] In one embodiment of Formula (I), R.sup.1 is selected from
the group consisting of hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.1 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, SR.sup.7, NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.1 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C(O)OH, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I. In another embodiment of Formula (I), R.sup.1 is
selected from the group consisting of hydrogen, CN, and
C.sub.1-C.sub.6 alkyl; wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, C(O)OH, OH, and CN. In another embodiment of
Formula (I), R.sup.1 is hydrogen. In another embodiment of Formula
(I), R.sup.1 is CN. In another embodiment of Formula (I), R.sup.1
is C.sub.1-C.sub.6 alkyl; which is unsubstituted. In another
embodiment of Formula (I), R.sup.1 is hydrogen or C.sub.1-C.sub.6
alkyl; which is unsubstituted. In another embodiment of Formula
(I), R.sup.1 is C.sub.1-C.sub.6 alkyl; wherein the R.sup.1
C.sub.1-C.sub.6 alkyl is optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, N(R.sup.7).sub.2, C(O)OH, OH, and CN.
[0159] In one embodiment of Formula (I), one of R.sup.2A, R.sup.2B,
R.sup.2C, and R.sup.2D is hydrogen, and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8,
NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I;
with the proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are each hydrogen, R.sup.1 is not hydrogen. In another
embodiment of Formula (I), one of R.sup.2A, R.sup.2B, R.sup.2C and
R.sup.2D is hydrogen, and the remaining are independently selected
from the group consisting of hydrogen, R.sup.8, OR.sup.8,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br;
with the proviso that, when R.sup.2A, R.sup.2B, R.sup.2C and
R.sup.2D are each hydrogen, R.sup.1 is not hydrogen. In another
embodiment of Formula (I), R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are hydrogen; with the proviso that R.sup.1 is not
hydrogen.
[0160] In one embodiment of Formula (I), two of R.sup.2A, R.sup.2B,
R.sup.2C and R.sup.2D on adjacent carbons form a fused ring
selected from the group consisting of phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F,
Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7
membered heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I. In another embodiment of Formula
(I), R.sup.2C and R.sup.2D form a 4-7 membered heterocyclyl; and
R.sup.2A and R.sup.2B are independently hydrogen.
[0161] In one embodiment of Formula (I), R.sup.3 is selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.3
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkoxy, phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.3 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (I), R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy and
phenyl; wherein the R.sup.3 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br.
In another embodiment of Formula (I), R.sup.3 is C.sub.1-C.sub.6
alkyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkoxy and phenyl. In
another embodiment of Formula (I), R.sup.3 is 6-10 membered aryl;
wherein the R.sup.3 6-10 membered aryl is optionally substituted
with one or more substituents independently selected from the group
consisting of R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, and Br. In another embodiment of Formula (I),
R.sup.3 is 5-11 membered heteroaryl; wherein the R.sup.3 5-11
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br.
In another embodiment of Formula (I), R.sup.3 is C.sub.3-C.sub.11
cycloalkyl; wherein the R.sup.3 C.sub.3-C.sub.11 cycloalkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.9, OR.sup.9,
C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2,
NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br. In another
embodiment of Formula (I), R.sup.3 is 4-12 membered heterocyclyl;
wherein the R.sup.3 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)R.sup.9,
C(O)OR.sup.9, SO.sub.2R.sup.9, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, and Br.
[0162] In one embodiment of Formula (I), R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I. In another embodiment of Formula (I), R.sup.4 is
hydrogen. In another embodiment of Formula (I), R.sup.4 is
C.sub.1-C.sub.6 alkyl; wherein the R.sup.4 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more R.sup.10.
[0163] In one embodiment of Formula (I), R.sup.5A, R.sup.5B,
R.sup.5C, and R.sup.5D are each independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.5A, R.sup.5B,
R.sup.5C, and R.sup.5D C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are
optionally substituted with one or more substituents independently
selected from the group consisting of 6-10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D 6-10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C(O)OH,
NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; or R.sup.5A and
R.sup.5B, together with the carbon atom to which they are attached,
form a C.sub.3-C.sub.7 monocyclic cycloalkyl or a 4-7 membered
monocyclic heterocycle; wherein the C.sub.3-C.sub.7 monocyclic
cycloalkyl and the 4-7 membered monocyclic heterocycle are each
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; and
R.sup.5C and R.sup.5D are each independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.5C and R.sup.5D
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally substituted with
one or more substituents independently selected from the group
consisting of 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, 4-12
membered heterocyclyl, C.sub.1-C.sub.6 thioalkyl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; wherein the R.sup.5C and R.sup.5D 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2, F,
Cl, Br and I; or R.sup.5A and R.sup.5B are each independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A
and R.sup.5B C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A and R.sup.5B 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; and R.sup.5C and R.sup.5D, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (I),
R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D are each independently
hydrogen. In another embodiment of Formula (I), R.sup.5A, R.sup.5B,
R.sup.5C, and R.sup.5D are each independently C.sub.1-C.sub.6
alkyl.
[0164] In one embodiment of Formula (I), R.sup.6A, R.sup.6B,
R.sup.6C, and R.sup.6D are each independently hydrogen.
[0165] In one embodiment of Formula (I), R.sup.7, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I. In another
embodiment of Formula (I), R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, 6-10 membered aryl, 5-11 membered heteroaryl, cycloalkyl,
and 4-12 membered heterocyclyl; wherein each R.sup.7
C.sub.1-C.sub.6 alkyl is optionally substituted with one or more
C.sub.1-C.sub.6 alkoxy; wherein each R.sup.7 5-11 membered
heteroaryl and 4-12 membered heterocyclyl is optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, F,
and Cl.
[0166] In one embodiment of Formula (I), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.8 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.11, OR.sup.11,
C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I. In another embodiment of Formula (I), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl and C.sub.2-C.sub.6 alkenyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, C(O)OR.sup.11,
OH, and F; wherein each R.sup.8 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
N(R.sup.12).sub.2, and F.
[0167] In one embodiment of Formula (I), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.9 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.13, OR.sup.13,
SR.sup.13, C(O)R.sup.13, NHR.sup.13, N(R.sup.13).sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.9 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl are
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.14, OR.sup.14,
C(O)R.sup.14, OC(O)R.sup.14, C(O)OR.sup.14, SO.sub.2R.sup.14,
NHR.sup.14, N(R.sup.14).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (I),
R.sup.9, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, 6-10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.13, OR.sup.13, C(O)R.sup.13,
N(R.sup.13).sub.2, OH, F, and Cl; wherein each R.sup.9 6-10
membered aryl and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, oxo, and F.
[0168] In one embodiment of Formula (I), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (I),
R.sup.10, at each occurrence, is independently C.sub.6-C.sub.10
membered aryl; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6
alkoxy.
[0169] In one embodiment of Formula (I), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.11 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.11
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I. In
another embodiment of Formula (I), R.sup.11, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl,
and 4-12 membered heterocyclyl; wherein each R.sup.11
C.sub.6-C.sub.10 membered aryl, is optionally substituted with one
or more C.sub.1-C.sub.6 alkoxy.
[0170] In one embodiment of Formula (I), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I. In
another embodiment of Formula (I), R.sup.12, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl,
and 4-12 membered heterocyclyl; wherein each R.sup.12
C.sub.1-C.sub.6 alkyl is optionally substituted with one or more F;
wherein each 4-12 membered heterocyclyl is optionally substituted
with one or more C.sub.1-C.sub.6 alkyl.
[0171] In one embodiment of Formula (I), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.13 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another R.sup.13, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl, and 4-12
membered heterocyclyl; wherein each R.sup.13 C.sub.6-C.sub.10
membered aryl and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, and Cl.
[0172] In one embodiment of Formula (I), R.sup.14, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.14 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12 membered
heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I. In another
embodiment of Formula (I), R.sup.14, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl; wherein each R.sup.14
C.sub.1-C.sub.6 alkyl is optionally substituted with one or more
independently selected 4-12 membered heterocyclyl.
[0173] One embodiment pertains to compounds of Formula (I), or a
pharmaceutically acceptable salt thereof,
wherein [0174] A.sup.1 is selected from the group consisting of
[0174] ##STR00019## [0175] X.sup.1 is C(R.sup.2A); [0176] X.sup.2
is N or C(R.sup.2B); [0177] X.sup.3 is C(R.sup.2C); [0178] X.sup.4
is N or C(R.sup.2D); [0179] R.sup.1 is selected from the group
consisting of hydrogen, CN, and C.sub.1-C.sub.6 alkyl; wherein the
R.sup.1 C.sub.1-C.sub.6 alkyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.7, OR.sup.7, N(R.sup.7).sub.2, C(O)OH, OH, and CN; [0180]
one of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and
the remaining are independently selected from the group consisting
of hydrogen, R.sup.8, OR.sup.8, C(O)OR.sup.8, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br; or [0181] two
of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D on adjacent carbons
form a 4-7 membered heterocyclyl; and the remaining are hydrogen;
[0182] R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy and
phenyl; wherein the R.sup.3 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br;
R.sup.4 is selected from the group consisting of hydrogen and
C.sub.1-C.sub.6 alkyl; wherein the R.sup.4 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more R.sup.10; [0183] R.sup.5A,
R.sup.5B, R.sup.5C, and R.sup.5D are each independently selected
from the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl;
[0184] R.sup.6A, R.sup.6B, R.sup.6C, and R.sup.6D are each
independently hydrogen; [0185] R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.7 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more C.sub.1-C.sub.6 alkoxy; wherein each
R.sup.7 5-11 membered heteroaryl and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, F, and Cl; [0186] R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl and C.sub.2-C.sub.6 alkenyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, C(O)OR.sup.11,
OH, and F; wherein each R.sup.8 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
N(R.sup.12).sub.2 and F; [0187] R.sup.9, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, 6-10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12
membered heterocyclyl; wherein each R.sup.9 C.sub.1-C.sub.6 alkyl
is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, C(O)R.sup.13, N(R.sup.13).sub.2, OH, F, and Cl; wherein
each R.sup.96-10 membered aryl and 4-12 membered heterocyclyl are
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.14, oxo, and F; [0188]
R.sup.10, at each occurrence, is independently C.sub.6-C.sub.10
membered aryl; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
[0189] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
[0190] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more F; wherein each 4-12
membered heterocyclyl is optionally substituted with one or more
C.sub.1-C.sub.6 alkyl; [0191] R.sup.13, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10 membered aryl and 4-12 membered
heterocyclyl; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl
and 4-12 membered heterocyclyl is optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl and Cl; and [0192] R.sup.14, at
each occurrence, is independently C.sub.1-C.sub.6 alkyl; wherein
each R.sup.14 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more 4-12 membered heterocyclyl; [0193] with the proviso
that R.sup.3 is not methyl; [0194] with the proviso that, when
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are each hydrogen,
R.sup.1 is not hydrogen; [0195] with the proviso that, when R.sup.3
is naphthyl, R.sup.2C is not 4-(1-methylethyl)phenoxy; and [0196]
with the proviso that, when R.sup.1 is C.sub.1-alkyl, R.sup.3 is
not 3-pyridinyl or 4-cyanobenzyl.
[0197] One embodiment pertains to a compound, or a pharmaceutically
acceptable salt thereof, wherein the compound is selected from the
group consisting of: [0198]
4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0199]
8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide; [0200]
(1R)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-
-carboxamide; [0201]
5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide; [0202]
1-benzyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide; [0203]
(1R)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0204]
4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0205]
4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0206]
1-benzyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydrona-
phthalene-1-carboxamide; [0207]
1-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide; [0208]
(1R)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide; [0209]
(1S)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide; [0210]
4-chloro-N-(2,2-difluoro-2H-1,3-benzodioxole-4-sulfonyl)-1-ethyl-2,3-dihy-
dro-1H-indene-1-carboxamide; [0211]
7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide; [0212]
8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide; [0213]
4-chloro-1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N-(naphthalene-1-sulfon-
yl)-2,3-dihydro-1H-indene-1-carboxamide; [0214]
(1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0215]
(1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0216]
4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide; [0217]
(6S)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][-
1,3]dioxole-6-carboxamide; [0218]
(6R)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][-
1,3]dioxole-6-carboxamide; [0219]
(1S)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0220]
(1R)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0221]
N-(naphthalene-1-sulfonyl)-6,7,8,9-tetrahydro-2H-naphtho[1,2-d][1,3]dioxo-
le-6-carboxamide; [0222]
(1S)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; [0223]
(1R)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; [0224]
4-bromo-1-ethyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0225]
4-chloro-1-(cyclopropylmethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H--
indene-1-carboxamide; [0226]
1-butyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0227]
4-chloro-1-ethyl-N-(8-hydroxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0228]
8-bromo-5-ethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide; [0229]
8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide; [0230]
8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide; [0231]
4-chloro-N-(naphthalene-1-sulfonyl)-1-{[6-(trifluoromethyl)pyridin-2-yl]m-
ethyl}-2,3-dihydro-1H-indene-1-carboxamide; [0232]
4-chloro-1-[(6-chloropyridin-3-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide; [0233]
4-chloro-1-[(6-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide; [0234]
4-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide; [0235]
4-chloro-N-(5-chloronaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide; [0236]
8-bromo-N-(naphthalene-1-sulfonyl)-5-[(propan-2-yl)oxy]-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide; [0237]
5-bromo-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide; [0238]
4-chloro-1-ethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide; [0239]
N-(1-benzothiophene-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1--
carboxamide; [0240]
4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide; [0241]
8-bromo-5-(2-methoxyethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide; [0242]
(1S)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide; [0243]
(1R)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide; [0244]
(1S)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide; [0245]
(1R)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide; [0246]
5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide; [0247]
(1S)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; [0248]
(1R)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; [0249]
4-bromo-7-ethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0250]
4-bromo-N-(naphthalene-1-sulfonyl)-7-[(propan-2-yl)oxy]-2,3-dihydro-1H-in-
dene-1-carboxamide; [0251]
4-bromo-7-(cyclopropylmethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H--
indene-1-carboxamide; [0252]
8-bromo-5-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide; [0253]
5-methoxy-8-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide; [0254]
4-bromo-7-(difluoromethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide; [0255]
4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide; [0256]
(1S)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide; [0257]
(1R)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide; [0258]
(1S)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphtha-
lene-1-carboxamide; [0259]
(1R)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphtha-
lene-1-carboxamide; [0260]
(1S)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide; [0261]
(1R)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide; [0262]
4-chloro-1-ethyl-N-(1-methyl-1H-indole-7-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0263]
5-methoxy-8-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide; [0264]
8-methoxy-5-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide; [0265]
5-cyclobutyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide; [0266]
5-chloro-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide; [0267]
(1S)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0268]
(1R)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0269]
5,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide; [0270]
4-chloro-1-ethyl-N-(1-methyl-1H-indole-4-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0271]
7-methoxy-4-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide; [0272]
4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; [0273]
4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide; [0274]
4-bromo-N-(imidazo[1,2-a]pyridine-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-in-
dene-1-carboxamide; [0275]
2-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trie-
ne-7-carboxamide; [0276]
(1S)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide; [0277]
(1R)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide; [0278]
8-cyclobutyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide; [0279]
7-cyclobutyl-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0280]
(1R)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; [0281]
(1S)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; [0282]
(1R)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0283]
(1S)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0284]
5-cyclopropyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaph-
thalene-1-carboxamide; [0285]
(1S)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide; [0286]
(1R)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide; [0287]
(1S)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0288]
(1R)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0289]
(1S)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-
-1H-indene-1-carboxamide; [0290]
(1R)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-
-1H-indene-1-carboxamide; [0291]
(1S)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1-
H-indene-1-carboxamide; [0292]
(1R)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1-
H-indene-1-carboxamide; [0293]
4-chloro-1-ethyl-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0294]
4-bromo-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0295]
4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-
-indene-1-carboxamide; [0296]
4-bromo-7-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0297]
4-bromo-7-methoxy-N-(2-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0298]
2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-
-triene-7-carboxamide; [0299]
(1R)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0300]
(1S)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0301]
4-bromo-N-(5-hydroxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0302]
(7S)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa--
1,3,5-triene-7-carboxamide; [0303]
(7R)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa--
1,3,5-triene-7-carboxamide; [0304]
(1R)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0305]
(1S)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0306]
4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]-
pyridine-7-carboxamide; [0307]
4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopen-
ta[c]pyridine-7-carboxamide; [0308]
4-chloro-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c-
]pyridine-7-carboxamide; [0309]
4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinoli-
ne-8-carboxamide; [0310]
2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-t-
riene-7-carboxamide; [0311]
(8S)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoqu-
inoline-8-carboxamide; [0312]
(8R)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoqu-
inoline-8-carboxamide; [0313]
(1S)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-d-
ihydro-1H-indene-1-carboxamide; [0314]
(1R)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-d-
ihydro-1H-indene-1-carboxamide; [0315]
4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dih-
ydro-1H-indene-1-carboxamide; [0316]
(8R)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydro-
isoquinoline-8-carboxamide; [0317]
(8S)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydro-
isoquinoline-8-carboxamide; [0318]
(1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide; [0319]
(1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide; [0320]
7-methoxy-N-(naphthalene-1-sulfonyl)-4-(prop-1-en-2-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0321]
4-(2-hydroxypropan-2-yl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-
-1H-indene-1-carboxamide; [0322]
(1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide; [0323]
(1S)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro--
1H-indene-1-carboxamide; [0324]
(1R)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro--
1H-indene-1-carboxamide; [0325]
(1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide; [0326]
(1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide; [0327]
(1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide; [0328]
2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]o-
cta-1,3,5-triene-7-carboxamide; [0329]
4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0330]
2-cyclobutyl-5-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)bicyclo[4.-
2.0]octa-1,3,5-triene-7-carboxamide; [0331]
4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro-
-1H-indene-1-carboxamide; [0332]
2-cyclobutyl-5-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)bicyclo[4.2.-
0]octa-1,3,5-triene-7-carboxamide; [0333]
2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[-
4.2.0]octa-1,3,5-triene-7-carboxamide; [0334]
7-methoxy-N-(naphthalene-1-sulfonyl)-4-(oxolan-2-yl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0335]
7-methoxy-4-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide; [0336]
7-methoxy-4-(2-methylpropyl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0337]
(1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0338]
(1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0339]
(7S)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.-
2.0]octa-1,3,5-triene-7-carboxamide; [0340]
(7R)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.-
2.0]octa-1,3,5-triene-7-carboxamide; [0341]
(7S)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bic-
yclo[4.2.0]octa-1,3,5-triene-7-carboxamide; [0342]
(7R)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bic-
yclo[4.2.0]octa-1,3,5-triene-7-carboxamide; [0343]
(7S)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,-
3,5-triene-7-carboxamide; [0344]
(7R)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,-
3,5-triene-7-carboxamide; [0345]
7-methoxy-3,3-dimethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide;
[0346]
(1R)-4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-
-2,3-dihydro-1H-indene-1-carboxamide; [0347]
7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide; [0348]
(1S)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0349]
(1R)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0350]
(7R)-2-cyclobutyl-5-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-
bicyclo[4.2.0]octa-1,3,5-triene-7-carboxamide; [0351]
N-(benzenesulfonyl)-4-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxamide-
; [0352]
4-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0353]
4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de; [0354]
(1S)-6-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0355]
(1R)-6-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0356]
4-chloro-N-(2-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de; [0357]
N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide; [0358]
5-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide; [0359]
5,6-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide; [0360]
8-chloro-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide; [0361]
N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0362]
6-fluoro-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthal-
ene-1-carboxamide; [0363]
(1R)-5-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide; [0364]
(1S)--N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide; [0365]
6,7-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide; [0366]
4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-2-carboxam-
ide; [0367]
(1R)--N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide; [0368]
(1S)-6-methoxy-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide; [0369]
7-chloro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0370]
4,5-difluoro-1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0371]
1-methyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de; [0372]
1,5-dimethyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0373]
4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide; [0374]
N-(2-ethylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxami-
de; [0375]
4-chloro-N-(2-ethylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0376]
4-chloro-N-(3-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de; [0377]
4-chloro-N-(4-chlorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide; [0378]
4-chloro-N-(2-fluorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de; [0379]
(1S)-4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide; [0380]
N-(2-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide; [0381]
4-methoxy-N-(2-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de; [0382]
4-chloro-1-ethyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H--
indene-1-carboxamide; [0383]
4-bromo-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamid-
e; [0384]
4-(3,6-dihydro-2H-pyran-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide; [0385]
4-cyclobutyl-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0386]
N-(2-methylbenzene-1-sulfonyl)-4-phenyl-2,3-dihydro-1H-indene-1-carboxami-
de; [0387]
4-methoxy-N-[2-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-
-1H-indene-1-carboxamide; [0388]
N-(2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide; [0389]
N-(2-bromobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxami-
de; [0390]
N-(2-methylbenzene-1-sulfonyl)-4-[(propan-2-yl)oxy]-2,3-dihydro-
-1H-indene-1-carboxamide; [0391]
7-bromo-4-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0392]
4-(2-methoxypyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0393]
5-methoxy-N-(quinoline-8-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carbox-
amide; [0394]
(1R)-5-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0395]
(1S)-5-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0396]
(1S)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0397]
4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyrrolidin-1-yl)methyl]-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0398]
4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-2-carboxamide;
[0399]
1-methyl-N-(naphthalene-1-sulfonyl)-6-(trifluoromethoxy)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0400]
8-bromo-5-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide; [0401]
5,6-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
amide; [0402]
N-(naphthalene-1-sulfonyl)-2,3,7,8,9,10-hexahydronaphtho[1,2-b][1,4]dioxi-
ne-7-carboxamide; [0403]
6,7-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide; [0404]
4-chloro-N-(2-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide; [0405]
4-chloro-1-ethyl-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0406]
4-chloro-1-ethyl-N-[5-methyl-2-(propan-2-yl)benzene-1-sulfonyl]-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0407]
4-chloro-N-[3-chloro-2-(methoxymethyl)benzene-1-sulfonyl]-1-ethyl-2,3-dih-
ydro-1H-indene-1-carboxamide; [0408]
4-chloro-1-ethyl-N-(2-fluorobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide; [0409]
4-chloro-1-ethyl-N-(2-phenoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0410]
4-chloro-1-ethyl-N-[2-(trifluoromethoxy)benzene-1-sulfonyl]-2,3-dihydro-1-
H-indene-1-carboxamide; [0411]
4-chloro-N-[2-(difluoromethoxy)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-1H-
-indene-1-carboxamide; [0412]
4-chloro-N-(2,5-dimethylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide; [0413]
4-chloro-1-ethyl-N-[2-(2-methoxyethoxy)benzene-1-sulfonyl]-2,3-dihydro-1H-
-indene-1-carboxamide; [0414]
N-([1,1'-biphenyl]-2-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide; [0415]
4-chloro-1-ethyl-N-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0416]
N-(benzenesulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxamide;
[0417]
N-(2,1,3-benzothiadiazole-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-
-1H-indene-1-carboxamide; [0418]
N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0419]
4-chloro-N-(naphthalene-1-sulfonyl)-1-[(oxolan-3-yl)methyl]-2,3-dihydro-1-
H-indene-1-carboxamide; [0420]
4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(1H-pyrazol-1-yl)ethyl]-2,3-dihy-
dro-1H-indene-1-carboxamide; [0421]
4-chloro-1-[(5-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide; [0422]
4-chloro-1-[(2-methoxypyridin-4-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide; [0423]
4-chloro-N-(naphthalene-1-sulfonyl)-1-{[3-(trifluoromethyl)pyridin-2-yl]m-
ethyl}-2,3-dihydro-1H-indene-1-carboxamide; [0424]
4-chloro-N-(2,3-dihydro-1,4-benzodioxine-5-sulfonyl)-1-ethyl-2,3-dihydro--
1H-indene-1-carboxamide; [0425]
4-bromo-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0426]
N-(4-bromonaphthalene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H--
indene-1-carboxamide; [0427]
4-chloro-1-ethyl-N-(4-fluoronaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide; [0428]
N-(5-bromonaphthalene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene--
1-carboxamide; [0429]
4-chloro-1-ethyl-N-(5,6,7,8-tetrahydronaphthalene-1-sulfonyl)-2,3-dihydro-
-1H-indene-1-carboxamide; [0430]
4-chloro-N-(3,4-dihydroquinoline-1(2H)-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0431]
4-chloro-1-(hydroxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0432]
4-cyclobutyl-N-(4-cyclobutylnaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1-
H-indene-1-carboxamide; [0433]
4-cyclobutyl-N-(5-cyclobutylnaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1-
H-indene-1-carboxamide; [0434]
8-bromo-5-(cyclohexylmethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide; [0435]
8-bromo-5-[(3-methoxyphenyl)methoxy]-N-(naphthalene-1-sulfonyl)-1,2,3,4-t-
etrahydronaphthalene-1-carboxamide; [0436]
8-bromo-5-[(3-methoxyphenyl)methoxy]-N-[(3-methoxyphenyl)methyl]-N-(napht-
halene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide;
ethyl({4-bromo-5-[(naphthalene-1-sulfonyl)carbamoyl]-5,6,7,8-tetrahydrona-
phthalen-1-yl}oxy)acetate; [0437]
8-bromo-5-(cyclopentyloxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide; [0438]
5-(benzyloxy)-8-bromo-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide; [0439]
N-benzyl-5-(benzyloxy)-8-bromo-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahy-
dronaphthalene-1-carboxamide; [0440]
8-bromo-N-(naphthalene-1-sulfonyl)-5-[(oxetan-3-yl)oxy]-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide; [0441]
8-bromo-N-(naphthalene-1-sulfonyl)-5-[(oxan-4-yl)oxy]-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide; [0442]
8-bromo-5-(2-hydroxy-2-methylpropoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide; [0443]
6,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide; [0444]
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[4-(trifluoromethoxy)phenyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide; [0445]
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[(E)-2-phenylethenyl]-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide; [0446]
8-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)-5-methoxy-N-(naphthalene-1-sulfo-
nyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide; [0447]
8-(2-fluoro-4-methylphenyl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide; [0448]
5-methoxy-N-(naphthalene-1-sulfonyl)-8-(2-phenoxyphenyl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide; [0449]
N-(3-bromo-2-methylbenzene-1-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-in-
dene-1-carboxamide; [0450]
4-chloro-1-ethyl-N-(3-fluoro-2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0451]
4-chloro-1-ethyl-N-[2-(methoxymethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0452]
4-chloro-N-(2,3-difluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide; [0453]
4-chloro-N-[2-(2,2-difluoroethoxy)benzene-1-sulfonyl]-1-ethyl-2,3-dihydro-
-1H-indene-1-carboxamide; [0454]
4-chloro-1-ethyl-N-(quinoxaline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0455]
4-chloro-N-(3-chloro-2-fluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0456]
4-chloro-N-(2,3-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide; [0457]
4-chloro-1-ethyl-N-(1-methyl-1H-indole-3-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0458]
5-[2-(1,3-dioxan-2-yl)ethyl]-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-
-tetrahydronaphthalene-1-carboxamide; [0459]
4-cyano-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide; [0460]
5-cyano-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide; [0461]
4-chloro-N-(3-cyclobutyl-2-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro--
1H-indene-1-carboxamide; [0462]
4-chloro-1-ethyl-N-(isoquinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide; [0463]
5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-car-
b oxamide; [0464]
8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide; [0465]
4-bromo-7-methoxy-N-(quinoline-8-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide; [0466]
4-bromo-N-(8-fluoroquinoline-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene--
1-carboxamide; [0467]
7-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trie-
ne-7-carb oxamide; [0468]
8-methoxy-N-(naphthalene-1-sulfonyl)-5-[3-(trifluoromethoxy)phenyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide; [0469]
8-methoxy-N-(naphthalene-1-sulfonyl)-5-[(E)-2-phenylethenyl]-1,2,3,4-tetr-
ahydronaphthalene-1-carboxamide; [0470]
5-(3,6-dihydro-2H-pyran-4-yl)-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide; [0471]
5-methoxy-8-(6-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide; [0472]
4-bromo-N-(2-ethoxyquinoline-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-indene--
1-carboxamide; [0473]
8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyrrolidin-1-yl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide; [0474]
4-chloro-1-ethyl-N-[2-methyl-3-(piperidin-1-yl)benzene-1-sulfonyl]-2,3-di-
hydro-1H-indene-1-carboxamide; [0475]
4-chloro-N-[3-(3,3-difluoroazetidin-1-yl)-2-methylbenzene-1-sulfonyl]-1-e-
thyl-2,3-dihydro-1H-indene-1-carboxamide; [0476]
4-chloro-N-[3-(3,3-difluoropyrrolidin-1-yl)-2-methylbenzene-1-sulfonyl]-1-
-ethyl-2,3-dihydro-1H-indene-1-carboxamide; [0477]
5-chloro-8-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide; [0478]
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[6-(trifluoromethyl)pyridin-3-yl]--
1,2,3,4-tetrahydronaphthalene-1-carboxamide; [0479]
8-(3,6-dihydro-2H-pyran-4-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide; [0480]
8-(6-cyclopropylpyridin-3-yl)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide; [0481]
4-bromo-7-methoxy-N-[2-(propan-2-yl)quinoline-5-sulfonyl]-2,3-dihydro-1H--
indene-1-carboxamide; [0482]
4-bromo-7-methoxy-N-(5-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0483] methyl
7-methoxy-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-c-
arboxylate; [0484] methyl
5-[(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]naphthal-
ene-1-carboxylate; [0485]
5-chloro-8-[2-(morpholin-4-yl)ethoxy]-N-(naphthalene-1-sulfonyl)-1,2,3,4--
tetrahydronaphthalene-1-carboxamide; [0486]
4-chloro-1-methyl-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0487]
4-chloro-N-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide; [0488]
4-chloro-N-(2-methoxyethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0489]
4-chloro-N-(propane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamid-
e; [0490]
8-methoxy-N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-2-carboxamide; [0491]
5-methoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide; [0492]
N-(2-methylbenzene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamid-
e; [0493]
4-methoxy-N-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)-2,3-dihydro-
-1H-indene-1-carboxamide; [0494]
4-methoxy-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide; [0495]
4-methoxy-N-(5-methylpyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide; [0496]
4-methoxy-N-(oxane-4-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0497]
4-methoxy-N-(3-methoxypropane-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0498]
4-methoxy-N-(2-methoxyethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide-
;
[0499]
4-methoxy-N-(propane-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de; [0500]
4-chloro-N-(2-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0501]
4-chloro-N-(5-methylpyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide; [0502]
N-(4-hydroxybenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxa-
mide; [0503]
4-methoxy-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0504]
N-(6-hydroxynaphthalene-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide; [0505]
4-methoxy-N-(4-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide; [0506]
N-(5-acetamido-1,3,4-thiadiazole-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-ind-
ene-1-carboxamide; [0507]
4-methoxy-N-[5-methyl-2-(propan-2-yl)benzene-1-sulfonyl]-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0508]
N-[4-(methanesulfonyl)benzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-
-1-carboxamide; [0509]
4-methoxy-N-(3-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxami-
de; [0510]
N-(4-chloro-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-
-indene-1-carboxamide; [0511]
N-(6-chloro-1,1-dioxo-1,2-dihydro-1.lamda..sup.6,2,4-benzothiadiazine-7-s-
ulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; [0512]
4-methoxy-N-(2-methyl-5-nitrobenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0513]
N-(4-acetamido-2-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide; [0514]
N-(4-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide; [0515]
N-(4-chloro-2-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1--
carboxamide; [0516]
4-methoxy-N-(naphthalene-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0517]
N-(3-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-c-
arboxamide; [0518]
4-methoxy-N-[4-(3-oxobutanamido)benzene-1-sulfonyl]-2,3-dihydro-1H-indene-
-1-carboxamide; [0519]
N-(2,4-dichlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide; [0520]
N-(4-amino-2-chloro-5-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H--
indene-1-carboxamide; [0521]
N-(2-chloro-5-methylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide; [0522]
N-(2-chloro-5-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1--
carboxamide; [0523]
N-(4-acetamidobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carbo-
xamide; [0524]
N-(4-acetamido-2-chlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide; [0525]
N-(4-butanamidobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide; [0526]
N-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-4-methoxy-2,3-dihydro-1H-
-indene-1-carboxamide; [0527]
N-(2,4-dihydroxy-6-methylpyrimidine-5-sulfonyl)-4-methoxy-2,3-dihydro-1H--
indene-1-carboxamide; [0528]
N-(4-cyanobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxami-
de; [0529]
4-methoxy-N-(2-oxo-2H-1-benzopyran-6-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0530] ethyl
4-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate;
[0531]
N-(2,4-dimethyl-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide; [0532]
N-{2-chloro-5-[(2,6-dimethylphenyl)carbamoyl]-4-hydroxybenzene-1-sulfonyl-
}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; [0533]
N-[1-(2-chloroethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonyl]-4-methoxy-2,3-d-
ihydro-1H-indene-1-carboxamide; [0534]
N-[3-({[2S)-1-ethylpyrrolidin-2-yl]methyl}carbamoyl)-4-methoxybenzene-1-s-
ulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; [0535]
N-(6-ethoxy-1,3-benzothiazole-2-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-
-1-carboxamide; [0536]
N-(4-hexanoylbenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carbox-
amide; [0537]
N-[4-(4-{2-[(1S)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazin-1-yl)be-
nzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
[0538] propan-2-yl
2-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]benzoate;
[0539]
N-{4-[(3-hydroxy-3-methylbutyl)amino]-3-nitrobenzene-1-sulfonyl}-4-methox-
y-2,3-dihydro-1H-indene-1-carboxamide; [0540]
N-[2-chloro-5-(1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)be-
nzene-1-sulfonyl]-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
[0541]
N-{7[(4-chlorophenyl)methyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-
-purine-8-sulfonyl}-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide;
[0542]
N-(9-benzyl-1,3-dimethyl-2,6-dioxo-2,3,6,9-tetrahydro-1H-purine-8-sulfony-
l)-4-methoxy-2,3-dihydro-1H-indene-1-carboxamide; [0543]
N-{4-[(dimethylamino)methyl]benzene-1-sulfonyl}-4-methoxy-2,3-dihydro-1H--
indene-1-carboxamide; [0544]
N-(2-cyano-3-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1--
carboxamide; [0545]
N-(4-hydroxy-3-nitrobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide; [0546]
N-(3-cyanobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxami-
de; [0547]
N-(5-bromopyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene--
1-carboxamide; [0548]
N-(6-hydroxypyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carbox-
amide; [0549]
N-(4-cyano-1,3-dimethyl-1H-pyrazole-5-sulfonyl)-4-methoxy-2,3-dihydro-1H--
indene-1-carboxamide; [0550] tert-butyl
5-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-1,3-dimethyl-1H-
-pyrazole-4-carboxylate; [0551]
N-[4-(hydroxymethyl)-1,3-dimethyl-1H-pyrazole-5-sulfonyl]-4-methoxy-2,3-d-
ihydro-1H-indene-1-carboxamide; [0552]
N-(3-chloro-2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide; [0553]
N-(2,6-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide; [0554]
4,5-dimethoxy-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide; [0555]
N-(5-chloro-2-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide; [0556]
N-(2,5-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide; [0557]
N-(2-chloro-5-fluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide; [0558]
N-(2,6-dichlorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide; [0559]
N-(2,4-difluorobenzene-1-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carb-
oxamide; [0560]
4-methoxy-N-[1-(2-methoxyethyl)-1H-pyrazole-4-sulfonyl]-2,3-dihydro-1H-in-
dene-1-carboxamide; [0561]
N-(3,5-dimethyl-1,2-oxazole-4-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-
-carboxamide; [0562]
N-(2,4-dimethyl-1,3-thiazole-5-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene--
1-carboxamide; [0563]
4-methoxy-N-(pyridine-3-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0564]
2-[(4-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-N,N-dime-
thylpyridine-3-carboxamide; [0565]
N-(2-cyanopyridine-3-sulfonyl)-4-methoxy-2,3-dihydro-1H-indene-1-carboxam-
ide; [0566]
4-methoxy-N-(pyridine-2-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0567]
4-(6-methoxypyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0568]
N-(2-methylbenzene-1-sulfonyl)-4-[6-(piperidin-1-yl)pyridin-3-yl]-2,3-dih-
ydro-1H-indene-1-carboxamide; [0569]
N-(2-methylbenzene-1-sulfonyl)-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-
-2,3-dihydro-1H-indene-1-carboxamide; [0570]
N-(2-methylbenzene-1-sulfonyl)-4-(2-methylpyridin-3-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0571]
4-(6-fluoropyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0572]
4[6-(dimethylamino)pyridin-3-yl]-N-(2-methylbenzene-1-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0573]
4-(5-fluoropyridin-3-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0574]
N-(2-methylbenzene-1-sulfonyl)-4-(5-methylpyridin-3-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0575]
4-(2-fluoropyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0576]
4-(3-fluoropyridin-4-yl)-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0577]
N-(2-methylbenzene-1-sulfonyl)-4-(3-methylpyridin-4-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0578]
N-(2-methylbenzene-1-sulfonyl)-4-(2-methylpyridin-4-yl)-2,3-dihydro-1H-in-
dene-1-carboxamide; [0579]
N-(2-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-4-yl)-2,3-dihydro-1H-indene--
1-carboxamide; [0580]
N-(2-methylbenzene-1-sulfonyl)-4-(1H-pyrazol-5-yl)-2,3-dihydro-1H-indene--
1-carboxamide; [0581]
N-(2-methylbenzene-1-sulfonyl)-4-(thiophen-3-yl)-2,3-dihydro-1H-indene-1--
carboxamide; [0582]
N-(2-methylbenzene-1-sulfonyl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-2,3-dih-
ydro-1H-indene-1-carboxamide; [0583]
N-(2-methylbenzene-1-sulfonyl)-4-(3-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-
H-indene-1-carboxamide; [0584]
N-(2-methylbenzene-1-sulfonyl)-4-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydro-1-
H-indene-1-carboxamide; [0585]
N-(2-methylbenzene-1-sulfonyl)-4-(5-methylfuran-2-yl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0586]
N-(2-methylbenzene-1-sulfonyl)-4-(2-methylfuran-3-yl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0587]
N-(2-methylbenzene-1-sulfonyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-2,3-di-
hydro-1H-indene-1-carboxamide; [0588]
N-(2-methylbenzene-1-sulfonyl)-4-(1-methyl-1H-pyrazol-5-yl)-2,3-dihydro-1-
H-indene-1-carboxamide; [0589]
(1R)--N-(2-aminopyridine-3-sulfonyl)-5-methoxy-1,2,3,4-tetrahydronaphthal-
ene-1-carboxamide; [0590]
N-(6-aminopyridine-2-sulfonyl)-1,5-dimethyl-2,3-dihydro-1H-indene-1-carbo-
xamide; [0591]
(1R)--N-(6-aminopyridine-2-sulfonyl)-5-methoxy-1,2,3,4-tetrahydronaphthal-
ene-1-carboxamide; [0592]
N-(6-aminopyridine-2-sulfonyl)-8-chloro-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide; [0593]
4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihy-
dro-1H-indene-1-carboxamide; [0594]
4-chloro-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-N-(naphthalene-1-sulf-
onyl)-2,3-dihydro-1H-indene-1-carboxamide; [0595]
4-chloro-N-(2,4-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide; [0596]
4-chloro-N-(2,4-dimethylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide; [0597]
4-chloro-N-(2,6-difluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide; [0598]
4-chloro-N-(2,5-dichlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-
-1-carboxamide; [0599]
4-chloro-N-(3-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide; [0600]
4-chloro-N-(2-chloro-5-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0601]
4-chloro-1-ethyl-N-[4-(trifluoromethoxy)benzene-1-sulfonyl]-2,3-dihydro-1-
H-indene-1-carboxamide; [0602]
4-chloro-N-(2-cyanobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-ca-
rboxamide; [0603]
4-chloro-N-(2,6-dimethoxybenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-inden-
e-1-carboxamide; [0604]
4-chloro-1-ethyl-N-[2-(trifluoromethyl)benzene-1-sulfonyl]-2,3-dihydro-1H-
-indene-1-carboxamide; [0605]
4-chloro-N-(2,3-dihydro-1,4-benzodioxine-6-sulfonyl)-1-ethyl-2,3-dihydro--
1H-indene-1-carboxamide; [0606]
4-chloro-N-(2-chloro-6-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0607]
4-chloro-N-(4-chlorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide; [0608]
4-chloro-1-ethyl-N-[2-methyl-6-(trifluoromethyl)benzene-1-sulfonyl]-2,3-d-
ihydro-1H-indene-1-carboxamide; [0609]
4-chloro-N-(2-cyano-3-fluorobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-in-
dene-1-carboxamide; [0610]
4-chloro-1-ethyl-N-(1-methylcyclopropane-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0611]
N-([1,1'-biphenyl]-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide; [0612]
4-chloro-N-{4-[(dimethylamino)methyl]benzene-1-sulfonyl}-1-ethyl-2,3-dihy-
dro-1H-indene-1-carboxamide; [0613]
4-chloro-N-(5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl)-1-ethyl-2,3-dih-
ydro-1H-indene-1-carboxamide; [0614]
4-chloro-N-(2-chloropyridine-3-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1--
carboxamide; [0615]
4-chloro-1-ethyl-N-(quinoline-6-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide; [0616]
4-chloro-N-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)-1-ethyl-2,3-d-
ihydro-1H-indene-1-carboxamide; [0617]
2-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-N,N-dime-
thylpyridine-3-carboxamide; [0618]
4-chloro-N-(cyclohexanesulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-carboxam-
ide; [0619]
4-chloro-1-ethyl-N-{4-[4-(propan-2-yl)piperazin-1-yl]pyridine-3-sulfonyl}-
-2,3-dihydro-1H-indene-1-carboxamide; [0620]
4-chloro-1-ethyl-N-{2-[2-(piperidin-1-yl)ethoxy]benzene-1-sulfonyl}-2,3-d-
ihydro-1H-indene-1-carboxamide; [0621]
4-chloro-1-ethyl-N-(4-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide; [0622]
4-chloro-1-ethyl-N-(phenylmethanesulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide; [0623]
4-chloro-1-ethyl-N-(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindole-4-sulfony-
l)-2,3-dihydro-1H-indene-1-carboxamide; [0624]
4-chloro-1-ethyl-N-(4-methoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0625]
4-chloro-1-ethyl-N-(4-phenoxybenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; [0626]
4-chloro-N-(3-cyanobenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene-1-ca-
rboxamide; [0627]
4-chloro-1-ethyl-N-(1H-pyrazole-3-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide; [0628]
3-{4-chloro-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-inden-1--
yl}propanoic acid; [0629]
4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyridin-2-yl)methyl]-2,3-dihydro--
1H-indene-1-carboxamide; [0630]
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[3-(trifluoromethoxy)phenyl]-1,2,3-
,4-tetrahydronaphthalene-1-carboxamide; [0631] methyl
2-chloro-6-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-
benzoate; [0632]
4-chloro-1-ethyl-N-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide; [0633]
4-chloro-1-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0634]
4-bromo-7-hydroxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide; [0635]
5-methoxy-8-(morpholin-4-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide; [0636]
5-methoxy-N-(naphthalene-1-sulfonyl)-8-[4-(trifluoromethyl)phenyl]-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide; [0637]
4-chloro-1-(cyanomethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide; [0638]
4-chloro-N-(3-chloro-2-methylbenzene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-i-
ndene-1-carboxamide; [0639]
8-chloro-1-cyano-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide; [0640]
4-bromo-7-methoxy-N-(2-methoxypyridine-3-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide; [0641]
N-(2-aminopyridine-3-sulfonyl)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1--
carboxamide; [0642]
N-(6-aminopyridine-2-sulfonyl)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1--
carboxamide; [0643]
4-bromo-N-(4-ethoxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide; [0644]
4-bromo-7-methoxy-N-(4-methoxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide; [0645]
4-bromo-7-methoxy-N-([1,2,4]triazolo[4,3-a]pyridine-8-sulfonyl)-2,3-dihyd-
ro-1H-indene-1-carboxamide; [0646]
8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyrimidin-5-yl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide; [0647]
5-(6-cyclopropylpyridin-3-yl)-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,-
4-tetrahydronaphthalene-1-carboxamide; [0648]
8-methoxy-N-(naphthalene-1-sulfonyl)-5-(pyridin-4-yl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide; [0649]
8-methoxy-5-(6-methylpyridin-3-yl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tet-
rahydronaphthalene-1-carboxamide; [0650]
7-methoxy-4-(pyrimidin-5-yl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide;
[0651]
4-(3,6-dihydro-2H-pyran-4-yl)-7-methoxy-N-(quinoline-5-sulfonyl)-2-
,3-dihydro-1H-indene-1-carboxamide; [0652]
8-methoxy-5-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydr-
onaphthalene-1-carboxamide; [0653]
8-methoxy-N-(naphthalene-1-sulfonyl)-5-[6-(trifluoromethyl)pyridin-3-yl]--
1,2,3,4-tetrahydronaphthalene-1-carboxamide; [0654]
4-chloro-1-ethyl-N-[2-methyl-3-(morpholin-4-yl)benzene-1-sulfonyl]-2,3-di-
hydro-1H-indene-1-carboxamide; [0655]
4-chloro-1-ethyl-N-{3-[(2-methoxyethyl)(methyl)amino]-2-methylbenzene-1-s-
ulfonyl}-2,3-dihydro-1H-indene-1-carboxamide; [0656]
5-methoxy-N-(naphthalene-1-sulfonyl)-8-(pyrrolidin-1-yl)-1,2,3,4-tetrahyd-
ronaphthalene-1-carboxamide; [0657]
2,3-dimethoxy-N-(2-methylbenzene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trie-
ne-7-carboxamide; [0658]
N-(2-methylbenzene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-triene-7-carboxami-
de; [0659]
2,3-dimethoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,-
5-triene-7-carboxamide; [0660]
2-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-
-5-carboxamide; [0661]
2-chloro-6-[(4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]-
benzoic acid; [0662]
1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-
-7-carboxamide; [0663]
5-[(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonyl)sulfamoyl]naphthal-
ene-1-carboxylic acid; [0664]
7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide;
[0665]
7-methoxy-1-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-ind-
ene-4-carboxylic acid; [0666] methyl
7-methoxy-3-[(naphthalene-1-sulfonyl)carbamoyl]-2,3-dihydro-1H-indene-4-c-
arboxylate; [0667]
4-(hydroxymethyl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide; [0668]
7-methoxy-N.sup.4-methyl-N.sup.1-(naphthalene-1-sulfonyl)-2,3-dihydro-1H--
indene-1,4-dicarboxamide; [0669]
7-methoxy-N.sup.4,N.sup.4-dimethyl-N.sup.1-(naphthalene-1-sulfonyl)-2,3-d-
ihydro-1H-indene-1,4-dicarboxamide; and [0670]
7-methoxy-N-(naphthalene-1-sulfonyl)-4-[(pyrrolidin-1-yl)methyl]-2,3-dihy-
dro-1H-indene-1-carboxamide.
[0671] One embodiment pertains to
(1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; or a pharmaceutically acceptable salt thereof. Another
embodiment pertains to
(1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide; or a pharmaceutically acceptable salt thereof. Another
embodiment pertains to
(1S)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide; or a pharmaceutically acceptable salt thereof. Another
embodiment pertains to
(1R)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide; or a pharmaceutically acceptable salt thereof. Another
embodiment pertains to
(1S)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1-
H-indene-1-carboxamide; or a pharmaceutically acceptable salt
thereof. Another embodiment pertains to
(1R)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1-
H-indene-1-carboxamide; or a pharmaceutically acceptable salt
thereof.
[0672] One embodiment pertains to a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from the group consisting of Examples: I-1; I-2; I-3; I-4;
I-5; I-6; I-7; I-8; I-9; I-10; I-11; I-12; I-13; I-14; I-15; I-16;
I-17; I-18; I-19; I-20; I-21; I-22; I-23; I-24; I-26; I-27; I-28;
I-29; I-30; I-31; I-32; I-33; I-34; I-35; I-36; I-37; I-38; I-39;
I-40; I-41; I-42; I-43; I-44; I-45; I-46; I-47; I-48; I-49; I-50;
I-51; I-52; I-53; I-54; I-55; I-56; I-57; I-58; I-59; I-60; I-61;
I-62; I-63; I-64; I-65; I-66; I-67; I-68; I-69; I-70; I-71; I-72;
I-73; I-74; I-75; I-76; I-77; I-78; I-79; I-80; I-81; I-82; I-83;
I-84; I-85; I-86; I-87; I-88; I-89; I-90; I-91; I-92; I-93; I-94;
I-95; I-96; I-97; I-98; I-99; I-100; I-101; I-102; I-103; I-104;
I-105; I-106; I-107; I-108; I-109; I-110; I-111; I-112; I-113;
I-114; I-115; I-116; I-117; I-118; I-119; I-120; I-121; I-122;
I-123; I-124; I-125; I-126; I-127; I-128; I-129; I-130; I-131;
I-132; I-133; I-134; I-135; I-136; I-137; I-138; I-139; I-140;
I-141; I-142; I-143; I-144; I-145; I-146; I-147; I-148; I-149;
I-151; I-152; I-153; I-154; I-155; II-1; II-2; II-3; II-4; II-5;
II-6; II-8; II-9; II-10; II-12; II-13; II-15; II-16; II-18; II-19;
II-20; II-21; II-22; II-23; II-24; II-25; II-26; II-27; II-28;
II-29; II-30; II-31; II-32; II-33; II-34; II-35; II-36; II-37;
II-38; II-39; II-40; II-41; II-42; II-43; II-44; II-45; II-46;
II-47; II-48; II-49; II-50; II-52; II-53; II-54; II-55; II-56;
II-57; II-58; II-59; II-60; II-61; II-62; II-63; II-64; II-65;
II-66; II-67; II-69; II-70; II-71; II-72; II-73; II-74; II-75;
II-76; II-77; II-78; II-79; II-80; II-81; II-82; II-83; II-84;
II-85; II-86; II-87; II-88; II-89; II-90; II-91; II-92; II-93;
II-94; II-95; II-96; II-97; II-98; II-99; II-100; II-101; II-102;
II-103; II-104; II-105; II-106; II-107; II-108; II-109; II-110;
II-111; II-112; II-113; II-114; II-115; II-116; II-117; II-118;
II-119; II-120; II-121; II-122; II-123; II-124; II-125; II-126;
II-127; II-128; II-129; II-130; II-131; II-132; II-133; II-134;
II-135; II-136; III-3; III-4; III-5; III-6; III-7; III-9; III-11;
III-12; III-13; III-14; III-15; III-16; III-17; III-18; III-19;
III-20; III-21; III-22; III-23; III-24; III-25; III-26; III-27;
III-28; III-29; III-30; III-31; III-32; III-33; III-34; III-35;
III-36; III-37; III-38; III-39; III-40; III-41; III-42; III-43;
III-44; III-45; III-46; III-47; III-48; III-49; III-50; III-51;
III-52; III-53; III-54; III-55; III-56; III-57; III-58; III-59;
III-60; III-61; III-62; III-63; III-64; III-65; III-66; III-67;
III-68; III-69; III-70; III-71; III-72; III-73; III-74; III-75;
III-76; III-77; III-78; III-79; III-80; III-81; III-82; III-83;
III-84; III-85; III-86; III-87; III-88; III-89; III-90; III-91;
III-92; III-93; III-94; III-95; III-96; III-97; III-98; III-99;
III-100; III-101; III-102; III-103; III-104; III-105; III-106;
III-107; III-108; III-109; III-110; III-111; III-112; III-113;
III-114; III-115; III-116; III-117; III-118; III-119; III-120;
III-121; III-122; III-123; III-124; III-125; III-126; III-127;
III-128; III-129; III-130; III-131; III-132; III-133; III-134;
III-135; III-136; III-137; III-138; III-139; III-140; III-141;
III-142; III-143; III-144; III-145; III-146; III-147; III-148;
III-149; III-150; III-151; III-152; III-153; III-154; III-155;
III-156; III-157; III-158; III-159; III-160; III-161; III-162;
III-163; III-164; III-165; III-166; III-167; III-168; III-169;
III-170; III-171; III-172; III-173; III-174; III-175; III-177;
III-178; III-179; III-180; III-181; III-182; III-183; III-184;
III-185; III-186; III-187; and III-188.
Formula (II)
[0673] One embodiment pertains to compounds of Formula (II), or a
pharmaceutically acceptable salt thereof,
##STR00020##
wherein [0674] R.sup.1 is selected from the group consisting of
hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein the R.sup.1 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.7, OR.sup.7, SR.sup.7,
NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2, C(O)OH, OH, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.1 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; [0675] one of
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the
remaining are independently selected from the group consisting of
hydrogen, R.sup.8, OR.sup.8, C(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN,
NO.sub.2, F, Cl, Br and I; or [0676] two of R.sup.2A, R.sup.2B,
R.sup.2C, and R.sup.2D on adjacent carbons form a fused ring
selected from the group consisting of phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN,
NO.sub.2, F, Cl, Br and I; wherein the phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and
I; [0677] R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl are
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy,
phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.3
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; [0678] R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0679] R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D are
each independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A,
R.sup.5B, R.sup.5C, and R.sup.5D C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, 4-12 membered
heterocyclyl, C.sub.1-C.sub.6 thioalkyl, OH, oxo, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.5A, R.sup.5B, R.sup.5C, and
R.sup.5D 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0680] R.sup.5A and R.sup.5B, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; and [0681] R.sup.5C and R.sup.5D are
each independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5C
and R.sup.5D C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5C and R.sup.5D 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0682] R.sup.5A and R.sup.5B are each
independently selected from the group consisting of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A
and R.sup.5B C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A and R.sup.5B 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; and [0683] R.sup.5C and R.sup.5D, together with
the carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; [0684] R.sup.6A and R.sup.6B are each
independently hydrogen; [0685] R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkoxy, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, oxo, OH, CN,
NO.sub.2, F, Cl, Br and I; [0686] R.sup.8, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.8 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.11, OR.sup.11,
C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0687] R.sup.9, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.13, OR.sup.13, SR.sup.13, C(O)R.sup.13,
NHR.sup.13, N(R.sup.13).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br
and I; wherein each R.sup.9 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, OR.sup.14, C(O)R.sup.14,
OC(O)R.sup.14, C(O)OR.sup.14, SO.sub.2R.sup.14, NHR.sup.14,
N(R.sup.14).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0688] R.sup.10, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally
substituted with one or more substituents independently selected
from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and
I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br
and I;
[0689] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11
cycloalkyl, 4-12 membered heterocyclyl, C.sub.4-C.sub.11
cycloalkenyl, and 5-6 membered heteroaryl; wherein each R.sup.11
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy is optionally
substituted with one or more substituents independently selected
from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and
I; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I; [0690] R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I;
[0691] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.13 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each
R.sup.13 C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered
heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; and [0692]
R.sup.14, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.14
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12
membered heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I;
[0693] with the proviso that R.sup.3 is not methyl; [0694] with the
proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are
each hydrogen, R.sup.1 is not hydrogen; [0695] with the proviso
that, when R.sup.3 is naphthyl, R.sup.2C is not
4-(1-methylethyl)phenoxy; and [0696] with the proviso that, when
R.sup.1 is C.sub.1-alkyl, R.sup.3 is not 3-pyridinyl or
4-cyanobenzyl.
[0697] In one embodiment of Formula (II), R.sup.1 is selected from
the group consisting of hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.1 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, SR.sup.7, NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.1 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C(O)OH, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I. In another embodiment of Formula (II), R.sup.1 is
selected from the group consisting of hydrogen, CN, and
C.sub.1-C.sub.6 alkyl; wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, C(O)OH, OH, and CN. In another embodiment of
Formula (II), R.sup.1 is hydrogen. In another embodiment of Formula
(II), R.sup.1 is CN. In another embodiment of Formula (II), R.sup.1
is C.sub.1-C.sub.6 alkyl; which is unsubstituted. In another
embodiment of Formula (II), R.sup.1 is C.sub.1-C.sub.6 alkyl;
wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is optionally substituted
with one or more substituents independently selected from the group
consisting of R.sup.7, OR.sup.7, N(R.sup.7).sub.2, C(O)OH, OH, and
CN.
[0698] In one embodiment of Formula (II), one of R.sup.2A,
R.sup.2B, R.sup.2C and R.sup.2D is hydrogen, and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8,
NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I;
with the proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D a are each hydrogen, R.sup.1 is not hydrogen. In another
embodiment of Formula (II), one of R.sup.2A, R.sup.2B, R.sup.2C,
and R.sup.2D a is hydrogen, and the remaining are independently
selected from the group consisting of hydrogen, R.sup.8, OR.sup.8,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br;
with the proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are each hydrogen, R.sup.1 is not hydrogen. In another
embodiment of Formula (II), R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D a are hydrogen; with the proviso that, R.sup.1 is not
hydrogen.
[0699] In one embodiment of Formula (II), two of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D on adjacent carbons form a fused
ring selected from the group consisting of phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F,
Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7
membered heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I. In another embodiment of Formula
(II), R.sup.2C and R.sup.2D form a 4-7 membered heterocyclyl; and
R.sup.2A and R.sup.2B are independently hydrogen.
[0700] In one embodiment of Formula (II), R.sup.3 is selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.3
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkoxy, phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.3 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (II), R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy and
phenyl; wherein the R.sup.3 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br.
In another embodiment of Formula (II), R.sup.3 is C.sub.1-C.sub.6
alkyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkoxy and phenyl. In
another embodiment of Formula (II), R.sup.3 is 6-10 membered aryl;
wherein the R.sup.3 6-10 membered aryl is optionally substituted
with one or more substituents independently selected from the group
consisting of R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, and Br. In another embodiment of Formula (II),
R.sup.3 is 5-11 membered heteroaryl; wherein the R.sup.3 5-11
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br.
In another embodiment of Formula (II), R.sup.3 is C.sub.3-C.sub.11
cycloalkyl; wherein the R.sup.3 C.sub.3-C.sub.11 cycloalkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.9, OR.sup.9,
C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2,
NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br. In another
embodiment of Formula (II), R.sup.3 is 4-12 membered heterocyclyl;
wherein the R.sup.3 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)R.sup.9,
C(O)OR.sup.9, SO.sub.2R.sup.9, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, and Br.
[0701] In one embodiment of Formula (II), R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I. In another embodiment of Formula (II), R.sup.4 is
hydrogen. In another embodiment of Formula (II), R.sup.4 is
C.sub.1-C.sub.6 alkyl; wherein the R.sup.4 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more R.sup.10.
[0702] In one embodiment of Formula (II), R.sup.5A, R.sup.5B,
R.sup.5C, and R.sup.5D are each independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.5A, R.sup.5B,
R.sup.5C, and R.sup.5D C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are
optionally substituted with one or more substituents independently
selected from the group consisting of 6-10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D 6-10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C(O)OH,
NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; or R.sup.5A and
R.sup.5B, together with the carbon atom to which they are attached,
form a C.sub.3-C.sub.7 monocyclic cycloalkyl or a 4-7 membered
monocyclic heterocycle; wherein the C.sub.3-C.sub.7 monocyclic
cycloalkyl and the 4-7 membered monocyclic heterocycle are each
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; and
R.sup.5C and R.sup.5D are each independently selected from the
group consisting of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.5C and R.sup.5D
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally substituted with
one or more substituents independently selected from the group
consisting of 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, 4-12
membered heterocyclyl, C.sub.1-C.sub.6 thioalkyl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; wherein the R.sup.5C and R.sup.5D 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2, F,
Cl, Br and I; or R.sup.5A and R.sup.5B are each independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A
and R.sup.5B C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A and R.sup.5B 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; and R.sup.5C and R.sup.5D, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (II),
R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D are each independently
hydrogen. In another embodiment of Formula (II), R.sup.5A,
R.sup.5B, R.sup.5C, and R.sup.5D are each independently
C.sub.1-C.sub.6 alkyl.
[0703] In one embodiment of Formula (II), R.sup.6A and R.sup.6B are
each independently hydrogen.
[0704] In one embodiment of Formula (II), R.sup.7, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I. In another
embodiment of Formula (II), R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.7 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more C.sub.1-C.sub.6 alkoxy; wherein each
R.sup.7 5-11 membered heteroaryl and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, F, and Cl.
[0705] In one embodiment of Formula (II), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.8 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.11, OR.sup.11,
C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I. In another embodiment of Formula (II), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl and C.sub.2-C.sub.6 alkenyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, C(O)OR.sup.11,
OH, and F; wherein each R.sup.8 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
N(R.sup.12).sub.2, and F.
[0706] In one embodiment of Formula (II), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.9 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.13, OR.sup.13,
SR.sup.13, C(O)R.sup.13, NHR.sup.13, N(R.sup.13).sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.9 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl are
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.14, OR.sup.14,
C(O)R.sup.14, OC(O)R.sup.14, C(O)OR.sup.14, SO.sub.2R.sup.14,
NHR.sup.14, N(R.sup.14).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (II),
R.sup.9, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, 6-10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.13, OR.sup.13, C(O)R.sup.13,
N(R.sup.13).sub.2, OH, F, and Cl; wherein each R.sup.9 6-10
membered aryl and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, oxo, and F.
[0707] In one embodiment of Formula (II), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (II),
R.sup.10, at each occurrence, is independently C.sub.6-C.sub.10
membered aryl; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6
alkoxy.
[0708] In one embodiment of Formula (II), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.11 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.11
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I. In
another embodiment of Formula (II), R.sup.11, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl is optionally
substituted with one or more C.sub.1-C.sub.6 alkoxy.
[0709] In one embodiment of Formula (II), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I. In
another embodiment of Formula (II), R.sup.12, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.12 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more F; wherein each 4-12 membered
heterocyclyl is optionally substituted with one or more
C.sub.1-C.sub.6 alkyl.
[0710] In one embodiment of Formula (II), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.13 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another R.sup.13, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl, and 4-12
membered heterocyclyl; wherein each R.sup.13 C.sub.6-C.sub.10
membered aryl and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, and Cl.
[0711] In one embodiment of Formula (II), R.sup.14, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.14 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12 membered
heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I. In another
embodiment of Formula (II), R.sup.14, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl; wherein each R.sup.14
C.sub.1-C.sub.6 alkyl is optionally substituted with one or more
independently selected 4-12 membered heterocyclyl.
[0712] One embodiment pertains to compounds of Formula (II), or a
pharmaceutically acceptable salt thereof, wherein [0713] R.sup.1 is
selected from the group consisting of hydrogen, CN, and
C.sub.1-C.sub.6 alkyl; wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, C(O)OH, OH, and CN; [0714] one of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)OR.sup.8, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br; or [0715] two
of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D on adjacent carbons
form a 4-7 membered heterocyclyl; and the remaining are hydrogen;
[0716] R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy and
phenyl; wherein the R.sup.3 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br;
[0717] R.sup.4 is selected from the group consisting of hydrogen
and C.sub.1-C.sub.6 alkyl; wherein the R.sup.4 C.sub.1-C.sub.6
alkyl is optionally substituted with one or more R.sup.10; [0718]
R.sup.5A, R.sup.5B, R.sup.5C, and R.sup.5D are each independently
selected from the group consisting of hydrogen and C.sub.1-C.sub.6
alkyl; [0719] R.sup.6A, R.sup.6B, R.sup.6C, and R.sup.6D are each
independently hydrogen; [0720] R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.7 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more C.sub.1-C.sub.6 alkoxy; wherein each
R.sup.7 5-11 membered heteroaryl and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, F, and Cl; [0721] R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl and C.sub.2-C.sub.6 alkenyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, C(O)OR.sup.11,
OH, and F; wherein each R.sup.8 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
N(R.sup.12).sub.2 and F; [0722] R.sup.9, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, 6-10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12
membered heterocyclyl; wherein each R.sup.9 C.sub.1-C.sub.6 alkyl
is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, C(O)R.sup.13, N(R.sup.13).sub.2, OH, F, and Cl; wherein
each R.sup.9 6-10 membered aryl and 4-12 membered heterocyclyl are
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.14, oxo, and F; [0723]
R.sup.10, at each occurrence, is independently C.sub.6-C.sub.10
membered aryl; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
[0724] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
[0725] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more F; wherein each 4-12
membered heterocyclyl is optionally substituted with one or more
C.sub.1-C.sub.6 alkyl; [0726] R.sup.13, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10 membered aryl and 4-12 membered
heterocyclyl; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl
and 4-12 membered heterocyclyl is optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl and Cl; and [0727] R.sup.14, at
each occurrence, is independently C.sub.1-C.sub.6 alkyl; wherein
each R.sup.14 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more 4-12 membered heterocyclyl; [0728] with the proviso
that R.sup.3 is not methyl; [0729] with the proviso that, when
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are each hydrogen,
R.sup.1 is not hydrogen; [0730] with the proviso that, when R.sup.3
is naphthyl, R.sup.2C is not 4-(1-methylethyl)phenoxy; and [0731]
with the proviso that, when R.sup.1 is C.sub.1-alkyl, R.sup.3 is
not 3-pyridinyl or 4-cyanobenzyl.
[0732] One embodiment pertains to a compound of Formula (II), or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from the group consisting of Examples: I-2; I-3; I-4; I-9;
I-10; I-11; I-12; I-15; I-24; I-32; I-33; I-34; I-40; I-41; I-45;
I-48; I-49; I-50; I-56; I-57; I-60; I-61; I-62; I-63; I-64; I-65;
I-67; I-68; I-69; I-70; I-73; I-82; I-88; II-8; II-9; II-10; II-12;
II-13; II-15; II-43; II-50; II-51; II-52; II-53; II-84; II-85;
II-86; II-87; II-88; II-89; II-90; II-91; II-92; II-93; II-94;
II-95; II-96; II-97; II-98; II-99; II-109; II-111; II-115; II-119;
II-120; II-121; II-122; II-124; II-128; II-129; II-130; II-131;
II-136; III-107; III-109; III-110; III-148; III-153; III-154;
III-157; III-164; III-165; III-166; III-167; III-170; III-171; and
III-174.
Formula (III)
[0733] One embodiment pertains to compounds of Formula (III), or a
pharmaceutically acceptable salt thereof,
##STR00021##
wherein [0734] R.sup.1 is selected from the group consisting of
hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein the R.sup.1 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.7, OR.sup.7, SR.sup.7,
NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2, C(O)OH, OH, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.1 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; [0735] one of
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the
remaining are independently selected from the group consisting of
hydrogen, R.sup.8, OR.sup.8, C(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN,
NO.sub.2, F, Cl, Br and I; or [0736] two of R.sup.2A, R.sup.2B,
R.sup.2C, an R.sup.2D on adjacent carbons form a fused ring
selected from the group consisting of phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN,
NO.sub.2, F, Cl, Br and I; wherein the phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and
I; [0737] R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl are
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy,
phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.3
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; [0738] R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0739] R.sup.5A and R.sup.5B are each independently
selected from the group consisting of hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.5A
and R.sup.5B C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, 4-12 membered heterocyclyl, C.sub.1-C.sub.6
thioalkyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.5A and R.sup.5B 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I; or [0740] R.sup.5A and R.sup.5B, together with the
carbon atom to which they are attached, form a C.sub.3-C.sub.7
monocyclic cycloalkyl or a 4-7 membered monocyclic heterocycle;
wherein the C.sub.3-C.sub.7 monocyclic cycloalkyl and the 4-7
membered monocyclic heterocycle are each optionally substituted
with one or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C(O)OH, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I; [0741] R.sup.6A and R.sup.6B are each
independently hydrogen; [0742] R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, cycloalkenyl, and 4-12 membered heterocyclyl; wherein
each R.sup.7 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and
C.sub.2-C.sub.6 alkynyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkoxy, OH, oxo, CN, NO.sub.2, F, Cl, Br and I;
wherein each R.sup.7 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I; [0743] R.sup.8,
at each occurrence, is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0744] R.sup.9, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.13, OR.sup.13, SR.sup.13, C(O)R.sup.13,
NHR.sup.13, N(R.sup.13).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br
and I; wherein each R.sup.9 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, OR.sup.14, C(O)R.sup.14,
OC(O)R.sup.14, C(O)OR.sup.14, SO.sub.2R.sup.14, NHR.sup.14,
N(R.sup.14).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0745] R.sup.10, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally
substituted with one or more substituents independently selected
from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and
I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, 5-6 membered heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br
and I; [0746] R.sup.11, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl; wherein
each R.sup.11 C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I; [0747] R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I;
[0748] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.13 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each
R.sup.13 C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered
heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; and [0749]
R.sup.14, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.14
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12
membered heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I;
[0750] with the proviso that R.sup.3 is not methyl; [0751] with the
proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are
each hydrogen, R.sup.1 is not hydrogen; [0752] with the proviso
that, when R.sup.3 is naphthyl, R.sup.2C is not
4-(1-methylethyl)phenoxy; and [0753] with the proviso that, when
R.sup.1 is C.sub.1-alkyl, R.sup.3 is not 3-pyridinyl or
4-cyanobenzyl.
[0754] In one embodiment of Formula (III), R.sup.1 is selected from
the group consisting of hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.1 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, SR.sup.7, NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.1 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C(O)OH, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I. In another embodiment of Formula (III), R.sup.1 is
selected from the group consisting of hydrogen, CN, and
C.sub.1-C.sub.6 alkyl; wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, C(O)OH, OH, and CN. In another embodiment of
Formula (III), R.sup.1 is hydrogen. In another embodiment of
Formula (III), R.sup.1 is CN. In another embodiment of Formula
(III), R.sup.1 is C.sub.1-C.sub.6 alkyl; which is unsubstituted. In
another embodiment of Formula (III), R.sup.1 is C.sub.1-C.sub.6
alkyl; wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.7, OR.sup.7, N(R.sup.7).sub.2,
C(O)OH, OH, and CN.
[0755] In one embodiment of Formula (III), one of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8,
NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I;
with the proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are each hydrogen, R.sup.1 is not hydrogen. In another
embodiment of Formula (III), one of R.sup.2A, R.sup.2B, R.sup.2C,
and R.sup.2D is hydrogen, and the remaining are independently
selected from the group consisting of hydrogen, R.sup.8, OR.sup.8,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br;
with the proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are each hydrogen, R.sup.1 is not hydrogen. In another
embodiment of Formula (III), R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are hydrogen; with the proviso that, R.sup.1 is not
hydrogen.
[0756] In one embodiment of Formula (III), two of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D on adjacent carbons form a fused
ring selected from the group consisting of phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F,
Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7
membered heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I. In another embodiment of Formula
(III), R.sup.2C and R.sup.2D form a 4-7 membered heterocyclyl; and
R.sup.2A and R.sup.2B are independently hydrogen.
[0757] In one embodiment of Formula (III), R.sup.3 is selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.3
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkoxy, phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.3 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (III), R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy and
phenyl; wherein the R.sup.3 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br.
In another embodiment of Formula (III), R.sup.3 is C.sub.1-C.sub.6
alkyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkoxy and phenyl. In
another embodiment of Formula (III), R.sup.3 is 6-10 membered aryl;
wherein the R.sup.3 6-10 membered aryl is optionally substituted
with one or more substituents independently selected from the group
consisting of R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, and Br. In another embodiment of Formula (III),
R.sup.3 is 5-11 membered heteroaryl; wherein the R.sup.3 5-11
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br.
In another embodiment of Formula (III), R.sup.3 is C.sub.3-C.sub.11
cycloalkyl; wherein the R.sup.3 C.sub.3-C.sub.11 cycloalkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.9, OR.sup.9,
C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2,
NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br. In another
embodiment of Formula (III), R.sup.3 is 4-12 membered heterocyclyl;
wherein the R.sup.3 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)R.sup.9,
C(O)OR.sup.9, SO.sub.2R.sup.9, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, and Br.
[0758] In one embodiment of Formula (III), R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I. In another embodiment of Formula (III), R.sup.4 is
hydrogen. In another embodiment of Formula (III), R.sup.4 is
C.sub.1-C.sub.6 alkyl; wherein the R.sup.4 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more R.sup.10.
[0759] In one embodiment of Formula (III), R.sup.5A and R.sup.5B
are each independently selected from the group consisting of
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein the R.sup.5A and R.sup.5B C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, 4-12 membered
heterocyclyl, C.sub.1-C.sub.6 thioalkyl, OH, oxo, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.5A and R.sup.5B 6-10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl are
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; or
R.sup.5A and R.sup.5B, together with the carbon atom to which they
are attached, form a C.sub.3-C.sub.7 monocyclic cycloalkyl or a 4-7
membered monocyclic heterocycle; wherein the C.sub.3-C.sub.7
monocyclic cycloalkyl and the 4-7 membered monocyclic heterocycle
are each optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C(O)OH, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, Br and I. In
another embodiment of Formula (III), R.sup.5A and R.sup.5B are each
independently hydrogen.
[0760] In one embodiment of Formula (III), R.sup.6A and R.sup.6B
are each independently hydrogen.
[0761] In one embodiment of Formula (III), R.sup.7, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I. In another
embodiment of Formula (III), R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.7 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more C.sub.1-C.sub.6 alkoxy; wherein each
R.sup.7 5-11 membered heteroaryl and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, F, and Cl.
[0762] In one embodiment of Formula (III), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.8 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.11, OR.sup.11,
C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I. In another embodiment of Formula (III), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl and C.sub.2-C.sub.6 alkenyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, C(O)OR.sup.11,
OH, and F; wherein each R.sup.8 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
N(R.sup.12).sub.2, and F.
[0763] In one embodiment of Formula (III), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.9 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.13, OR.sup.13,
SR.sup.13, C(O)R.sup.13, NHR.sup.13, N(R.sup.13).sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.9 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl are
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.14, OR.sup.14,
C(O)R.sup.14, OC(O)R.sup.14, C(O)OR.sup.14, SO.sub.2R.sup.14,
NHR.sup.14, N(R.sup.14).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (III),
R.sup.9, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, 6-10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.13, OR.sup.13, C(O)R.sup.13,
N(R.sup.13).sub.2, OH, F, and Cl; wherein each R.sup.9 6-10
membered aryl and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, oxo, and F.
[0764] In one embodiment of Formula (III), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (III),
R.sup.10, at each occurrence, is independently C.sub.6-C.sub.10
membered aryl; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6
alkoxy.
[0765] In one embodiment of Formula (III), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.11 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.11
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I. In
another embodiment of Formula (III), R.sup.11, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl, is optionally
substituted with one or more C.sub.1-C.sub.6 alkoxy.
[0766] In one embodiment of Formula (III), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I. In
another embodiment of Formula (III), R.sup.12, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.12 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more F; wherein each 4-12 membered
heterocyclyl is optionally substituted with one or more
C.sub.1-C.sub.6 alkyl.
[0767] In one embodiment of Formula (III), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.13 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another R.sup.13, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl, and 4-12
membered heterocyclyl; wherein each R.sup.13 C.sub.6-C.sub.10
membered aryl and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, and Cl.
[0768] In one embodiment of Formula (III), R.sup.14, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.14 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12 membered
heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I. In another
embodiment of Formula (III), R.sup.14, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl; wherein each R.sup.14
C.sub.1-C.sub.6 alkyl is optionally substituted with one or more
independently selected 4-12 membered heterocyclyl.
[0769] One embodiment pertains to compounds of Formula (III), or a
pharmaceutically acceptable salt thereof, wherein [0770] R.sup.1 is
selected from the group consisting of hydrogen, CN, and
C.sub.1-C.sub.6 alkyl; wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, C(O)OH, OH, and CN; [0771] one of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)OR.sup.8, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br; or [0772] two
of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D on adjacent carbons
form a 4-7 membered heterocyclyl; and the remaining are hydrogen;
[0773] R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy and
phenyl; wherein the R.sup.3 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br;
[0774] R.sup.4 is selected from the group consisting of hydrogen
and C.sub.1-C.sub.6 alkyl; wherein the R.sup.4 C.sub.1-C.sub.6
alkyl is optionally substituted with one or more R.sup.10; [0775]
R.sup.5A and R.sup.5B are each independently selected from the
group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; [0776]
R.sup.6A and R.sup.6B are each independently hydrogen; [0777]
R.sup.7, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
wherein each R.sup.7 5-11 membered heteroaryl and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, F, and Cl;
[0778] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.8 C.sub.1-C.sub.6 alkyl and C.sub.2-C.sub.6
alkenyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, C(O)OR.sup.11, OH, and F; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl and 4-12
membered heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.12, OR.sup.12, N(R.sup.12).sub.2 and F; [0779] R.sup.9, at
each occurrence, is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, 6-10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.13, OR.sup.13, C(O)R.sup.13,
N(R.sup.13).sub.2, OH, F, and Cl; wherein each R.sup.9 6-10
membered aryl and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, oxo, and F; [0780] R.sup.10,
at each occurrence, is independently C.sub.6-C.sub.10 membered
aryl; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl is
optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
[0781] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
[0782] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more F; wherein each 4-12
membered heterocyclyl is optionally substituted with one or more
C.sub.1-C.sub.6 alkyl; [0783] R.sup.13, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10 membered aryl and 4-12 membered
heterocyclyl; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl
and 4-12 membered heterocyclyl is optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl and Cl; and [0784] R.sup.14, at
each occurrence, is independently C.sub.1-C.sub.6 alkyl; wherein
each R.sup.14 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more 4-12 membered heterocyclyl; [0785] with the proviso
that R.sup.3 is not methyl; [0786] with the proviso that, when
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are each hydrogen,
R.sup.1 is not hydrogen; [0787] with the proviso that, when R.sup.3
is naphthyl, R.sup.2C is not 4-(1-methylethyl)phenoxy; and [0788]
with the proviso that, when R.sup.1 is C.sub.1-alkyl, R.sup.3 is
not 3-pyridinyl or 4-cyanobenzyl.
[0789] One embodiment pertains to a compound of Formula (III), or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from the group consisting of Examples: I-1; I-5; I-6; I-7;
I-8; I-13; I-14; I-16; I-17; I-18; I-19; I-20; I-21; I-22; I-23;
I-26; I-27; I-28; I-29; I-30; I-31; I-35; I-36; I-37; I-38; I-39;
I-42; I-43; I-44; I-46; I-47; I-51; I-52; I-53; I-54; I-55; I-58;
I-59; I-66; I-71; I-72; I-74; I-75; I-76; I-77; I-78; I-80; I-81;
I-83; I-84; I-85; I-86; I-87; I-89; I-90; I-91; I-92; I-93; I-94;
I-95; I-96; I-97; I-98; I-99; I-100; I-101; I-103; I-104; I-105;
I-108; I-109; I-117; I-118; I-119; I-122; I-123; I-124; I-125;
I-126; I-127; I-128; I-129; I-130; I-131; I-133; I-135; I-138;
I-139; I-140; I-141; I-142; I-149; I-151; I-152; I-153; I-154;
II-2; II-3; II-4; II-5; II-6; II-18; II-19; II-20; II-21; II-22;
II-23; II-24; II-26; II-27; II-28; II-29; II-30; II-31; II-32;
II-33; II-34; II-35; II-36; II-37; II-38; II-39; II-40; II-41;
II-42; II-44; II-45; II-46; II-47; II-49; II-54; II-55; II-56;
II-57; II-58; II-59; II-60; II-61; II-62; II-63; II-64; II-65;
II-66; II-67; II-69; II-70; II-71; II-72; II-73; II-74; II-75;
II-76; II-77; II-78; II-79; II-80; II-81; II-82; II-83; II-100;
II-101; II-102; II-103; II-104; II-105; II-106; II-107; II-108;
II-110; II-112; II-113; II-116; II-117; II-123; II-125; II-126;
II-127; II-132; II-133; II-134; II-135; III-3; III-4; III-5; III-6;
III-9; III-11; III-12; III-13; III-14; III-15; III-16; III-17;
III-18; III-19; III-20; III-21; III-22; III-23; III-24; III-25;
III-26; III-27; III-28; III-29; III-30; III-31; III-32; III-33;
III-34; III-35; III-36; III-37; III-38; III-39; III-40; III-41;
III-42; III-43; III-44; III-45; III-46; III-47; III-48; III-49;
III-50; III-51; III-52, III-53; III-54; III-55; III-56; III-57;
III-58; III-59; III-60; III-61; III-62; III-63; III-64; III-65;
III-66; III-67; III-68; III-69; III-70; III-71; III-72; III-73;
III-74; III-75; III-76; III-77; III-78; III-79; III-80; III-81;
III-82; III-83; III-84; III-85; III-86; III-87; III-88; III-89;
III-90; III-91; III-92; III-93; III-94; III-95; III-96; III-97;
III-98; III-99; III-100; III-101; III-102; III-103; III-104;
III-105; III-106; III-108; III-111; III-112; III-113; III-114;
III-115; III-116; III-117; III-118; III-119; III-120 III-121;
III-122; III-123; III-124; III-125; III-126; III-127; III-128;
III-129; III-130; III-131; III-132; III-33; III-134; III-135;
III-136; III-137; III-138; III-139; III-140; III-141; III-142;
III-143; III-144; III-145; III-146; III-147; III-149; III-150;
III-151; III-152; III-155; III-156; III-158; III-159; III-160;
III-161; III-162; III-163; III-168; III-169; III-172; III-173;
III-179; III-181; III-182; III-183; III-184; III-185; III-186;
III-187; and III-188.
Formula (IV)
[0790] One embodiment pertains to compounds of Formula (IV), or a
pharmaceutically acceptable salt thereof,
##STR00022##
wherein [0791] R.sup.1 is selected from the group consisting of
hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein the R.sup.1 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, and C.sub.1-C.sub.6 alkoxy are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.7, OR.sup.7, SR.sup.7,
NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2, C(O)OH, OH, CN, NO.sub.2, F,
Cl, Br and I; wherein the R.sup.1 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; [0792] one of
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the
remaining are independently selected from the group consisting of
hydrogen, R.sup.8, OR.sup.8, C(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN,
NO.sub.2, F, Cl, Br and I; or [0793] two of R.sup.2A, R.sup.2B,
R.sup.2C, an R.sup.2D on adjacent carbons form a fused ring
selected from the group consisting of phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NH.sub.2, C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN,
NO.sub.2, F, Cl, Br and I; wherein the phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.8, OR.sup.8, C(O)R.sup.8,
OC(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8, NHR.sup.8,
N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and
I; [0794] R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl are
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy,
phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.3
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; [0795] R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0796] R.sup.6A and R.sup.6B are each independently
hydrogen; [0797] R.sup.7, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.7
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkoxy, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each
R.sup.7 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I; [0798] R.sup.8,
at each occurrence, is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; [0799] R.sup.9, at each occurrence, is independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.9
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.13,
OR.sup.13, SR.sup.13, C(O)R.sup.13, NHR.sup.13, N(R.sup.13).sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.9
6-10 membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.14, OR.sup.14, C(O)R.sup.14, OC(O)R.sup.14, C(O)OR.sup.14,
SO.sub.2R.sup.14, NHR.sup.14, N(R.sup.14).sub.2, NH.sub.2, C(O)OH,
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; [0800] R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I;
[0801] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11
cycloalkyl, 4-12 membered heterocyclyl, C.sub.4-C.sub.11
cycloalkenyl, and 5-6 membered heteroaryl; wherein each R.sup.11
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 alkoxy is optionally
substituted with one or more substituents independently selected
from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and
I; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, 4-12 membered heterocyclyl,
C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered heteroaryl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I; [0802] R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I;
[0803] R.sup.13, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl;
wherein each R.sup.13 C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 alkynyl is optionally substituted with
one or more substituents independently selected from the group
consisting of OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each
R.sup.13 C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered
heteroaryl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; and [0804]
R.sup.14, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein each R.sup.14
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl is optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12
membered heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I;
[0805] with the proviso that R.sup.3 is not methyl; [0806] with the
proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are
each hydrogen, R.sup.1 is not hydrogen; [0807] with the proviso
that, when R.sup.3 is naphthyl, R.sup.2C is not
4-(1-methylethyl)phenoxy; and [0808] with the proviso that, when
R.sup.1 is C.sub.1-alkyl, R.sup.3 is not 3-pyridinyl or
4-cyanobenzyl.
[0809] In one embodiment of Formula (IV), R.sup.1 is selected from
the group consisting of hydrogen, OH, CN, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6
alkoxy, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein the R.sup.1 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, and
C.sub.1-C.sub.6 alkoxy are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.7, OR.sup.7, SR.sup.7, NHR.sup.7, N(R.sup.7).sub.2, NH.sub.2,
C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I; wherein the R.sup.1 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
alkoxy, C.sub.1-C.sub.6 haloalkoxy, C(O)OH, OH, oxo, CN, NO.sub.2,
F, Cl, Br and I. In another embodiment of Formula (IV), R.sup.1 is
selected from the group consisting of hydrogen, CN, and
C.sub.1-C.sub.6 alkyl; wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, C(O)OH, OH, and CN. In another embodiment of
Formula (IV), R.sup.1 is hydrogen. In another embodiment of Formula
(IV), R.sup.1 is CN. In another embodiment of Formula (IV), R.sup.1
is C.sub.1-C.sub.6 alkyl; which is unsubstituted. In another
embodiment of Formula (IV), R.sup.1 is C.sub.1-C.sub.6 alkyl;
wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is optionally substituted
with one or more substituents independently selected from the group
consisting of R.sup.7, OR.sup.7, N(R.sup.7).sub.2, C(O)OH, OH, and
CN.
[0810] In one embodiment of Formula (IV), one of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, C(O)OR.sup.8, SO.sub.2R.sup.8,
NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)NH.sub.2, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F, Cl, Br and I;
with the proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are each hydrogen, R.sup.1 is not hydrogen. In another
embodiment of Formula (IV), one of R.sup.2A, R.sup.2B, R.sup.2C,
and R.sup.2D is hydrogen, and the remaining are independently
selected from the group consisting of hydrogen, R.sup.8, OR.sup.8,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br;
with the proviso that, when R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are each hydrogen, R.sup.1 is not hydrogen. In another
embodiment of Formula (IV), R.sup.2A, R.sup.2B, R.sup.2C, and
R.sup.2D are hydrogen; with the proviso that, R.sup.1 is not
hydrogen.
[0811] In one embodiment of Formula (IV), two of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D on adjacent carbons form a fused
ring selected from the group consisting of phenyl, 5-6 membered
heteroaryl, C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7
cycloalkenyl, and 4-7 membered heterocyclyl; and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2,
C(O)NHR.sup.8, C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, NO.sub.2, F,
Cl, Br and I; wherein the phenyl, 5-6 membered heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, C.sub.4-C.sub.7 cycloalkenyl, and 4-7
membered heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.8, OR.sup.8, C(O)R.sup.8, OC(O)R.sup.8, C(O)OR.sup.8,
SO.sub.2R.sup.8, NHR.sup.8, N(R.sup.8).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I. In another embodiment of Formula
(IV), R.sup.2C and R.sup.2D form a 4-7 membered heterocyclyl; and
R.sup.2A and R.sup.2B are independently hydrogen.
[0812] In one embodiment of Formula (IV), R.sup.3 is selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11
cycloalkenyl, and 4-12 membered heterocyclyl; wherein the R.sup.3
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
alkynyl are optionally substituted with one or more substituents
independently selected from the group consisting of C.sub.1-C.sub.6
alkoxy, phenyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein the
R.sup.3 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl are optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.9, OR.sup.9, C(O)R.sup.9, OC(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NH.sub.2, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, C(O)OH, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I. In another embodiment of
Formula (IV), R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy and
phenyl; wherein the R.sup.3 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br.
In another embodiment of Formula (IV), R.sup.3 is C.sub.1-C.sub.6
alkyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkoxy and phenyl. In
another embodiment of Formula (IV), R.sup.3 is 6-10 membered aryl;
wherein the R.sup.3 6-10 membered aryl is optionally substituted
with one or more substituents independently selected from the group
consisting of R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9,
SO.sub.2R.sup.9, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, and Br. In another embodiment of Formula (IV),
R.sup.3 is 5-11 membered heteroaryl; wherein the R.sup.3 5-11
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br.
In another embodiment of Formula (IV), R.sup.3 is C.sub.3-C.sub.11
cycloalkyl; wherein the R.sup.3 C.sub.3-C.sub.11 cycloalkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.9, OR.sup.9,
C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9, C(O)NHR.sup.9,
C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2,
NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br. In another
embodiment of Formula (IV), R.sup.3 is 4-12 membered heterocyclyl;
wherein the R.sup.3 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.9, OR.sup.9, C(O)R.sup.9,
C(O)OR.sup.9, SO.sub.2R.sup.9, C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2,
NHC(O)R.sup.9, NHR.sup.9, N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN,
NO.sub.2, F, Cl, and Br.
[0813] In one embodiment of Formula (IV), R.sup.4 is selected from
the group consisting of hydrogen and C.sub.1-C.sub.6 alkyl; wherein
the R.sup.4 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more substituents independently selected from the group
consisting of R.sup.10, OR.sup.10, SR.sup.10, NHR.sup.10,
N(R.sup.10).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I. In another embodiment of Formula (IV), R.sup.4 is
hydrogen. In another embodiment of Formula (IV), R.sup.4 is
C.sub.1-C.sub.6 alkyl; wherein the R.sup.4 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more R.sup.10.
[0814] In one embodiment of Formula (IV), R.sup.6A and R.sup.6B are
each independently hydrogen.
[0815] In one embodiment of Formula (IV), R.sup.7, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy, OH,
oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.7 6-10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkyl, oxo, OH, CN, NO.sub.2, F, Cl, Br and I. In another
embodiment of Formula (IV), R.sup.7, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.7 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more C.sub.1-C.sub.6 alkoxy; wherein each
R.sup.7 5-11 membered heteroaryl and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, F, and Cl.
[0816] In one embodiment of Formula (IV), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.8 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.11, OR.sup.11,
C(O)OR.sup.11, NHR.sup.11, N(R.sup.11).sub.2, NH.sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl is optionally substituted with one or
more substituents independently selected from the group consisting
of R.sup.12, OR.sup.12, C(O)OR.sup.12, NHR.sup.12,
N(R.sup.12).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN, NO.sub.2, F, Cl,
Br and I. In another embodiment of Formula (IV), R.sup.8, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.6-C.sub.10
membered aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11
cycloalkyl, and 4-12 membered heterocyclyl; wherein each R.sup.8
C.sub.1-C.sub.6 alkyl and C.sub.2-C.sub.6 alkenyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.11, OR.sup.11, C(O)OR.sup.11,
OH, and F; wherein each R.sup.8 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.12, OR.sup.12,
N(R.sup.12).sub.2, and F.
[0817] In one embodiment of Formula (IV), R.sup.9, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, 6-10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.9 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.13, OR.sup.13,
SR.sup.13, C(O)R.sup.13, NHR.sup.13, N(R.sup.13).sub.2, C(O)OH, OH,
CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.9 6-10 membered
aryl, 5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl are
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.14, OR.sup.14,
C(O)R.sup.14, OC(O)R.sup.14, C(O)OR.sup.1, SO.sub.2R.sup.14,
NHR.sup.14, N(R.sup.14).sub.2, NH.sub.2, C(O)OH, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (IV),
R.sup.9, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, 6-10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.13, OR.sup.13, C(O)R.sup.13,
N(R.sup.13).sub.2, OH, F, and Cl; wherein each R.sup.9 6-10
membered aryl and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, oxo, and F.
[0818] In one embodiment of Formula (IV), R.sup.10, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.10 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another embodiment of Formula (IV),
R.sup.10, at each occurrence, is independently C.sub.6-C.sub.10
membered aryl; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6
alkoxy.
[0819] In one embodiment of Formula (IV), R.sup.11, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.11 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.11
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I. In
another embodiment of Formula (IV), R.sup.11, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl is optionally
substituted with one or more C.sub.1-C.sub.6 alkoxy.
[0820] In one embodiment of Formula (IV), R.sup.12, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12 membered
heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6 membered
heteroaryl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 alkoxy is optionally substituted with one or more
substituents independently selected from the group consisting of
OH, oxo, CN, NO.sub.2, F, Cl, Br and I; wherein each R.sup.12
C.sub.6-C.sub.10 membered aryl, C.sub.3-C.sub.11 cycloalkyl, 4-12
membered heterocyclyl, C.sub.4-C.sub.11 cycloalkenyl, and 5-6
membered heteroaryl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, F, Cl, Br and I. In
another embodiment of Formula (IV), R.sup.12, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.12 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more F; wherein each 4-12 membered
heterocyclyl is optionally substituted with one or more
C.sub.1-C.sub.6 alkyl.
[0821] In one embodiment of Formula (IV), R.sup.13, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.13 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of OH, oxo, CN, NO.sub.2, F, Cl,
Br and I; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl,
5-11 membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl,
C.sub.4-C.sub.11 cycloalkenyl, and 4-12 membered heterocyclyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, OH, oxo, CN,
NO.sub.2, F, Cl, Br and I. In another R.sup.13, at each occurrence,
is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10 membered aryl, and 4-12
membered heterocyclyl; wherein each R.sup.13 C.sub.6-C.sub.10
membered aryl and 4-12 membered heterocyclyl is optionally
substituted with one or more substituents independently selected
from the group consisting of C.sub.1-C.sub.6 alkyl, and Cl.
[0822] In one embodiment of Formula (IV), R.sup.14, at each
occurrence, is independently selected from the group consisting of
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, C.sub.4-C.sub.11 cycloalkenyl, and
4-12 membered heterocyclyl; wherein each R.sup.14 C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 alkynyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, 5-6 membered heteroaryl, 4-12 membered
heterocyclyl, OH, oxo, CN, NO.sub.2, F, Cl, Br and I. In another
embodiment of Formula (IV), R.sup.14, at each occurrence, is
independently C.sub.1-C.sub.6 alkyl; wherein each R.sup.14
C.sub.1-C.sub.6 alkyl is optionally substituted with one or more
independently selected 4-12 membered heterocyclyl.
[0823] One embodiment pertains to compounds of Formula (IV), or a
pharmaceutically acceptable salt thereof, wherein [0824] R.sup.1 is
selected from the group consisting of hydrogen, CN, and
C.sub.1-C.sub.6 alkyl; wherein the R.sup.1 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of R.sup.7, OR.sup.7,
N(R.sup.7).sub.2, C(O)OH, OH, and CN; [0825] one of R.sup.2A,
R.sup.2B, R.sup.2C, and R.sup.2D is hydrogen, and the remaining are
independently selected from the group consisting of hydrogen,
R.sup.8, OR.sup.8, C(O)OR.sup.8, C(O)NHR.sup.8,
C(O)N(R.sup.8).sub.2, C(O)OH, OH, CN, F, Cl, and Br; or [0826] two
of R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D on adjacent carbons
form a 4-7 membered heterocyclyl; and the remaining are hydrogen;
[0827] R.sup.3 is selected from the group consisting of
C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein the R.sup.3 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more substituents independently
selected from the group consisting of C.sub.1-C.sub.6 alkoxy and
phenyl; wherein the R.sup.3 6-10 membered aryl, 5-11 membered
heteroaryl, C.sub.3-C.sub.11 cycloalkyl and 4-12 membered
heterocyclyl are optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.9, OR.sup.9, C(O)R.sup.9, C(O)OR.sup.9, SO.sub.2R.sup.9,
C(O)NHR.sup.9, C(O)N(R.sup.9).sub.2, NHC(O)R.sup.9, NHR.sup.9,
N(R.sup.9).sub.2, NH.sub.2, OH, oxo, CN, NO.sub.2, F, Cl, and Br;
[0828] R.sup.4 is selected from the group consisting of hydrogen
and C.sub.1-C.sub.6 alkyl; wherein the R.sup.4 C.sub.1-C.sub.6
alkyl is optionally substituted with one or more R.sup.16; [0829]
R.sup.6A and R.sup.6B are each independently hydrogen; [0830]
R.sup.7, at each occurrence, is independently selected from the
group consisting of C.sub.1-C.sub.6 alkyl, 6-10 membered aryl, 5-11
membered heteroaryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.7 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
wherein each R.sup.7 5-11 membered heteroaryl and 4-12 membered
heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, F, and Cl;
[0831] R.sup.8, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.8 C.sub.1-C.sub.6 alkyl and C.sub.2-C.sub.6
alkenyl is optionally substituted with one or more substituents
independently selected from the group consisting of R.sup.11,
OR.sup.11, C(O)OR.sup.11, OH, and F; wherein each R.sup.8
C.sub.6-C.sub.10 membered aryl, 5-11 membered heteroaryl and 4-12
membered heterocyclyl is optionally substituted with one or more
substituents independently selected from the group consisting of
R.sup.12, OR.sup.12, N(R.sup.12).sub.2 and F; [0832] R.sup.9, at
each occurrence, is independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl, 6-10 membered aryl,
C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered heterocyclyl;
wherein each R.sup.9 C.sub.1-C.sub.6 alkyl is optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.13, OR.sup.13, C(O)R.sup.13,
N(R.sup.13).sub.2, OH, F, and Cl; wherein each R.sup.9 6-10
membered aryl and 4-12 membered heterocyclyl are optionally
substituted with one or more substituents independently selected
from the group consisting of R.sup.14, oxo, and F; [0833] R.sup.10,
at each occurrence, is independently C.sub.6-C.sub.10 membered
aryl; wherein each R.sup.10 C.sub.6-C.sub.10 membered aryl is
optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
[0834] R.sup.11, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.11 C.sub.6-C.sub.10 membered aryl
is optionally substituted with one or more C.sub.1-C.sub.6 alkoxy;
[0835] R.sup.12, at each occurrence, is independently selected from
the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.6-C.sub.10
membered aryl, C.sub.3-C.sub.11 cycloalkyl, and 4-12 membered
heterocyclyl; wherein each R.sup.12 C.sub.1-C.sub.6 alkyl is
optionally substituted with one or more F; wherein each 4-12
membered heterocyclyl is optionally substituted with one or more
C.sub.1-C.sub.6 alkyl; [0836] R.sup.13, at each occurrence, is
independently selected from the group consisting of C.sub.1-C.sub.6
alkyl, C.sub.6-C.sub.10 membered aryl and 4-12 membered
heterocyclyl; wherein each R.sup.13 C.sub.6-C.sub.10 membered aryl
and 4-12 membered heterocyclyl is optionally substituted with one
or more substituents independently selected from the group
consisting of C.sub.1-C.sub.6 alkyl and Cl; and [0837] R.sup.14, at
each occurrence, is independently C.sub.1-C.sub.6 alkyl; wherein
each R.sup.14 C.sub.1-C.sub.6 alkyl is optionally substituted with
one or more 4-12 membered heterocyclyl; [0838] with the proviso
that R.sup.3 is not methyl; [0839] with the proviso that, when
R.sup.2A, R.sup.2B, R.sup.2C, and R.sup.2D are each hydrogen,
R.sup.1 is not hydrogen; [0840] with the proviso that, when R.sup.3
is naphthyl, R.sup.2C is not 4-(1-methylethyl)phenoxy; and [0841]
with the proviso that, when R.sup.1 is C.sub.1-alkyl, R.sup.3 is
not 3-pyridinyl or 4-cyanobenzyl.
[0842] One embodiment pertains to a compound of Formula (IV), or a
pharmaceutically acceptable salt thereof, wherein the compound is
selected from the group consisting of Examples: I-79, I-102; I-106;
I-107; I-114: I-132; I-134; I-136; I-137; I-143; I-144; I-145:
I-146; I-147: I-148; I-155; II-114; II-118; III-175; and
III-177.
[0843] Compounds of the invention were named using Name 2016.1.1
(File Version N30E41, Build 86668, 25 May, 2016) naming algorithm
by Advanced Chemical Development, Inc., or Struct=Name naming
algorithm as part of CHEMDRAW.RTM. ULTRA v. 12.0.2.1076 or
Professional Version 15.0.0.106.
[0844] Compounds of the invention may exist as stereoisomers
wherein asymmetric or chiral centers are present. These
stereoisomers are "R" or "S" depending on the configuration of
substituents around the chiral carbon atom. The terms "R" and "S"
used herein are configurations as defined in IUPAC 1974
Recommendations for Section E, Fundamental Stereochemistry, in Pure
Appl. Chem., 1976, 45: 13-30. The invention contemplates various
stereoisomers and mixtures thereof and these are specifically
included within the scope of this invention. Stereoisomers include
enantiomers and diastereomers, and mixtures of enantiomers or
diastereomers. Individual stereoisomers of compounds of the
invention may be prepared synthetically from commercially available
starting materials which contain asymmetric or chiral centers or by
preparation of racemic mixtures followed by methods of resolution
well-known to those of ordinary skill in the art. These methods of
resolution are exemplified by (1) attachment of a mixture of
enantiomers to a chiral auxiliary, separation of the resulting
mixture of diastereomers by precipitation or chromatography and
optional liberation of the optically pure product from the
auxiliary as described in Furniss, Hannaford, Smith, and Tatchell,
"Vogel's Textbook of Practical Organic Chemistry", 5th edition
(1989), Longman Scientific & Technical, Essex CM20 2JE,
England, or (2) direct separation of the mixture of optical
enantiomers on chiral chromatographic columns or (3) fractional
recrystallization methods.
[0845] Compounds of the invention may exist as cis or trans
isomers, wherein substituents on a ring may attached in such a
manner that they are on the same side of the ring (cis) relative to
each other, or on opposite sides of the ring relative to each other
(trans). For example, cyclobutane may be present in the cis or
trans configuration, and may be present as a single isomer or a
mixture of the cis and trans isomers. Individual cis or trans
isomers of compounds of the invention may be prepared synthetically
from commercially available starting materials using selective
organic transformations, or prepared in single isomeric form by
purification of mixtures of the cis and trans isomers. Such methods
are well-known to those of ordinary skill in the art, and may
include separation of isomers by precipitation or
chromatography.
[0846] It should be understood that the compounds of the invention
may possess tautomeric forms, as well as geometric isomers, and
that these also constitute an aspect of the invention.
[0847] The present disclosure includes all pharmaceutically
acceptable isotopically-labelled compounds of Formula (I) wherein
one or more atoms are replaced by atoms having the same atomic
number, but an atomic mass or mass number different from the atomic
mass or mass number which predominates in nature. Examples of
isotopes suitable for inclusion in the compounds of the disclosure
include isotopes of hydrogen, such as .sup.2H and .sup.3H, carbon,
such as .sup.11C, .sup.13C and .sup.14C, chlorine, such as
.sup.36Cl, fluorine, such as .sup.18F, iodine, such as .sup.123I
and .sup.125I, nitrogen, such as .sup.13N and .sup.15N, oxygen,
such as .sup.15O, .sup.17O and .sup.18O, phosphorus, such as
.sup.32P, and sulphur, such as .sup.35S. Certain
isotopically-labelled compounds of Formula (I) for example, those
incorporating a radioactive isotope, are useful in drug and/or
substrate tissue distribution studies. The radioactive isotopes
tritium, i.e. .sup.3H, and carbon-14, i.e. .sup.14C, are
particularly useful for this purpose in view of their ease of
incorporation and ready means of detection. Substitution with
heavier isotopes such as deuterium, i.e. .sup.2H, may afford
certain therapeutic advantages resulting from greater metabolic
stability, for example, increased in vivo half-life or reduced
dosage requirements, and hence may be preferred in some
circumstances. Substitution with positron emitting isotopes, such
as .sup.11C, .sup.18F, .sup.15O and .sup.13N, can be useful in
Positron Emission Topography (PET) studies for examining substrate
receptor occupancy. Isotopically-labeled compounds of Formula (I)
may generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described in
the accompanying Examples using an appropriate isotopically-labeled
reagents in place of the non-labeled reagent previously
employed.
[0848] Thus, the formula drawings within this specification can
represent only one of the possible tautomeric, geometric, or
stereoisomeric forms. It is to be understood that the invention
encompasses any tautomeric, geometric, or stereoisomeric form, and
mixtures thereof, and is not to be limited merely to any one
tautomeric, geometric, or stereoisomeric form utilized within the
formula drawings.
[0849] Compounds of Formula (I) may be used in the form of
pharmaceutically acceptable salts. The phrase "pharmaceutically
acceptable salt" means those salts which are, within the scope of
sound medical judgement, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity,
irritation, allergic response and the like and are commensurate
with a reasonable benefit/risk ratio.
[0850] Pharmaceutically acceptable salts have been described in S.
M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.
[0851] Compounds of Formula (I) may contain either a basic or an
acidic functionality, or both, and can be converted to a
pharmaceutically acceptable salt, when desired, by using a suitable
acid or base. The salts may be prepared in situ during the final
isolation and purification of the compounds of the invention.
[0852] Examples of acid addition salts include, but are not limited
to acetate, adipate, alginate, citrate, aspartate, benzoate,
benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate,
malate, maleate, methanesulfonate, nicotinate,
2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,
3-phenylpropionate, picrate, pivalate, propionate, succinate,
tartrate, thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic
nitrogen-containing groups may be quaternized with such agents as
lower alkyl halides such as, but not limited to, methyl, ethyl,
propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates
like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain
halides such as, but not limited to, decyl, lauryl, myristyl and
stearyl chlorides, bromides and iodides; arylalkyl halides like
benzyl and phenethyl bromides and others. Water or oil-soluble or
dispersible products are thereby obtained. Examples of acids which
may be employed to form pharmaceutically acceptable acid addition
salts include such inorganic acids as hydrochloric acid,
hydrobromic acid, sulfuric acid, and phosphoric acid and such
organic acids as acetic acid, fumaric acid, maleic acid,
4-methylbenzenesulfonic acid, succinic acid, and citric acid.
[0853] Basic addition salts may be prepared in situ during the
final isolation and purification of compounds of this invention by
reacting a carboxylic acid-containing moiety with a suitable base
such as, but not limited to, the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with
ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts include, but are not limited to,
cations based on alkali metals or alkaline earth metals such as,
but not limited to, lithium, sodium, potassium, calcium, magnesium
and aluminum salts and the like and nontoxic quaternary ammonia and
amine cations including ammonium, tetramethylammonium,
tetraethylammonium, methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine and the like. Other
examples of organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like.
[0854] The term "pharmaceutically acceptable prodrug" or "prodrug"
as used herein, refers to derivatives of the compounds of the
invention which have cleavable groups. Such derivatives become, by
solvolysis or under physiological conditions, the compounds of the
invention which are pharmaceutically active in vivo. Prodrugs of
the compounds of the invention are, within the scope of sound
medical judgement, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation,
allergic response, and the like, commensurate with a reasonable
benefit/risk ratio, and effective for their intended use.
[0855] The invention contemplates compounds of Formula (I) formed
by synthetic means or formed by in vivo biotransformation of a
prodrug.
[0856] Compounds described herein may exist in unsolvated as well
as solvated forms, including hydrated forms, such as hemi-hydrates.
In general, the solvated forms, with pharmaceutically acceptable
solvents such as water and ethanol among others are equivalent to
the unsolvated forms for the purposes of the invention.
Pharmaceutical Compositions
[0857] When employed as a pharmaceutical, a compound of the
invention is typically administered in the form of a pharmaceutical
composition. Such compositions can be prepared in a manner well
known in the pharmaceutical art and comprise a therapeutically
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof together with a
pharmaceutically acceptable carrier. The phrase "pharmaceutical
composition" refers to a composition suitable for administration in
medical or veterinary use.
[0858] The pharmaceutical compositions that comprise a compound of
Formula (I), alone or in combination with further therapeutically
active ingredient, may be administered to the subjects orally,
rectally, parenterally, intracisternally, intravaginally,
intraperitoneally, topically (as by powders, ointments or drops),
bucally or as an oral or nasal spray. The term "parenterally" as
used herein, refers to modes of administration which include
intravenous, intramuscular, intraperitoneal, intrasternal,
subcutaneous and intraarticular injection and infusion.
[0859] The term "pharmaceutically acceptable carrier" as used
herein, means a non-toxic, inert solid, semi-solid or liquid
filler, diluent, encapsulating material or formulation auxiliary of
any type. Some examples of materials which may serve as
pharmaceutically acceptable carriers are sugars such as, but not
limited to, lactose, glucose and sucrose; starches such as, but not
limited to, corn starch and potato starch; cellulose and its
derivatives such as, but not limited to, sodium carboxymethyl
cellulose, ethyl cellulose and cellulose acetate; powdered
tragacanth; malt; gelatin; talc; excipients such as, but not
limited to, cocoa butter and suppository waxes; oils such as, but
not limited to, peanut oil, cottonseed oil, safflower oil, sesame
oil, olive oil, corn oil and soybean oil; glycols; such a propylene
glycol; esters such as, but not limited to, ethyl oleate and ethyl
laurate; agar; buffering agents such as, but not limited to,
magnesium hydroxide and aluminum hydroxide; alginic acid;
pyrogen-free water; isotonic saline; Ringer's solution; ethyl
alcohol, and phosphate buffer solutions, as well as other non-toxic
compatible lubricants such as, but not limited to, sodium lauryl
sulfate and magnesium stearate, as well as coloring agents,
releasing agents, coating agents, sweetening, flavoring and
perfuming agents, preservatives and antioxidants may also be
present in the composition, according to the judgment of the
formulator.
[0860] Pharmaceutical compositions for parenteral injection
comprise pharmaceutically acceptable sterile aqueous or nonaqueous
solutions, dispersions, suspensions or emulsions as well as sterile
powders for reconstitution into sterile injectable solutions or
dispersions just prior to use. Examples of suitable aqueous and
nonaqueous diluents, solvents, or vehicles include water, ethanol,
polyols (such as glycerol, propylene glycol, polyethylene glycol
and the like), vegetable oils (such as olive oil), injectable
organic esters (such as ethyl oleate), and suitable mixtures
thereof. Proper fluidity may be maintained, for example, by the use
of coating materials such as lecithin, by the maintenance of the
required particle size in the case of dispersions and by the use of
surfactants.
[0861] These compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents and dispersing
agents. Prevention of the action of microorganisms may be ensured
by the inclusion of various antibacterial and antifungal agents,
for example, paraben, chlorobutanol, phenol sorbic acid, and the
like. It may also be desirable to include isotonic agents such as
sugars, sodium chloride, and the like. Prolonged absorption of the
injectable pharmaceutical form may be brought about by the
inclusion of agents which delay absorption, such as aluminum
monostearate and gelatin.
[0862] In some cases, in order to prolong the effect of the drug,
it may be desirable to slow the absorption of the drug from
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the
drug then depends upon its rate of dissolution which, in turn, may
depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally-administered drug form may be
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0863] Injectable depot forms are made by forming microencapsule
matrices of the drug in biodegradable polymers such as
polylactide-polyglycolide. Depending upon the ratio of drug to
polymer and the nature of the particular polymer employed, the rate
of drug release may be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot
injectable formulations are also prepared by entrapping the drug in
liposomes or microemulsions which are compatible with body
tissues.
[0864] The injectable formulations may be sterilized, for example,
by filtration through a bacterial-retaining filter or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium just prior to use.
[0865] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In certain embodiments,
solid dosage forms may contain from 1% to 95% (w/w) of a compound
of Formula (I). In certain embodiments, the compound of Formula
(I), or pharmaceutically acceptable salts thereof, may be present
in the solid dosage form in a range of from 5% to 70% (w/w). In
such solid dosage forms, the active compound may be mixed with at
least one inert, pharmaceutically acceptable carrier, such as
sodium citrate or dicalcium phosphate and/or a), fillers or
extenders such as starches, lactose, sucrose, glucose, mannitol,
and silicic acid; b) binders such as carboxymethylcellulose,
alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c)
humectants such as glycerol; d) disintegrating agents such as
agar-agar, calcium carbonate, potato or tapioca starch, alginic
acid, certain silicates, and sodium carbonate; e) solution
retarding agents such as paraffin; f) absorption accelerators such
as quaternary ammonium compounds; g) wetting agents such as cetyl
alcohol and glycerol monostearate; h) absorbents such as kaolin and
bentonite clay and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0866] The pharmaceutical composition may be a unit dosage form. In
such form the preparation is subdivided into unit doses containing
appropriate quantities of the active component. The unit dosage
form can be a packaged preparation, the package containing discrete
quantities of preparation, such as packeted tablets, capsules, and
powders in vials or ampules. Also, the unit dosage form may be a
capsule, tablet, cachet, or lozenge itself, or it may be the
appropriate number of any of these in packaged form. The quantity
of active component in a unit dose preparation may be varied or
adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to
95% (w/w) of a unit dose, according to the particular application
and the potency of the active component. The composition may, if
desired, also contain other compatible therapeutic agents.
[0867] The dose to be administered to a subject may be determined
by the efficacy of the particular compound employed and the
condition of the subject, as well as the body weight or surface
area of the subject to be treated. The size of the dose also will
be determined by the existence, nature, and extent of any adverse
side-effects that accompany the administration of a particular
compound in a particular subject. In determining the effective
amount of the compound to be administered in the treatment or
prophylaxis of the disorder being treated, the physician may
evaluate factors such as the circulating plasma levels of the
compound, compound toxicities, and/or the progression of the
disease, etc.
[0868] For administration, compounds may be administered at a rate
determined by factors that may include, but are not limited to, the
LD.sub.50 of the compound, the pharmacokinetic profile of the
compound, contraindicated drugs, and the side-effects of the
compound at various concentrations, as applied to the mass and
overall health of the subject. Administration may be accomplished
via single or divided doses.
[0869] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
carriers as lactose or milk sugar as well as high molecular weight
polyethylene glycols and the like.
[0870] The solid dosage forms of tablets, dragees, capsules, pills
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well-known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and may also be of a composition such that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions which can be used
include polymeric substances and waxes.
[0871] The active compounds may also be in micro-encapsulated form,
if appropriate, with one or more of the above-mentioned
carriers.
[0872] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs. In addition to the active compounds, the liquid
dosage forms may contain inert diluents commonly used in the art
such as, for example, water or other solvents, solubilizing agents
and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols, and fatty acid esters of sorbitan and mixtures
thereof.
[0873] Besides inert diluents, the oral compositions may also
include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring and perfuming agents.
[0874] Suspensions, in addition to the active compounds, may
contain suspending agents as, for example, ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite,
agar-agar, tragacanth and mixtures thereof.
[0875] Compositions for rectal or vaginal administration are
preferably suppositories which may be prepared by mixing the
compounds with suitable non-irritating carriers or carriers such as
cocoa butter, polyethylene glycol, or a suppository wax which are
solid at room temperature but liquid at body temperature and
therefore melt in the rectum or vaginal cavity and release the
active compound.
[0876] Compounds may also be administered in the form of liposomes.
Liposomes generally may be derived from phospholipids or other
lipid substances. Liposomes are formed by mono- or multi-lamellar
hydrated liquid crystals which are dispersed in an aqueous medium.
Any non-toxic, physiologically acceptable and metabolizable lipid
capable of forming liposomes may be used. The present compositions
in liposome form may contain, in addition to a compound of the
invention, stabilizers, preservatives, excipients, and the like.
Examples of lipids include, but are not limited to, natural and
synthetic phospholipids, and phosphatidyl cholines (lecithins),
used separately or together.
[0877] Methods to form liposomes have been described, see example,
Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press,
New York, N.Y. (1976), p. 33 et seq.
[0878] Dosage forms for topical administration of a compound
described herein include powders, sprays, ointments, and inhalants.
The active compound may be mixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives,
buffers or propellants which may be required. Ophthalmic
formulations, eye ointments, powders and solutions are also
contemplated as being within the scope of this invention.
[0879] A compound of the invention may also be administered in
sustained release forms or from sustained release drug delivery
systems.
Methods of Use
[0880] The compounds and compositions using any amount and any
route of administration may be administered to a subject for the
treatment or prevention of cystic fibrosis, pancreatic
insufficiency, Sjogren's syndrome (SS), chronic obstructive lung
disease (COLD), or chronic obstructive airway disease (COAD).
[0881] The term "administering" refers to the method of contacting
a compound with a subject. Thus, the compounds may be administered
by injection, that is, intravenously, intramuscularly,
intracutaneously, subcutaneously, intraduodenally, parentally, or
intraperitoneally. Also, the compounds described herein may be
administered by inhalation, for example, intranasally.
Additionally, the compounds may be administered transdermally,
topically, and via implantation. In certain embodiments, the
compounds and compositions thereof may be delivered orally. The
compounds may also be delivered rectally, bucally, intravaginally,
ocularly, or by insufflation. CFTR-modulated disorders and
conditions may be treated prophylactically, acutely, and
chronically using compounds and compositions thereof, depending on
the nature of the disorder or condition. Typically, the host or
subject in each of these methods is human, although other mammals
may also benefit from the administration of compounds and
compositions thereof as set forth hereinabove.
[0882] Compounds of the invention are useful as modulators of CFTR.
Thus, the compounds and compositions are particularly useful for
treating or lessening the severity or progression of a disease,
disorder, or a condition where hyperactivity or inactivity of CFTR
is involved. Accordingly, the invention provides a method for
treating cystic fibrosis, pancreatic insufficiency, Sjogren's
syndrome (SS), chronic obstructive lung disease (COLD), or chronic
obstructive airway disease (COAD) in a subject, wherein the method
comprises the step of administering to said subject a
therapeutically effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, or a preferred embodiment
thereof as set forth above, with or without a pharmaceutically
acceptable carrier. Particularly, the method is for the treatment
or prevention of cystic fibrosis. In a more particular embodiment,
the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or
VI mutation.
[0883] In a particular embodiment, the present invention provides
compounds of the invention, or a pharmaceutically acceptable salt
thereof, or a pharmaceutical composition comprising a compound of
the invention, for use in medicine. In a particular embodiment, the
present invention provides compounds of the invention, or a
pharmaceutically acceptable salt thereof, or pharmaceutical
compositions comprising a compound of the invention, for use in the
treatment of cystic fibrosis, pancreatic insufficiency, Sjogren's
syndrome (SS), chronic obstructive lung disease (COLD) or chronic
obstructive airway disease (COAD). In a more particular embodiment,
the present invention provides compounds of the invention or
pharmaceutical compositions comprising a compound of the invention,
for use in the treatment of cystic fibrosis. In a more particular
embodiment, the cystic fibrosis is caused by a Class I, II, III,
IV, V, and/or VI mutation.
[0884] One embodiment is directed to the use of a compound
according to Formula (I) or a pharmaceutically acceptable salt
thereof in the preparation of a medicament. The medicament
optionally can comprise one or more additional therapeutic agents.
In some embodiments, the medicament is for use in the treatment of
cystic fibrosis, pancreatic insufficiency, Sjogren's syndrome (SS),
chronic obstructive lung disease (COLD) or chronic obstructive
airway disease (COAD). In a particular embodiment, the medicament
is for use in the treatment of cystic fibrosis. In a more
particular embodiment, the cystic fibrosis is caused by a Class I,
II, III, IV, V, and/or VI mutation.
[0885] This invention also is directed to the use of a compound
according to Formula (I) or a pharmaceutically acceptable salt
thereof in the manufacture of a medicament for the treatment of
cystic fibrosis, Sjogren's syndrome, pancreatic insufficiency,
chronic obstructive lung disease, and chronic obstructive airway
disease. The medicament optionally can comprise one or more
additional therapeutic agents. In a particular embodiment, the
invention is directed to the use of a compound according to Formula
(I) or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament for the treatment of cystic fibrosis.
In a more particular embodiment, the cystic fibrosis is caused by a
Class I, II, III, IV, V, and/or VI mutation.
[0886] In one embodiment, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
or a pharmaceutically acceptable salt thereof, and one or more
additional therapeutic agents. In another embodiment, the present
invention provides pharmaceutical compositions comprising a
compound of the invention, or a pharmaceutically acceptable salt
thereof, and one or more additional therapeutic agents wherein the
additional therapeutic agents are selected from the group
consisting of CFTR modulators and CFTR amplifiers. In another
embodiment, the present invention provides pharmaceutical
compositions comprising a compound of the invention, or a
pharmaceutically acceptable salt thereof, and one or more
additional therapeutic agents wherein the additional therapeutic
agents are CFTR modulators.
[0887] In one embodiment, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
or a pharmaceutically acceptable salt thereof, and one or more
additional therapeutic agents. In one embodiment, the present
invention provides pharmaceutical compositions comprising a
compound of the invention, or a pharmaceutically acceptable salt
thereof, one potentiator, and one or more additional correctors. In
one embodiment, the present invention provides pharmaceutical
compositions comprising a compound of the invention, and another
therapeutic agent. In a particular embodiment, the other
therapeutic agent is a cystic fibrosis treatment agent. In one
embodiment, the present invention provides a method for treating
cystic fibrosis in a subject comprising administering a compound of
the invention, or a pharmaceutically acceptable salt thereof, and
one or more additional therapeutic agents. In another embodiment,
the present invention provides a method for treating cystic
fibrosis in a subject comprising administering a compound of the
invention, or a pharmaceutically acceptable salt thereof, and one
or more additional therapeutic agents wherein the additional
therapeutic agents are selected from the group consisting of CFTR
modulators and CFTR amplifiers. In one embodiment, the present
invention provides a method for treating cystic fibrosis in a
subject comprising administering a compound of the invention, or a
pharmaceutically acceptable salt thereof, and one or more
additional therapeutic agents wherein the additional therapeutic
agents are CFTR modulators. In one embodiment, the present
invention provides a method for treating cystic fibrosis in a
subject comprising administering a compound of the invention, or a
pharmaceutically acceptable salt thereof, and, and another
therapeutic agent. In a particular embodiment, the other
therapeutic agent is a cystic fibrosis treatment agent. In one
embodiment, the present invention provides a method for treating
cystic fibrosis in a subject comprising administering a
therapeutically effective amount of a compound of the invention, or
a pharmaceutically acceptable salt thereof. In a particular
embodiment, the additional therapeutic agent(s) are one
potentiator, and one or more additional correctors. In another
embodiment, the additional therapeutic agent(s) is selected from
the group consisting of CFTR modulators and CFTR amplifiers. In
another embodiment, the other therapeutic agent(s) is a CFTR
modulator. In a more particular embodiment, the cystic fibrosis is
caused by a Class I, II, III, IV, V, and/or VI mutation.
[0888] The present compounds or pharmaceutically acceptable salts
thereof may be administered as the sole active agent or it may be
co-administered with other therapeutic agents, including other
compounds or pharmaceutically acceptable salts thereof, that
demonstrate the same or a similar therapeutic activity and that are
determined to be safe and efficacious for such combined
administration. The present compounds may be co-administered to a
subject. The term "co-administered" means the administration of two
or more different therapeutic agents to a subject in a single
pharmaceutical composition or in separate pharmaceutical
compositions. Thus co-administration involves administration at the
same time of a single pharmaceutical composition comprising two or
more therapeutic agents or administration of two or more different
compositions to the same subject at the same or different
times.
[0889] The compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with a
therapeutically effective amount of one or more additional
therapeutic agents to treat a CFTR mediated disease, where examples
of the therapeutic agents include, but are not limited to
antibiotics (for example, aminoglycosides, colistin, aztreonam,
ciprofloxacin, and azithromycin), expectorants (for example,
hypertonic saline, acetylcysteine, dornase alfa, and denufosol),
pancreatic enzyme supplements (for example, pancreatin, and
pancrelipase), epithelial sodium channel blocker (ENaC) inhibitors,
CFTR modulators (for example, CFTR potentiators, CFTR correctors),
and CFTR amplifiers. In one embodiment, the CFTR mediated disease
is cystic fibrosis, chronic obstructive pulmonary disease (COPD),
dry eye disease, pancreatic insufficiency, or Sjogren's syndrome.
In one embodiment, the CFTR mediated disease is cystic fibrosis. In
one embodiment, the compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with one or two
CFTR modulators and one CFTR amplifier. In one embodiment, the
compounds of the invention or pharmaceutically acceptable salts
thereof may be co-administered with one potentiator, one or more
correctors, and one CFTR amplifier. In one embodiment, the
compounds of the invention or pharmaceutically acceptable salts
thereof may be co-administered with one or more CFTR modulators. In
one embodiment, the compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with one CFTR
modulators. In one embodiment, the compounds of the invention or
pharmaceutically acceptable salts thereof may be co-administered
with two CFTR modulators. In one embodiment, the compounds of the
invention or pharmaceutically acceptable salts thereof may be
co-administered with three CFTR modulators. In one embodiment, the
compounds of the invention or pharmaceutically acceptable salts
thereof may be co-administered with one potentiator and one or more
correctors. In one embodiment, the compounds of the invention or
pharmaceutically acceptable salts thereof may be co-administered
with one potentiator and two correctors. In one embodiment, the
compounds of the invention or pharmaceutically acceptable salts
thereof may be co-administered with one potentiator. In one
embodiment, the compounds of the invention or pharmaceutically
acceptable salts thereof may be co-administered with one or more
correctors. In one embodiment, the compounds of the invention or
pharmaceutically acceptable salts thereof may be co-administered
with one corrector. In one embodiment, the compounds of the
invention or pharmaceutically acceptable salts thereof may be
co-administered with two correctors.
[0890] Examples of CFTR potentiators include, but are not limited
to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, GLPG2451,
GLPG3067, GLPG1837, PTI-808,
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-1H-pyrazole-5-carboxamide, and
3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}-
pyridine-2-carboxamide. Examples of potentiators are also disclosed
in publications: WO2005120497, WO2008147952, WO2009076593,
WO2010048573, WO2006002421, WO2008147952, WO2011072241,
WO2011113894, WO2013038373, WO2013038378, WO2013038381,
WO2013038386, WO2013038390, WO2014180562, WO2015018823,
WO2014/180562, WO2015018823, WO 2016193812 and WO2017208115.
[0891] In one embodiment, the potentiator can be selected from the
group consisting of [0892] Ivacaftor (VX-770,
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carbox-
amide); [0893] GLPG1837; [0894] GLP-2451; [0895] PTI-808; [0896]
CTP-656; [0897] NVS-QBW251, [0898] FD1860293 [0899] GLPG3067;
[0900]
2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyr-
an-3-carboxamide; [0901]
N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl-
)-1H-pyrazole-5-carboxamide; [0902]
2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]py-
ran-3-carboxamide [0903]
2-(1-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-t-
hieno[2,3-c]pyran-3-carboxamide; [0904]
5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thien-
o[2,3-c]pyran-3-carboxamide; [0905]
2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thie-
no[2,3-c]pyran-3-carboxamide; [0906]
2-(1-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihy-
dro-4H-thieno[2,3-c]pyran-3-carboxamide; [0907]
2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H--
thieno[2,3-c]pyran-3-carboxamide; [0908]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-methyl-1H-pyrazole-3-carboxamide; [0909]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-cyclopropyl-1H-pyrazole-3-carboxamide; [0910]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-isopropyl-1H-pyrazole-3-carboxamide; [0911]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide; [0912]
5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-
-c]pyran-2-yl)-1H-pyrazole-3-carboxamide; [0913]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-5-ethyl-1H-pyrazole-3-carboxamide; [0914]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide; [0915]
2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]-
pyran-3-carboxamide; [0916]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-4-chloro-1H-pyrazole-3-carboxamide; [0917]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide; [0918]
4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]py-
ran-2-yl)-1H-pyrazole-3-carboxamide; [0919]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide; [0920]
N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl-
)-4-methyl-1H-pyrazole-3-carboxamide; [0921]
2-(2-hydroxy-3,3-dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-t-
hieno[2,3-c]pyran-3-carboxamide; [0922]
2-[(2-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-
-c]pyran-3-carboxamide; [0923]
5-(2-methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid
(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)--
amide; [0924]
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-metho-
xypropyl)-1H-pyrazole-3-carboxamide; [0925]
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethox-
yethyl)-1H-pyrazole-3-carboxamide; [0926]
2-[[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-th-
ieno[2,3-c]pyran-3-carboxamide; [0927]
2-[[(2R)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-th-
ieno[2,3-c]pyran-3-carboxamide; [0928]
2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thie-
no[2,3-c]pyran-3-carboxamide; [0929]
[5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl-
]pyrazol-1-yl]methyl dihydrogen phosphate; [0930]
[3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl-
]pyrazol-1-yl]methyl dihydrogen phosphate; [0931]
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dio-
xan-2-yl)-1H-pyrazole-3-carboxamide; [0932]
5,5,7,7-tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl-
]amino]-4H-thieno[2,3-c]pyran-3-carboxamide; [0933]
2-[[(2S)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]py-
ran-3-carboxamide; [0934]
3-amino-N-(2-hydroxy-2-methylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfo-
nyl}pyridine-2-carboxamide; [0935]
3-amino-N-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]-5-{[4-(trifluorometh-
oxy)phenyl]sulfonyl}pyridine-2-carboxamide; [0936]
3-amino-N-(3-hydroxy-2,2-dimethylpropyl)-5-{[4-(trifluoromethoxy)phenyl]s-
ulfonyl}pyridine-2-carboxamide; [0937]
3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]pyri-
dine-2-carboxamide; [0938]
3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(2R)-3,3,3-trifluoro-2-hydroxypro-
pyl]pyridine-2-carboxamide; [0939]
3-amino-5-[(3-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-methylpropyl)pyridine-
-2-carboxamide; [0940]
3-amino-N-[2-(cyclopropylamino)-2-oxoethyl]-5-{[4-(trifluoromethoxy)pheny-
l]sulfonyl}pyridine-2-carboxamide; [0941]
(3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(azetidin-1-
-yl)methanone; [0942]
(3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-(hydroxy-
methyl)azetidin-1-yl]methanone; [0943]
(3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-fluoroaz-
etidin-1-yl)methanone; [0944]
3-amino-N-[(2R)-2-hydroxy-3-methoxypropyl]-5-{[4-(trifluoromethyl)phenyl]-
sulfonyl}pyridine-2-carboxamide; [0945]
(3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-
-hydroxyazetidin-1-yl)methanone; [0946]
(3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3,3-difluo-
roazetidin-1-yl)methanone; [0947]
rac-3-amino-N-[(3R,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-{[2-(trifluor-
omethoxy)phenyl]sulfonyl}pyridine-2-carboxamide; [0948]
3-amino-5-[(4,4-difluoropiperidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hyd-
roxypropyl)pyridine-2-carboxamide; [0949]
(3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy--
3-(trifluoromethyl)azetidin-1-yl]methanone; [0950]
3-amino-N-(2-hydroxy-4-methylpentyl)-5-{[4-(trifluoromethoxy)phenyl]sulfo-
nyl}pyridine-2-carboxamide; [0951]
(3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxy-3-
-methylazetidin-1-yl)methanone; [0952]
3-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-{[4-(trifluoromethyl)piperi-
din-1-yl]sulfonyl}pyridine-2-carboxamide; [0953]
3-amino-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]-5-{[4-(trifluoromethoxy)ph-
enyl]sulfonyl}pyridine-2-carboxamide; [0954]
3-amino-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydr-
oxypropyl)pyridine-2-carboxamide; [0955]
3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2S)-2-hydrox-
ypropyl]pyridine-2-carboxamide; [0956]
3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2R)-2-hydrox-
y-3-methoxypropyl]pyridine-2-carboxamide; [0957]
3-amino-N-[2-oxo-2-(propan-2-ylamino)ethyl]-5-{[4-(trifluoromethyl)phenyl-
]sulfonyl}pyridine-2-carboxamide; [0958]
(3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-
-(trifluoromethyl)azetidin-1-yl]methanone; [0959]
3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3R)-tetrahyd-
rofuran-3-ylmethyl]pyridine-2-carboxamide; [0960]
(3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3--
hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone; [0961]
3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3S)-tetrahyd-
rofuran-3-ylmethyl]pyridine-2-carboxamide; [0962]
3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}-N-[(3S)-tetrahy-
drofuran-3-ylmethyl]pyridine-2-carboxamide; [0963]
3-amino-N-[2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl]-5-{[4-(trifluoromet-
hyl)phenyl]sulfonyl}pyridine-2-carboxamide; [0964]
3-amino-N-(3-tert-butoxy-2-hydroxypropyl)-5-{[2-fluoro-4-(trifluoromethyl-
)phenyl]sulfonyl}pyridine-2-carboxamide; [0965]
[3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)aze-
tidin-1-yl]methanone; [0966]
{3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl}[3-hydroxy-3-(trifluoro-
methyl)azetidin-1-yl]methanone; and [0967]
3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}-
pyridine-2-carboxamide.
[0968] Non-limiting examples of correctors include Lumacaftor
(VX-809),
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-f-
luoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxam-
ide (VX-661), VX-983, GLPG2851, GLPG2222, GLPG2665, GLPG2737,
GLPG3221, PTI-801, VX-152, VX-440, VX-445, VX-659, FDL169, FDL304,
FD2052160, and FD2035659. Examples of correctors are also disclosed
in WO2016069757, WO2016069891, WO2017009804, WO2017060874,
WO2017060873, WO2017187321 and U.S. patent application Ser. Nos.
15/723,896, 15/726,075 and PCT Patent Application No.
PCT/IB2017/058179.
[0969] In one embodiment, the corrector(s) can be selected from the
group consisting of [0970] Lumacaftor (VX-809); [0971]
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-f-
luoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxam-
ide (VX-661); [0972] PTI-801; [0973] VX-983; [0974] GLPG2665;
[0975] GLPG2851; [0976] GLPG2222; [0977] GLPG2737; [0978] GLPG3221;
[0979] VX-152; [0980] VX-440; [0981] VX-659; [0982] VX-445; [0983]
FDL169 [0984] FDL304; [0985] FD2052160; [0986] FD2035659; [0987]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [0988]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [0989]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [0990]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [0991]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [0992]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxy-
lic acid; [0993]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [0994]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic
acid; [0995]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [0996]
3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcy-
clopentanecarboxylic acid; [0997]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]-
benzamide; [0998]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [0999]
3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl-
)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [1000]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [1001]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [1002]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexane-
carboxylic acid; [1003]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1004]
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1005]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid; [1006]
4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic
acid; [1007]
rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cycloprop-
yl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1008]
rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carb-
onyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1009]
3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1010]
3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1011]
rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]c-
arbonyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid;
[1012]
3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid; [1013]
3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbo-
nyl}amino)-6-phenyltetrahydro-2H-pyran-2-yl]benzoic acid; [1014]
4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)tetrahydro-2H-pyran-2-yl]benzoic acid; [1015]
3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,-
4-b]pyridine-6-carboxylic acid; [1016]
3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-py-
razolo[3,4-b]pyridine-6-carboxylic acid; [1017]
5-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]-
benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]-
pyrazine-2-carboxylic acid; [1018]
6-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]-
benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzo-
pyran-2-yl]pyridine-3-carboxylic acid; [1019]
trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f-
][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-
-benzopyran-2-yl]cyclohexane-1-carboxylic acid; [1020]
6-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-
-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzop-
yran-2-yl]pyridine-3-carboxylic acid; [1021]
trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f-
][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-
-2-yl]cyclohexane-1-carboxylic acid; [1022] ethyl
trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-d-
ihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1--
benzopyran-2-yl]cyclohexane-1-carboxylate; [1023]
cis-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][-
1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-b-
enzopyran-2-yl]cyclohexane-1-carboxylic acid; [1024]
trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-d-
ihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1--
benzopyran-2-yl]cyclohexane-1-carboxylic acid; [1025]
1-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]-
benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzo-
pyran-2-yl]cyclopropane-1-carboxylic acid; [1026]
trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[-
5,6-d][1,3]dioxole-5-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-
-benzopyran-2-yl]cyclohexane-1-carboxylic acid; [1027]
trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[-
5,6-d][1,3]dioxole-5-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-
-2-yl]cyclohexane-1-carboxylic acid; [1028]
trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f-
][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-
-2-yl]cyclohexane-1-carboxylic acid; [1029]
trans-4-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-d-
ihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1--
benzopyran-2-yl]cyclohexane-1-carboxylic acid; and [1030]
trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f-
][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-
-benzopyran-2-yl]cyclohexane-1-carboxylic acid.
[1031] In one embodiment, the additional therapeutic agent is a
CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR
modulators, such as potentiators and correctors. Examples of CFTR
amplifiers are PTI130 and PTI-428. Examples of amplifiers are also
disclosed in International Patent Publication Nos.: WO2015138909
and WO2015138934.
[1032] In one embodiment, the additional therapeutic agent is a
CFTR stabilizer. CFTR stabilizers enhance the stability of
corrected CFTR that has been treated with a corrector,
corrector/potentiator or other CFTR modulator combination(s). An
example of a CFTR stabilizer is cavosonstat (N91115). Examples of
stabilizers are also disclosed in International Patent Publication
No.: WO2012048181.
[1033] In one embodiment, the additional therapeutic agent is an
agent that reduces the activity of the epithelial sodium channel
blocker (ENaC) either directly by blocking the channel or
indirectly by modulation of proteases that lead to an increase in
ENaC activity (e.g., serine proteases, channel-activating
proteases). Exemplary of such agents include camostat (a
trypsin-like protease inhibitor), QAU145, 552-02, GS-9411,
INO-4995, Aerolytic, amiloride, and VX-371. Additional agents that
reduce the activity of the epithelial sodium channel blocker (ENaC)
can be found, for example, in International Patent Publication Nos.
WO2009074575 and WO2013043720; and U.S. Pat. No. 8,999,976.
[1034] In one embodiment, the ENaC inhibitor is VX-371.
[1035] In one embodiment, the ENaC inhibitor is SPX-101 (S18).
[1036] In one embodiment, the present invention provides
pharmaceutical compositions comprising a compound of the invention,
or a pharmaceutically acceptable salt thereof, and one or more
additional therapeutic agents. In a particular embodiment, the
additional therapeutic agents are selected from the group
consisting of CFTR modulators and CFTR amplifiers. In a further
embodiment, the additional therapeutic agents are CFTR modulators.
In one embodiment, the present invention provides pharmaceutical
compositions comprising a compound of the invention, or a
pharmaceutically acceptable salt thereof, one potentiator, and one
or more additional correctors.
[1037] The present invention also is directed to kits that comprise
one or more compounds and/or salts of the invention, and,
optionally, one or more additional therapeutic agents.
[1038] The present invention also is directed to methods of use of
the compounds, salts, compositions, and/or kits of the invention
to, with or without one or more additional therapeutic agents, for
example, modulate the Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR) protein, and treat a disease treatable by
modulating the Cystic Fibrosis Transmembrane Conductance Regulator
(CFTR) protein (including cystic fibrosis, Sjogren's syndrome,
pancreatic insufficiency, chronic obstructive lung disease, and
chronic obstructive airway disease).
Chemical Synthetic Procedures
General
[1039] The compounds of the invention can be prepared from readily
available starting materials using the following general methods
and procedures. It will be appreciated that where typical or
preferred process conditions (i.e. reaction temperatures, times,
mole ratios of reactants, solvents, pressures, etc.) were given,
other process conditions can also be used unless otherwise stated.
Optimum reaction conditions may vary with the particular reactants
or solvent used, but such conditions can be determined by one
skilled in the art by routine optimization procedures.
[1040] Additionally, as will be apparent to those skilled in the
art, conventional protecting groups may be necessary to prevent
certain functional groups from undergoing undesired reactions. The
choice of a suitable protecting group for a particular functional
group as well as suitable conditions for protection and
deprotection are well known in the art (Protective Groups in
Organic Synthesis Third Edition; Greene, T W and Wuts, P G M, Eds.;
Wiley-Interscience: New York, 1991).
[1041] The following methods are presented with details as to the
preparation of a compound of the invention as defined hereinabove
and the comparative examples. A compound of the invention may be
prepared from known or commercially available starting materials
and reagents by one skilled in the art of organic synthesis.
[1042] All reagents were of commercial grade and were used as
received without further purification, unless otherwise stated.
Commercially available anhydrous solvents were used for reactions
conducted under inert atmosphere. Reagent grade solvents were used
in all other cases, unless otherwise specified. Column
chromatography was performed on silica gel 60 (35-70 .mu.m). Thin
layer chromatography was carried out using pre-coated silica gel
F-254 plates (thickness 0.25 mm). .sup.1H NMR spectra were recorded
on a Bruker Advance 300 NMR spectrometer (300 MHz), an Agilent 400
MHz NMR spectrometer or a 500 MHz spectrometer. Chemical shifts
(.delta.) for .sup.1H NMR spectra were reported in parts per
million (ppm) relative to tetramethylsilane (.delta. 0.00) or the
appropriate residual solvent peak, i.e. CHCl.sub.3 (.delta. 7.27),
as internal reference. Multiplicities were given as singlet (s),
doublet (d), doublet of doublets of doublets (ddd), doublet of
doublets of doublets of doublets (dddd), doublet of doublets of
quartets (ddq), doublet of doublets of triplets (ddt), doublet of
quartets (dq), doublet of triplets of doublets (dtd), heptet
(hept), triplet (t), triplet of doublets of doublets (tdd), triplet
of quartets (tq), quartet (q), quartet of doublets (qd), quartet of
triplets (qt), quintuplet (quin), multiplet (m) and broad (br).
Electrospray MS spectra were obtained on a Waters platform LC/MS
spectrometer or with Waters Acquity H-Class UPLC coupled to a
Waters Mass detector 3100 spectrometer. Columns used: Waters
Acquity UPLC BEH C18 1.7 .mu.m, 2.1 mm ID.times.50 mm L, Waters
Acquity UPLC BEH C18 1.7 .mu.m, 2.1 mm ID.times.30 mm L, or Waters
Xterra.RTM. MS 5 .mu.m C18, 100.times.4.6 mm. The methods were
using either MeCN/H.sub.2O gradients (H.sub.2O contains either 0.1%
TFA or 0.1% NH.sub.3) or CH.sub.3OH/H.sub.2O gradients (H.sub.2O
contains 0.05% TFA). Microwave heating was performed with a
Biotage.RTM. Initiator.
[1043] Racemic mixtures were separated on an Agilent HP1100 system
with UV detection. Column used: Chiralpak.RTM. IA (10.times.250 mm,
5 .mu.m). Solvents used: iPrOH and tBME. Enantiomeric purity was
determined on an Agilent HP1100 system with UV detection. Column
used: Chiralpak.RTM. IA (4.6.times.250 mm, 5 .mu.m). Solvents used:
iPrOH and tBME.
Reverse Phase Purification Methods
Prep LC/MS Method TFA6
[1044] Samples were purified by reverse phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 um 100 .ANG. AXIA.TM. column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 40
mL/minute (0-0.5 minute 15% A, 0.5-8.0 minute linear gradient
15-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1
minute linear gradient 100-15% A, 9.1-10 minute 15% A). A custom
purification system was used, consisting of the following modules:
Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson
UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Prep LC/MS Method TFA7
[1045] Samples were purified by reverse phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 um 100 .ANG. AXIA.TM. column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 40
mL/minute (0-0.5 minute 25% A, 0.5-8.0 minute linear gradient
25-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1
minute linear gradient 100-25% A, 9.1-10 minute 25% A). A custom
purification system was used, consisting of the following modules:
Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson
UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Prep LC/MS Method TFA8
[1046] Samples were purified by reverse phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 um 100 .ANG. AXIA.TM. column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 40
mL/minute (0-0.5 minute 35% A, 0.5-8.0 minute linear gradient
35-100% A, 8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1
minute linear gradient 100-35% A, 9.1-10 minute 35% A). A custom
purification system was used, consisting of the following modules:
Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson
UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Prep LC/MS Method TFA10
[1047] Samples were purified by reverse phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 um 100 .ANG. AXIA.TM. column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 30
mL/minute (0-0.2 minute 5% A, 0.2-3.0 minute linear gradient 5-100%
A, 4.1-4.5 minute 100-5% A, 4.5-5.0 minute 5% A). A custom
purification system was used, consisting of the following modules:
Gilson 305 and 306 pumps; Gilson 806 Manometric module; Gilson
UV/Vis 155 detector; Gilson 506C interface box; Gilson FC204
fraction collector; Agilent G1968D Active Splitter; Thermo MSQ Plus
mass spectrometer. The system was controlled through a combination
of Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Prep LC/MS Method AA6
[1048] Samples were purified by reverse phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 um 100 .ANG. AXIA.TM. column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium
acetate in water (B) was used, at a flow rate of 40 mL/minute
(0-0.5 minute 15% A, 0.5-8.0 minute linear gradient 15-100% A,
8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear
gradient 100-15% A, 9.1-10 minute 15% A). A custom purification
system was used, consisting of the following modules: Gilson 305
and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155
detector; Gilson 506C interface box; Gilson FC204 fraction
collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass
spectrometer. The system was controlled through a combination of
Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Prep LC/MS Method AA7
[1049] Samples were purified by reverse phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 um 100 .ANG. AXIA.TM. column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium
acetate in water (B) was used, at a flow rate of 40 mL/minute
(0-0.5 minute 25% A, 0.5-8.0 minute linear gradient 25-100% A,
8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear
gradient 100-25% A, 9.1-10 minute 25% A). A custom purification
system was used, consisting of the following modules: Gilson 305
and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155
detector; Gilson 506C interface box; Gilson FC204 fraction
collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass
spectrometer. The system was controlled through a combination of
Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
Prep LC/MS Method AA8
[1050] Samples were purified by reverse phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 um 100 .ANG. AXIA.TM. column (50
mm.times.21.2 mm). A gradient of acetonitrile (A) and 0.1% ammonium
acetate in water (B) was used, at a flow rate of 40 mL/minute
(0-0.5 minute 35% A, 0.5-8.0 minute linear gradient 35-100% A,
8.0-9.0 minute 100% A, 7.0-8.9 minute 100% A, 9.0-9.1 minute linear
gradient 100-35% A, 9.1-10 minute 35% A). A custom purification
system was used, consisting of the following modules: Gilson 305
and 306 pumps; Gilson 806 Manometric module; Gilson UV/Vis 155
detector; Gilson 506C interface box; Gilson FC204 fraction
collector; Agilent G1968D Active Splitter; Thermo MSQ Plus mass
spectrometer. The system was controlled through a combination of
Thermo Xcalibur 2.0.7 software and a custom application written
in-house using Microsoft Visual Basic 6.0.
[1051] Stereochemistry of final compounds was arbitrarily assigned
in some cases, based on the order of elution and/or activity with
respect to existing analogs.
[1052] List of abbreviations used in the experimental section:
TABLE-US-00001 Abbreviation Definition MeCN acetonitrile TFA
trifluoroacetic acid NMR nuclear magnetic resonance DMSO dimethyl
sulfoxide LC/MS or LCMS liquid chromatography-mass spectrometry
MeOH methanol tBME tert-butyl methyl ether s singlet br s broad
singlet d duplet or doublet dd double duplet or doublet of doublets
m multiplet min minute mL milliliter .mu.L microliter g gram mg
milligram mmol millimoles HPLC high pressure liquid chromatography
Ppm parts per million .mu.m micrometer
Synthetic Preparation of the Compounds of the Invention
Schemes
[1053] The compounds of the present disclosure can be better
understood in connection with the following synthetic schemes and
methods which illustrate a means by which the compounds can be
prepared. The compounds of this disclosure can be prepared by a
variety of synthetic procedures.
##STR00023##
[1054] Compounds of formula (7), which are representative of
compounds of Formula (I), can be prepared as described in Scheme 1.
A mixture of toluenesulfonylmethyl isocyanide and a compound of
formula (1), wherein X.sup.1, X.sup.2, X.sup.3, X.sup.4, R.sup.5A,
R.sup.5B, R.sup.6A, and R.sup.6B are as described herein, can be
treated with potassium tert-butoxide to provide compounds of
formula (2). The addition is typically performed under an inert
atmosphere at low temperature, and in a solvent such as, but not
limited to, dimethoxyethane, before warming up to ambient
temperature. Compounds of formula (2) can be treated with a
solution of aqueous sodium or lithium hydroxide to provide
compounds of formula (3). The reaction is typically performed at an
elevated temperature in a solvent such as, but not limited to,
ethanol. Alternatively, compounds of formula (3) can be prepared by
treating compounds of formula (1) with a cold mixture of
1,3-dithiane and n-butyllithium, followed by a quench with citric
acid, and then treatment with 4-toluenesulfonic acid.
[1055] Carboxylic acids of formula (3) can be coupled with
sulfonamides of formula (4), wherein R.sup.3 is as described
herein, to provide compounds of formula (5). Examples of conditions
known to generate compounds of formula (5) from a mixture of a
carboxylic acid and a sulfonamide include, but are not limited to,
adding a coupling reagent such as, but not limited to,
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI)
or the corresponding hydrochloride salt,
1,3-dicyclohexylcarbodiimide (DCC),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-meth-
ylmethanaminium hexafluorophosphate N-oxide or
2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate or
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU),
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (HBTU), and
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
(T3P.RTM.). The coupling reagents may be added as a solid, a
solution, or as the reagent bound to a solid support resin. In
addition to the coupling reagents, auxiliary-coupling reagents may
facilitate the coupling reaction. Auxiliary coupling reagents that
are often used in the coupling reactions include, but are not
limited to, 4-(dimethylamino)pyridine (DMAP),
1-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole
(HOBT). The reaction may be carried out optionally in the presence
of a base such as, but not limited to, triethylamine,
N,N-diisopropylethylamine or pyridine. The coupling reaction may be
carried out in solvents such as, but not limited to,
tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide,
dimethyl sulfoxide, dichloromethane, and ethyl acetate. The
reactions may be carried out at ambient temperature or an elevated
temperature. The heating can be accomplished either conventionally
or with microwave irradiation.
[1056] Alternatively, carboxylic acids of formula (3) can be
treated with oxalyl chloride and a catalytic amount of
N,N-dimethylformamide to provide compounds of formula (6). The
reaction is typically performed in a solvent such as, but not
limited to, dichloromethane, and may be performed at ambient or low
temperature. Acid chlorides of formula (6) can be coupled with
sulfonamides of formula (4), wherein R.sup.3 is as described
herein, to provide compounds of formula (5). The reaction is
typically performed in the presence of a base such as, but not
limited to, triethylamine, and may be carried out in the presence
of an auxiliary coupling reagents such as, but not limited to,
4-(dimethylamino)pyridine (DMAP).
[1057] Treatment of compounds of formula (5) with R.sup.1X, wherein
R.sup.1 is as described herein and X is a halogen, and a base such
as lithium bis(trimethylsilyl)amide, in a solvent system such as,
but not limited to, tetrahydrofuran, and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, provides
compounds of formula (7). The reaction is typically performed at
low temperature before warming up to ambient temperature.
##STR00024##
[1058] As shown in Scheme 2, compounds of formula (11) and (13),
which are representative of compounds of Formula (I), can be
prepared from compounds of formula (8). Compounds of formula (8)
can be treated with 1-((isocyanomethyl)sulfonyl)-4-methylbenzene in
the presence of a base such as potassium tert-butoxide, to provide
compounds of formula (15). The reaction is typically performed at
low temperature in a solvent such as, but not limited to, a mixture
of dichloromethane and ethanol.
[1059] Alternatively, compounds of formula (8) can be treated with
diethyl cyanophosphonate and LiCN to provide compounds of formula
(14). The additions are typically performed at low temperature,
such as 0.degree. C., before warming up to ambient temperature, in
a solvent such as, but not limited to, N,N-dimethylformamide.
Compounds of formula (15) can be prepared by treating compounds of
formula (14) with sodium borohydride. The reaction is typically
performed at an elevated temperature in a solvent such as, but not
limited to, ethanol.
[1060] Compounds of formula (15) can be treated with potassium
hydroxide to provide compounds of formula (10). The reaction is
typically performed at an elevated temperature in a solvent such
as, but not limited to, a mixture of water and ethylene glycol.
[1061] Compounds of formula (9) can be prepared by treating
compounds of formula (8) with a mixture of
(methoxymethyl)triphenylphosphonium chloride and potassium
tert-butoxide. The reaction is typically performed at ambient
temperature in a solvent such as, but not limited to,
tetrahydrofuran. Compounds of formula (9) can be treated with
chromium trioxide in aqueous sulfuric acid to provide compounds of
formula (10). The reaction is typically performed at low
temperature in a solvent such as, but not limited to, acetone.
[1062] Carboxylic acids of formula (10) can be coupled with
sulfonamides of formula (4), wherein R.sup.3 is as described
herein, to provide compounds of formula (11), which are
representative of compounds of Formula (I). Examples of conditions
known to generate compounds of formula (11) from a mixture of a
carboxylic acid and a sulfonamide include, but are not limited to,
adding a coupling reagent such as, but not limited to,
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC, EDAC or EDCI)
or the corresponding hydrochloride salt,
1,3-dicyclohexylcarbodiimide (DCC),
bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-meth-
ylmethanaminium hexafluorophosphate N-oxide or
2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate or
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU),
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium
hexafluorophosphate(V) (HBTU), and
2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide
(T3P.RTM.). The coupling reagents may be added as a solid, a
solution, or as the reagent bound to a solid support resin. In
addition to the coupling reagents, auxiliary-coupling reagents may
facilitate the coupling reaction. Auxiliary coupling reagents that
are often used in the coupling reactions include, but are not
limited to, 4-(dimethylamino)pyridine (DMAP),
1-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole
(HOBT). The reaction may be carried out optionally in the presence
of a base such as, but not limited to, triethylamine,
N,N-diisopropylethylamine or pyridine. The coupling reaction may be
carried out in solvents such as, but not limited to,
tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide,
dimethyl sulfoxide, dichloromethane, and ethyl acetate. The
reactions may be carried out at ambient temperature or an elevated
temperature. The heating can be accomplished either conventionally
or with microwave irradiation.
[1063] Treatment of compounds of formula (15) with sodium hydroxide
provides compounds of formula (16). The reaction is typically
performed at an elevated temperature in a solvent such as, but not
limited to, ethanol. Compounds of formula (16) can be treated with
sodium hydride and then reacted with compounds of formula (17),
wherein R.sup.3 is as described herein, to provide compounds of
formula (11), which are representative of compounds of Formula (I).
The reaction is typically performed at ambient temperature in a
solvent such as, but not limited to, tetrahydrofuran.
[1064] Compounds of formula (10) can be treated with sulfuryl
chloride to provide compounds of formula (12), wherein Y is Cl. The
reaction is typically performed at low temperature, such as
0.degree. C., and in a solvent such as, but not limited to,
dichloromethane.
[1065] Carboxylic acids of formula (12) can be coupled with
sulfonamides of formula (4), wherein R.sup.3 is as described
herein, under conditions described for the preparation of compounds
of formula (11) from compounds of formula (10), to provide
compounds of formula (13), which are representative of compounds of
Formula (I).
##STR00025## ##STR00026##
[1066] Compounds of formula (29), which are representative of
compounds of Formula (I), can be prepared as described in Scheme 3.
Compounds of formula (18), wherein X.sup.1, X.sup.2, X.sup.3,
X.sup.4 are as described herein, can be treated with a prepared
solution of tetrahydrofuran and n-butyllithium followed by lithium
tetramethylpiperidine, to provide compounds of formula (19). The
reaction is typically performed in tetrahydrofuran at low
temperature, such as -78.degree. C. Compounds of formula (20) can
be treated with a prepared mixture of oxalyl chloride and dimethyl
sulfoxide, followed by triethylamine, to provide compounds of
formula (20). The reaction is typically performed in a solvent such
as, but not limited to, dichloromethane, at a low temperature, such
as -78.degree. C. Compounds of formula (21) can be prepared by
reacting a mixture of (methoxymethyl)triphenylphosphonium chloride
and potassium tert-butoxide with compounds of formula (20). The
reaction is typically performed at ambient temperature under a
N.sub.2 atmosphere in a solvent such as, but not limited to,
tetrahydrofuran. Aldehydes of formula (23) can be prepared by
reacting compounds of formula (21) with aqueous HCl. The reaction
is typically performed at ambient temperature in a solvent such as,
but not limited to, tetrahydrofuran. Treatment of compounds of
formula (23) with CrO.sub.3 in aqueous H.sub.2SO.sub.4 can provide
compounds of formula (24). The reaction is typically performed at
low temperature, such as 0.degree. C., in a solvent such as, but
not limited to, acetone, before being quenched with 2-propanol.
Compounds of formula (24) can be reacted with, for example, ethanol
in a strong base such as, but not limited to, H.sub.2SO.sub.4, to
provide compounds of formula (25), wherein R.sup.x
CH.sub.2CH.sub.3. Compounds of formula (26), wherein Y is a
halogen, can be prepared by reacting compounds of formula (25)
under various conditions, for example, treatment with
N-bromosuccinimide at low temperature in a solvent such as, but not
limited to, acetonitrile to provide compounds of formula (26),
wherein Y is Br.
[1067] Compounds of formula (26) can be reacted with boronic acids
of formula (10A) (or the boronic ester equivalent) or zinc halides
of formula (11A) wherein R.sup.8 is as described herein and X is I,
Br, Cl or triflate, to provide compounds of formula (27). For
example, compounds of formula (27) can be prepared by reacting
compounds of formula (26) wherein Y is I, Br, Cl or triflate with
boronic acid compounds of formula (10A), wherein R.sup.8 is as
described herein (or the boronic ester equivalents), under Suzuki
coupling conditions known to those skilled in the art and widely
available in the literature. The reaction typically requires the
use of a base and a catalyst. Examples of bases include, but are
not limited to, potassium carbonate, potassium t-butoxide, sodium
carbonate, cesium carbonate, and cesium fluoride. Examples of
catalysts include, but are not limited to,
tetrakis(triphenylphosphine)palladium(0),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane, bis(triphenylphosphine)palladium(II) dichloride,
and tris(dibenzylideneacetone)dipalladium(0). The reaction may be
conducted in a solvent such as, but not limited to, water, dioxane,
1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,
tetrahydrofuran and the like or mixtures thereof. The reaction may
be conducted at ambient or elevated temperatures, and optionally in
a microwave oven. Compounds of formula (27) can also be prepared by
reacting compounds of formula (26) wherein X is I, Br, Cl or
triflate with organozinc compounds of formula (11A), wherein
R.sup.8 is as described herein, under Negishi coupling conditions
known to those skilled in the art and widely available in the
literature. The reaction typically requires the use of a palladium
or nickel catalyst. Examples of catalysts include, but are not
limited to,
dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-
-chloropyridyl)palladium(II) (PEPPSI-IPentCl),
tetrakis(triphenylphosphine)nickel(0),
tetrakis(triphenylphosphine)palladium(0),
bis(triphenylphosphine)palladium(II) dichloride,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane, tris(dibenzylideneacetone)dipalladium(0), and
palladium(II) acetate. The reaction may be conducted in a solvent
such as, but not limited to, water, dioxane,
1-methyl-2-pyrrolidinone, N,N-dimethylacetamide,
1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,
tetrahydrofuran and the like, or mixtures thereof. The reaction may
be conducted at ambient or elevated temperatures, and optionally in
a microwave oven.
[1068] Compounds of formula (27) can be treated with aqueous sodium
hydroxide to provide compounds of formula (28). The reaction may be
conducted at ambient or elevated temperatures and in a solvent such
as, but not limited to, tetrahydrofuran and methanol, or mixtures
thereof.
[1069] Carboxylic acids of formula (28) can be coupled with
sulfonamides of formula (4), wherein R.sup.3 is as described
herein, under conditions described herein for the preparation of
compounds of formula (11) from compounds of formula (10), to
provide compounds of formula (29), which are representative of
compounds of Formula (I).
##STR00027##
[1070] Compounds of formula (29), which are representative of
compounds of Formula (I), can be prepared as described in Scheme 4.
Compounds of formula (19), which can be prepared as described in
Scheme 3, can be treated with N-bromosuccinimide to provide
compounds of formula (30). The reaction is typically performed at
ambient temperature, and in a solvent such as, but not limited to,
acetonitrile. Compounds of formula (30) can be treated with carbon
tetrabromide and triphenylphosphine to provide compounds of formula
(31). The reaction is typically performed at ambient temperature,
and in a solvent such as, but not limited to, methyl tert-butyl
ether. Compounds of formula (32) can be prepared by treating
compounds of formula (31) with tetrabutylammonium cyanide. The
reaction is typically performed at ambient temperature, and in a
solvent such as, but not limited to, tetrahydrofuran.
[1071] Compounds of formula (33) can also be prepared by reacting
compounds of formula (32) with organozinc compounds of formula
(11A), wherein R.sup.8 is as described herein, under Negishi
coupling conditions known to those skilled in the art and widely
available in the literature. The reaction typically requires the
use of a palladium or nickel catalyst. Examples of catalysts
include, but are not limited to,
dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-
-chloropyridyl)palladium(II) (PEPPSI-IPentCl),
tetrakis(triphenylphosphine)nickel(0),
tetrakis(triphenylphosphine)palladium(0),
bis(triphenylphosphine)palladium(II) dichloride,
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane, tris(dibenzylideneacetone)dipalladium(0), and
palladium(II) acetate. The reaction may be conducted in a solvent
such as, but not limited to, water, dioxane,
1-methyl-2-pyrrolidinone, N,N-dimethylacetamide,
1,2-dimethoxyethane, N,N-dimethylformamide, toluene, ethanol,
tetrahydrofuran and the like, or mixtures thereof. The reaction may
be conducted at ambient or elevated temperatures, and optionally in
a microwave oven.
[1072] Compounds of formula (33) can be treated with aqueous sodium
hydroxide to provide compounds of formula (28). The reaction may be
conducted at ambient or elevated temperatures and in a solvent such
as, but not limited to, ethanol, tetrahydrofuran and methanol, or
mixtures thereof.
[1073] Carboxylic acids of formula (28) can be coupled with
sulfonamides of formula (4), wherein R.sup.3 is as described
herein, under conditions described for the preparation of compounds
of formula (11) from compounds of formula (10), to provide
compounds of formula (29), which are representative of compounds of
Formula (I).
EXAMPLES
Example I-1
4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide
[1074] The title compound was prepared and purified as described in
Example I-6, substituting
4-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid for
(R)-4-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.71-8.64 (m, 1H), 8.31-8.23 (m, 2H), 8.12 (d,
J=8.3 Hz, 1H), 7.88-7.79 (m, 1H), 7.78-7.63 (m, 2H), 6.89 (t, J=7.9
Hz, 1H), 6.70 (d, J=8.2 Hz, 1H), 6.56 (d, J=7.5 Hz, 1H), 3.98 (dd,
J=8.5, 5.7 Hz, 1H), 3.69 (s, 3H), 2.67 (h, J=9.3 Hz, 2H), 2.18-2.05
(m, 1H), 2.03-1.92 (m, 1H). MS (APCI+) m/z 381.9 (M+H).sup.+.
Example I-2
8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carbox-
amide
Example I-2A
8-chloro-1,2,3,4-tetrahydronaphthalene-1-carbonitrile
[1075] Into a 20 mL vial containing a solution of
8-chloro-3,4-dihydronaphthalen-1(2H)-one (0.196 g, 1.085 mmol)
(CAS#68449-32-1, purchased from AK) and
1-((isocyanomethyl)sulfonyl)-4-methylbenzene (0.328 g, 1.682 mmol)
in dichloromethane (5 mL) at -78.degree. C. was added a solution of
potassium 2-methylpropan-2-olate (2.007 mL, 2.007 mmol) and ethanol
(0.070 g, 1.519 mmol). The reaction was allowed to warm to room
temperature, was stirred for 16 hours, and quenched with aqueous
HCl (0.5 M, 5 mL). The organic layer was separated and
concentrated. The residue was chromatographed using a 25 g silica
gel cartridge with a gradient of 5-50% ethyl acetate/hexanes over
20 minutes to give
8-chloro-1,2,3,4-tetrahydronaphthalene-1-carbonitrile. .sup.1H NMR
(400 MHz, Chloroform-d) .delta. ppm 7.31-7.25 (m, 1H), 7.20 (t,
J=7.8 Hz, 1H), 7.08 (dd, J=7.6, 1.2 Hz, 1H), 4.20 (dd, J=5.2, 2.4
Hz, 1H), 2.99-2.89 (m, 1H), 2.87-2.80 (m, 1H), 2.47-2.33 (m, 1H),
2.04 (tdq, J=10.4, 4.8, 2.5 Hz, 2H), 1.95-1.83 (m, 1H).
Example I-2B
8-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxamide
[1076] Example I-2A (0.447 g, 2.332 mmol) was dissolved in ethanol
(7.77 mL). A solution of 3.0 M aqueous sodium hydroxide (7.77 mL,
23.32 mmol) was added, and the resulting mixture was heated at
80.degree. C. for 16 hours. The reaction was cooled in an ice bath
and was acidified with 6 M aqueous HCl (5 mL). The resulting
precipitate was filtered and washed with water to give
8-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxamide. .sup.1H NMR
(400 MHz, Chloroform-d) .delta. ppm 7.26 (d, J=7.2 Hz, 1H), 7.17
(t, J=7.7 Hz, 1H), 7.09 (dd, J=7.7, 1.2 Hz, 1H), 5.49 (s, 1H), 5.25
(s, 1H), 3.95 (dd, J=6.2, 2.8 Hz, 1H), 2.90 (dt, J=17.2, 4.6 Hz,
1H), 2.86-2.75 (m, 1H), 2.42 (dddd, J=12.6, 7.3, 3.9, 2.5 Hz, 1H),
1.97-1.78 (m, 3H). MS (ESI+) m/z 210 (M+H.sup.+).
Example I-2C
8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carbox-
amide
[1077] Example I-2B (50 mg, 0.238 mmol) was dissolved in
tetrahydrofuran (2 mL) and sodium hydride (19.08 mg, 0.477 mmol)
was added in portions. After stirring at room temperature for one
hour, naphthalene-1-sulfonyl chloride (108 mg, 0.477 mmol) was
added. After 30 minutes, the solvent was reduced in volume and the
reaction was quenched with 0.5 mL of 1 N aqueous HCl. The organics
were purified using a 12 g silica gel cartridge with an ethyl
acetate/hexane solvent system to give
8-chloro-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carb-
oxamide. .sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 8.57-8.49
(m, 1H), 8.47-8.38 (m, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.11-8.02 (m,
1H), 8.02-7.92 (m, 1H), 7.69-7.56 (m, 3H), 7.17 (t, J=7.7 Hz, 1H),
7.09 (dd, J=14.2, 7.7 Hz, 2H), 3.80 (dd, J=6.6, 3.3 Hz, 1H), 2.72
(dddd, J=23.1, 17.1, 11.0, 5.5 Hz, 2H), 2.23-2.11 (m, 1H), 1.85
(ddq, J=15.7, 10.0, 3.4 Hz, 1H), 1.73-1.58 (m, 1H), 1.52 (dd,
J=8.5, 1.0 Hz, 1H). MS (APCI+) m/z 400 (M+H.sup.+).
Example I-3
(1R)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide
Example I-3A
(R)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonyl chloride
[1078] To a solution of
(R)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (58
mg, 0.281 mmol) in dichloromethane (2 mL) was added two drops of
N,N-dimethylformamide followed by oxalyl dichloride (0.422 mL,
0.844 mmol). The reaction bubbled, and was stirred at ambient
temperature for 1 hour. The solvent was removed under a stream of
nitrogen and the resulting material was azeotroped with 1 mL of
dichloromethane, and put under high vacuum for 5 minutes. The
resulting (R)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonyl
chloride was used directly in the next step.
Example I-3B
(1R)-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1--
carboxamide
[1079] Naphthalene-1-sulfonamide (59 mg, 0.285 mmol) was dissolved
in pyridine (0.5 mL) and cooled in an ice bath. A solution of
Example I-3A (63 mg, 0.280 mmol) in 1 mL of dichloromethane was
added dropwise over 5 minutes. The reaction was allowed to warm to
room temperature. After 1 hour, the solvent was reduced under a
stream of nitrogen. The reaction was quenched with 1 mL of 1 N
aqueous HCl and dichloromethane. The organics were purified using a
10 g silica gel cartridge with an ethyl acetate/hexanes solvent
system to give the title compound. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm 8.53 (dd, J=7.5, 1.2 Hz, 1H), 8.29-8.20
(m, 1H), 8.15 (d, J=8.2 Hz, 1H), 8.01-7.92 (m, 1H), 7.63 (td,
J=7.1, 6.5, 3.9 Hz, 3H), 7.13 (t, J=7.9 Hz, 1H), 6.84 (d, J=8.2 Hz,
1H), 6.46 (d, J=7.6 Hz, 1H), 3.90 (s, 3H), 3.88-3.79 (m, 1H), 3.56
(t, J=5.2 Hz, 1H), 2.62 (dt, J=18.0, 5.3 Hz, 1H), 2.56-2.43 (m,
1H), 2.02 (d, J=7.9 Hz, 1H), 1.85-1.69 (m, 1H), 1.66-1.55 (m, 1H).
MS (APCI+) m/z 396 (M+H.sup.+).
Example I-4
5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carbo-
xamide
[1080] To a solution of
5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.494 g,
2.407 mmol) in tetrahydrofuran (6.02 mL) and N,N-dimethylformamide
(6.02 mL) was added sodium hydride (0.193 g, 4.81 mmol) in
portions. After stirring at room temperature for one hour,
naphthalene-1-sulfonyl chloride (0.553 g, 2.440 mmol) was added in
portions. After 1 hour, additional naphthalene-1-sulfonyl chloride
(0.553 g, 2.440 mmol) was added and the reaction was stirred at
room temperature for 16 hours. The solvent was reduced in vacuo.
The reaction was quenched with 6 mL of 1 N aqueous HCl and water
(10 mL) and stirred until cool. Crude material separated and was
purified using a 10 g silica gel cartridge with an ethyl
acetate/hexane solvent system to give
5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthalene-1-car-
boxamide. .sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 8.53 (dd,
J=7.5, 1.3 Hz, 1H), 8.28-8.18 (m, 1H), 8.15 (d, J=8.2 Hz, 1H),
8.03-7.96 (m, 1H), 7.98 (s, 1H), 7.70-7.57 (m, 3H), 7.14 (t, J=7.9
Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.46 (d, J=7.7 Hz, 1H), 3.90 (s,
3H), 3.56 (t, J=5.2 Hz, 1H), 2.62 (dt, J=18.7, 5.2 Hz, 1H), 2.49
(ddd, J=17.4, 9.5, 6.5 Hz, 1H), 2.11-1.98 (m, 1H), 1.85-1.70 (m,
1H), 1.67-1.55 (m, 1H), 1.38-1.23 (m, 1H). MS (APCI+) m/z 396
(M+H.sup.+).
Example I-5
1-benzyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide
[1081] Example I-8B (58 mg, <0.15 mmol) was dissolved into
anhydrous N,N-dimethylimidazolinone (50 .mu.L) and anhydrous
tetrahydrofuran (250 .mu.L), treated with benzyl bromide (19 .mu.L,
0.16 mmol) and cooled below -15.degree. C. with a dry ice/brine
bath. Over 15 minutes, a solution of 1 M LiHMDS (lithium
bis(trimethylsilyl)amide) in tetrahydrofuran (320 .mu.L, 0.32 mmol)
was added dropwise to the reaction mixture. The reaction mixture
was kept .ltoreq.-15.degree. C. for 40 minutes before being allowed
to warm to 10.degree. C. over two hours. The bath was removed and
the reaction mixture was stirred at room temperature for 16 hours.
Additional 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in
tetrahydrofuran (80 .mu.L, 0.08 mmol) was added and the reaction
mixture was stirred at room temperature for 70 minutes before
additional benzyl bromide (9 .mu.L, 0.08 mmol) was added followed
by additional 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in
tetrahydrofuran (80 .mu.L, 0.08 mmol). After another 90 minutes,
the reaction was quenched with 1 M aqueous citric acid (300 .mu.L)
and was diluted with brine. The aqueous phase was separated and was
extracted with methyl tert-butyl ether. The combined organic phases
were dried (Na.sub.2SO.sub.4), filtered, concentrated and
chromatographed on silica prepped with 1% acetic acid in 4:1
CHCl.sub.3/heptane (80 to 100% CHCl.sub.3/heptane). The crude
product was suspended into 2:1 methyl tert-butyl ether/heptane and
was collected by filtration. The collection vial was replaced and
the material was rinsed through with dichloromethane. The second
fraction was concentrated to give the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.33 (bs, 1H),
8.63 (d, J=7.9 Hz, 1H), 8.34-8.28 (m, 2H), 8.16-8.11 (m, 1H),
7.75-7.64 (m, 3H), 7.22 (d, J=7.9 Hz, 1H), 7.14-7.08 (m, 1H),
7.07-7.01 (m, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.91-6.84 (m, 2H), 6.62
(d, J=7.4 Hz, 2H), 3.23 (d, J=13.6 Hz, 1H), 2.94 (d, J=13.6 Hz,
1H), 2.65-2.55 (m, 1H), 2.28-2.12 (m, 3H). MS (ESI+) m/z 476
(M+H).sup.+.
Example I-6
(1R)-4-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1082] Into a 4 mL vial was added
(R)-4-methoxy-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (11
mg, 0.053 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (20.45 mg, 0.107 mmol), and
N,N-dimethylpyridin-4-amine (7.17 mg, 0.059 mmol) in
dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (11.05 mg,
0.053 mmol) was added neat and the reaction was stirred for 16
hours at room temperature. The solvent was removed under a stream
of nitrogen. The residue was reconstituted in acetonitrile and was
purified using preparative reverse phase HPLC/MS method TFA8 to
provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.62-8.54 (m,
1H), 8.30-8.22 (m, 2H), 8.19-8.03 (m, 1H), 7.76-7.64 (m, 3H), 7.06
(t, J=7.8 Hz, 1H), 6.77 (d, J=8.1 Hz, 1H), 6.61 (d, J=7.6 Hz, 1H),
3.74 (s, 3H), 2.74-2.55 (m, 2H), 2.42-2.30 (m, 1H), 1.85-1.73 (m,
1H), 1.27 (s, 3H). MS (APCI+) m/z 396.0 (M+H).sup.+.
Example I-7
4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide
[1083] Example I-8B (58 mg, <0.15 mmol) was dissolved into
anhydrous N,N-dimethylimidazolinone (50 .mu.L) and anhydrous
tetrahydrofuran (250 .mu.L), treated with iodoethane (27 .mu.L,
0.34 mmol) and cooled to 0.degree. C. A solution of 1 M LiHMDS
(lithium bis(trimethylsilyl)amide) in tetrahydrofuran (450 .mu.L,
0.45 mmol) was added dropwise and the reaction mixture was stirred
cold five minutes before the bath was removed. Stirring was
continued at room temperature for 16 hours. Additional iodoethane
(9 .mu.L, 0.11 mmol) was added followed by dropwise addition of 1 M
LiHMDS in tetrahydrofuran (70 .mu.L, 0.07 mmol). After the mixture
had been stirred for 40 minutes, the reaction was quenched with 1 M
aqueous citric acid (300 .mu.L), concentrated, and purified by
reverse-phase HPLC [Waters XBridge.TM. C18 5 .mu.m OBD column,
30.times.100 mm, flow rate 40 mL/minute, 20 to 90% gradient of
acetonitrile in 0.1% aqueous TFA] to give the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.12
(bs, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.30-8.23 (m, 2H), 8.11-8.07 (m,
1H), 7.73-7.63 (m, 3H), 7.25-7.19 (m, 2H), 7.18-7.13 (m, 1H),
2.84-2.73 (m, 2H), 2.37-2.29 (m, 1H), 2.04-1.90 (m, 2H), 1.68-1.60
(m, 1H), 0.46 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 414 (M+H).sup.+.
Example I-8
4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamide
Example I-8A
4-chloro-2,3-dihydro-1H-indene-1-carboxylic acid
[1084] A solution of 1,3-dithiane (7.58 g, 63.0 mmol) in anhydrous
tetrahydrofuran (100 mL) under nitrogen was cooled to -35.degree.
C. n-Butyllithium in hexanes (1.6 M, 39 mL, 62 mmol) was added
portionwise over one hour, keeping the internal temperature below
-25.degree. C. during the entire addition. After 30 minutes near
-25.degree. C., the internal temperature was allowed to slowly rise
to -5.degree. C., over another hour. A solution of 4-chloroindanone
(10.0 g, 60.0 mmol) in anhydrous tetrahydrofuran (270 mL) was added
over 35 minutes, keeping the internal temperature below 0.degree.
C. during the entire addition. The reaction mixture was permitted
to very slowly warm to room temperature over the weekend and was
quenched with 3 M aqueous citric acid (7 mL) and was diluted with
brine (20 mL). The resulting aqueous suspension was separated, and
the aqueous phase was further extracted with methyl tert-butyl
ether. The combined organic phases were washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
dissolved into toluene (120 mL). 4-Toluenesulfonic acid hydrate
(1.14 g, 6.0 mmol) was added, and the solution was refluxed for two
hours with a Dean-Stark apparatus attached to the flask. The
reaction mixture was cooled to near room temperature, washed twice
with water, and each aqueous layer was back-extracted once with
methyl tert-butyl ether. The combined organic phases were
concentrated. The residue was dissolved in acetic acid (200 mL),
treated with concentrated aqueous HCl (60 mL), and heated at
100.degree. C. for three hours. The mixture was concentrated. The
residue was dissolved in chloroform, dried (Na.sub.2SO.sub.4),
filtered, and concentrated. Chloroform (20 mL) was added to the
residue, and the mixture was treated slowly with heptane (30 mL).
The resulting suspension was left standing for 16 hours. The
material was collected by filtration, rinsed with 1:4
CHCl.sub.3/heptane, and dried under vacuum. Three additional crops
were obtained in a similar fashion to provide the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.31 (d, J=7.5 Hz,
1H), 7.22 (d, J=7.9 Hz, 1H), 7.14 (dd, J=7.9, 7.5 Hz, 1H), 4.14
(dd, J=8.7, 6.0 Hz, 1H), 3.15 (ddd, J=16.5, 8.8, 6.1 Hz, 1H), 2.97
(ddd, J=16.5, 8.8, 6.1 Hz, 1H), 2.47 (dddd, J=13.2, 8.8, 6.1, 6.0
Hz, 1H), 2.37 (dddd, J=13.2, 8.8, 8.7, 6.1 Hz, 1H). MS (DCI) m/z
214 (M.sup.+NH.sub.4).sup.+.
Example I-8B
4-chloro-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide
[1085] To a suspension of Example I-8A (1.18 g, 6.0 mmol) and
1-hydroxy-7-azabenzotriazole (136 mg, 1.0 mmol) in anhydrous
acetonitrile (10 mL) was added a suspension of carbonyl diimidazole
(1.07 g, 6.6 mmol) in acetonitrile (10 mL) over four minutes. The
resulting solution was stirred at room temperature for 30 minutes
before napthalene-1-sulfonamide (1.37 g, 6.6 mmol) was added, and
the reaction mixture was heated at 65.degree. C. for 16 hours. The
reaction mixture was cooled to near room temperature, acidified
with trifluoroacetic acid (1.2 mL), and concentrated. The crude
material was partitioned between water and methyl tert-butyl ether.
The aqueous phase was separated and extracted with methyl
tert-butyl ether. The combined organic phases were washed with
brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
residue was chromatographed on silica (30 to 65% methyl tert-butyl
ether/heptane) to provide the crude title compound. The crude
material was further purified by reverse-phase HPLC (Waters
XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm, flow rate 40
mL/minute, 20 to 70% gradient of acetonitrile in 0.1% aqueous TFA).
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.84
(bs, 1H), 8.70-8.65 (m, 1H), 8.30-8.26 (m, 2H), 8.14-8.10 (m, 1H),
7.84 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.72 (ddd, J=8.1, 6.9, 1.1 Hz,
1H), 7.67 (dd, J=7.8, 7.8 Hz, 1H), 7.18-7.13 (m, 1H), 6.97-6.92 (m,
2H), 4.09 (dd, J=8.6, 5.7 Hz, 1H), 2.82-2.76 (m, 2H), 2.22-2.12 (m,
1H), 2.05-1.96 (m, 1H). MS (ESI+) m/z 386 (M+H).sup.+.
Example I-9
1-benzyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide
[1086] Example I-4 (20 mg, 50 .mu.mol) was dissolved into a mixture
of anhydrous N,N-dimethylimidazolinone (20 .mu.L) and anhydrous
tetrahydrofuran (100 .mu.L), cooled to 0.degree. C. and treated
with 1 M LiHMDS (lithium bis(trimethylsilyl)amide)in
tetrahydrofuran (100 .mu.L, 0.10 mmol). After several minutes,
benzyl bromide (12 .mu.L, 0.10 mmol) was added dropwise, followed
after several more minutes by dropwise addition of additional 1 M
LiHMDS in tetrahydrofuran (50 .mu.L, 0.05 mmol). The reaction
mixture was stirred cold 20 minutes, then removed from the bath and
stirred at room temperature for 16 hours. Additional 1 M LiHMDS in
tetrahydrofuran (50 .mu.L, 0.05 mmol) was added, followed by benzyl
bromide (6 .mu.L, 0.05 mmol). After the reaction mixture had been
stirred for about two hours and again after another two hours, the
same amounts of each reagent were added. After stirring for another
two hours, the reaction was quenched with 1 M aqueous citric acid
(150 .mu.L), concentrated and purified by reverse-phase HPLC
[Waters XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm, flow
rate 40 mL/minute, 20 to 90% gradient of acetonitrile in 0.1%
aqueous TFA] to give the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 11.94 (bs, 1H), 8.52-8.47
(m, 1H), 8.34-8.29 (m, 2H), 8.15-8.10 (m, 1H), 7.75-7.69 (m, 1H),
7.69-7.58 (m, 2H), 7.41-7.36 (m, 1H), 7.30-7.24 (m, 1H), 7.05-7.00
(m, 1H), 6.99-6.93 (m, 1H), 6.92-6.86 (m, 1H), 6.78-6.71 (m, 2H),
6.40-6.35 (m, 1H), 3.75 (s, 3H), 3.21 (d, J=13.8 Hz, 1H), 2.92 (d,
J=13.8 Hz, 1H), 2.43-2.36 (m, 2H), 2.05-1.96 (m, 1H), 1.47-1.20 (m,
3H). MS (ESI+) m/z 486 (M+H).sup.+.
Example I-10
1-ethyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide
[1087] Example I-4 (20 mg, 50 .mu.mol) was dissolved into a mixture
of anhydrous N,N-dimethylimidazolinone (20 .mu.L) and anhydrous
tetrahydrofuran (100 .mu.L), cooled to 0.degree. C. and treated
with 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in
tetrahydrofuran (100 .mu.L, 0.10 mmol). After several minutes,
iodoethane (8.1 .mu.L, 0.10 mmol) was added dropwise, followed
after several more minutes by dropwise addition of more 1 M LiHMDS
in tetrahydrofuran (50 .mu.L, 0.05 mmol). The reaction mixture was
stirred cold 20 minutes, then removed from the bath and stirred at
room temperature for 16 hours. Additional 1 M LiHMDS in
tetrahydrofuran (50 .mu.L, 0.05 mmol) was added, followed by
additional iodoethane (4 .mu.L, 0.05 mmol). After the reaction
mixture had been stirred for about two hours and again after
another two hours, the same amounts of each reagent were added.
After being stirred another two hours, the reaction was quenched
with 1 M aqueous citric acid (150 .mu.L), concentrated and purified
by reverse-phase HPLC [Waters XBridge.TM. C18 5 .mu.m OBD column,
30.times.100 mm, flow rate 40 mL/minute, 20 to 80% gradient of
acetonitrile in 0.1% aqueous TFA] to give the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 11.81
(bs, 1H), 8.53-8.49 (m, 1H), 8.31-8.26 (m, 2H), 8.13-8.09 (m, 1H),
7.72-7.61 (m, 3H), 6.90-6.85 (m, 1H), 6.77-6.74 (m, 1H), 6.25-6.21
(m, 1H), 3.74 (s, 3H), 2.55-2.40 (m, 2H), 2.08-1.99 (m, 1H),
1.88-1.77 (m, 1H), 1.61-1.50 (m, 2H), 1.50-1.38 (m, 2H), 0.57 (t,
J=7.3 Hz, 3H). MS (ESI+) m/z=424 (M+H).sup.+.
Example I-11
(1R)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide
[1088] Example I-2 (125 mg) was separated by chiral preparative SFC
chromatography using a CHIRALPAK OJ-H, column size 21.times.250 mm,
5 micron, serial Number: OJHSAMA003-810291, using a concentration
of 12.4 mg/mL in methanol at a flow rate of 56 g/minute CO.sub.2
and UV monitoring at 220 nm to provide the title compound. R.sub.T
(chiral SFC)=4.2 minutes. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. ppm 8.52 (dd, J=7.4, 1.3 Hz, 1H), 8.50-8.43 (m, 1H), 8.27
(s, 1H), 8.13 (dt, J=8.2, 1.0 Hz, 1H), 8.02-7.94 (m, 1H), 7.62
(dqd, J=11.3, 8.1, 7.5, 4.7 Hz, 3H), 7.18-7.11 (m, 1H), 7.05 (ddd,
J=14.7, 7.7, 1.4 Hz, 2H), 3.80 (dd, J=6.6, 3.3 Hz, 1H), 2.70 (dddd,
J=23.0, 16.9, 10.9, 5.4 Hz, 2H), 2.21-2.10 (m, 1H), 1.84 (dddd,
J=13.7, 12.0, 6.6, 3.4 Hz, 1H), 1.69-1.43 (m, 2H). MS (APCI+) m/z
400 (M+H.sup.+).
Example I-12
(1S)-8-chloro-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide
[1089] Example I-2 (125 mg) was separated by chiral preparative SFC
chromatography using a CHIRALPAK OJ-H, column size 21.times.250 mm,
5 micron, serial Number: OJHSAMA003-810291, using a concentration
of 12.4 mg/mL in methanol at a flow rate of 56 g/minute CO.sub.2
and UV monitoring at 220 nm to provide the title compound. R.sub.T
(chiral SFC)=3.3 min. .sup.1H NMR (400 MHz, Chloroform-d) .delta.
ppm 8.52 (dd, J=7.4, 1.3 Hz, 1H), 8.47-8.42 (m, 1H), 8.22 (s, 1H),
8.15-8.11 (m, 1H), 8.01-7.95 (m, 1H), 7.70-7.58 (m, 3H), 7.15 (t,
J=7.7 Hz, 1H), 7.07 (ddd, J=14.4, 7.7, 1.4 Hz, 2H), 3.80 (dd,
J=6.7, 3.3 Hz, 1H), 2.71 (dddd, J=22.9, 16.8, 10.9, 5.3 Hz, 2H),
2.24-2.11 (m, 1H), 1.85 (dddd, J=13.7, 11.9, 6.6, 3.4 Hz, 1H),
1.72-1.44 (m, 2H). MS (APCI+) m/z 400 (M+H.sup.+). The absolute
structure of the title compound was determined by X-ray
crystallography.
Example I-13
4-chloro-N-(2,2-difluoro-2H-1,3-benzodioxole-4-sulfonyl)-1-ethyl-2,3-dihyd-
ro-1H-indene-1-carboxamide
[1090] To a solution of Example I-17A (27 mg, 0.12 mmol) and PyBOP
(benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate, 83 mg, 0.16 mmol) in anhydrous
N,N-dimethylformamide (300 .mu.L) at room temperature was added
N,N-diisopropylethylamine (63 .mu.L, 0.36 mmol) followed by
2,2-difluorobenzo[d][1,3]dioxole-4-sulfonamide (38 mg, 0.16 mmol
[Enamine]). The solution was heated at 45.degree. C. for 16 hours.
The reaction mixture was brought to room temperature, diluted with
methanol and purified by reverse-phase HPLC [Waters XBridge.TM. C18
5 .mu.m OBD column, 30.times.100 mm, flow rate 40 mL/minute, 20 to
80% gradient of acetonitrile in 0.1% aqueous TFA] to give the title
compound. .sup.1H NMR (501 MHz, CDCl.sub.3) .delta. ppm 8.10 (bs,
1H), 7.72 (dd, J=8.2, 1.2 Hz, 1H), 7.34 (dd, J=8.1, 1.2 Hz, 1H),
7.30 (dd, J=7.9, 0.9 Hz, 1H), 7.27 (dd, J=8.2, 8.1 Hz, 1H),
7.25-7.21 (m, 1H), 7.10 (dd, J=7.5, 0.9 Hz, 1H), 3.05-2.94 (m, 2H),
2.47 (ddd, J=13.3, 8.5, 6.4 Hz, 1H), 2.12 (ddd, J=13.3, 8.3, 6.4
Hz, 1H), 1.93 (dq, J=14.2, 7.4 Hz, 2H), 1.86 (dq, J=14.2, 7.4 Hz,
1H), 0.75 (dd, J=7.4 Hz, 3H). MS (ESI+) m/z 444 (M+H).sup.+.
Example I-14
7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide
[1091] Into a 4 mL vial was added
7-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (54 mg,
0.256 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,-
3-diamine hydrochloride (98 mg, 0.513 mmol), and
N,N-dimethylpyridin-4-amine (34.4 mg, 0.282 mmol) in
dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (53.1 mg, 0.256
mmol) was added neat and the mixture was stirred at room
temperature for 16 hours. The solvent was removed under a stream of
nitrogen. The residue was reconstituted in acetonitrile and was
purified using preparative reverse phase HPLC/MS method TFA8 to
provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.65-8.56 (m,
1H), 8.35-8.25 (m, 2H), 8.16-8.07 (m, 1H), 7.75-7.64 (m, 3H),
7.30-7.17 (m, 2H), 7.14-7.07 (m, 1H), 3.02-2.84 (m, 2H), 2.22 (dt,
J=12.6, 9.4 Hz, 1H), 1.82-1.71 (m, 1H), 1.22 (s, 3H). MS (APCI+)
m/z 400.0 (M+H).sup.+.
Example I-15
8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide
Example I-15A
8-bromo-5-methoxy-3,4-dihydronaphthalene-1-carbonitrile
[1092] A flask containing 1.6 M n-butyllithium in hexanes (4.66 mL,
7.46 mmol) was cooled to -78.degree. C. under N.sub.2 and was
treated dropwise with a solution of trimethylsilyl cyanide (1 mL,
7.46 mmol) in tetrahydrofuran (5 mL). The mixture was warmed to
room temperature and was stirred for 1 hour. The mixture was
diluted with heptanes (50 mL) and the material was collected by
filtration to provide material which contained LiCN. In a separate
flask, a solution of
8-bromo-5-methoxy-3,4-dihydronaphthalen-1(2H)-one (CAS#3693944-3,
2.8 g, 10.98 mmol) in N,N-dimethylformamide (10 mL) was cooled to
0.degree. C., treated with diethyl cyanophosphonate (3.33 mL, 21.95
mmol), and treated with 190 mg of the prepared LiCN containing
material. The mixture was stirred at room temperature for 2 hours
and was partitioned between methyl tert-butyl ether (.about.100 mL)
and water (.about.50 mL). The aqueous layer was extracted with
methyl tert-butyl ether (2.times.30 mL). The combined methyl
tert-butyl ether layers were washed with water (25 mL), washed with
brine (10 mL), dried (MgSO.sub.4), filtered, and concentrated. The
residue was dissolved in toluene (100 mL), treated with
p-toluenesulfonic acid monohydrate (0.209 g, 1.098 mmol), and
heated to reflux for 3 hours. The mixture was cooled, diluted with
methyl tert-butyl ether (.about.100 mL), washed with aqueous
NaHCO.sub.3 solution (.about.50 mL), washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel, eluting with a gradient of 20% to
50% dichloromethane in heptanes to provide the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.44 (d, J=8.9 Hz,
1H), 7.19 (t, J=5.3 Hz, 1H), 6.75 (d, J=8.9 Hz, 1H), 3.83 (s, 3H),
2.81-2.77 (m, 2H), 2.36-2.30 (m, 2H).
Example I-15B
8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile
[1093] A solution of Example I-15A (2.47 g, 9.35 mmol) in ethanol
(75 mL) was treated with NaBH.sub.4 (2.123 g, 56.1 mmol), and the
mixture was heated to reflux for 25 minutes. The mixture was
concentrated to dryness. The residue was treated with saturated
aqueous NaHCO.sub.3 solution (100 mL) and methyl tert-butyl ether
(150 mL), and stirred for 15 minutes. The layers were separated,
and the aqueous layer was extracted with methyl tert-butyl ether
(75 mL). The combined methyl tert-butyl ether layers were washed
with brine, dried (MgSO.sub.4), filtered, and concentrated. The
residue was chromatographed on silica gel, eluting with a gradient
of 5% to 15% ethyl acetate in heptanes to provide the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.41 (d,
J=8.7 Hz, 1H), 6.69 (d, J=8.7 Hz, 1H), 4.13 (d, J=4.3 Hz, 1H), 3.81
(s, 3H), 2.93 (dd, J=18.3, 5.4 Hz, 1H), 2.47 (ddd, J=18.4, 11.8,
6.7 Hz, 1H), 2.36-2.29 (m, 1H), 2.10-2.02 (m, 1H), 1.94 (qdd,
J=13.5, 5.5, 2.2 Hz, 1H), 1.81 (tdd, J=13.3, 4.9, 2.7 Hz, 1H).
Example I-15C
8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide
[1094] A solution of Example I-15B (1.68 g, 6.31 mmol) in ethanol
(20 mL) was treated with 3 M aqueous NaOH (21.04 mL, 63.1 mmol),
and the mixture was heated to 80.degree. C. 16 hours. The mixture
was cooled to 0.degree. C., treated with water (100 mL), and
stirred at 0.degree. C. for 15 minutes. The material was collected
by filtration, washed with water, and dried under vacuum for 1 hour
at 50.degree. C. to provide the title compound. .sup.1H NMR (400
MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 7.35 (d, J=8.7 Hz,
1H), 7.27 (bs, 1H), 6.88 (bs, 1H), 6.78 (d, J=8.8 Hz, 1H), 3.77 (s,
3H), 3.74-3.71 (m, 1H), 2.70 (dd, J=17.9, 4.2 Hz, 1H), 2.39 (ddd,
J=17.7, 11.1, 6.4 Hz, 1H), 2.12-2.01 (m, 1H), 1.80-1.55 (m, 3H).
LC/MS (APCI+) m/z 284,286 (M+H).sup.+.
Example I-15D
8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide
[1095] A solution of Example I-15C (1.51 g, 5.31 mmol) in
tetrahydrofuran (50 mL) under N.sub.2 was treated with 60%
dispersion of sodium hydride in mineral oil (0.468 g, 11.69 mmol),
stirred at room temperature for 1 hour, and cooled to 0.degree. C.
The mixture was treated dropwise with a solution of
1-naphthalenesulfonyl chloride (1.325 g, 5.85 mmol) in
tetrahydrofuran (20 mL), stirred at room temperature for 1 hour,
and heated to reflux for 16 hours. The mixture was cooled and
concentrated to remove the majority of the tetrahydrofuran. The
mixture was treated with methyl tert-butyl ether (.about.20 mL) and
1 M aqueous HCl (15 mL), and then treated with additional methyl
tert-butyl ether (.about.100 mL). The layers were separated, and
the organic layer was washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. The residue was treated with methyl
tert-butyl ether (.about.15 mL) and stirred. Material began to
precipitate, and heptanes (30-50 mL) were slowly added. The
material was collected by filtration, washed with cold 5:1
heptanes:methyl tert-butyl ether, and dried under vacuum with
heating at 50.degree. C. for 30 minutes to provide the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.71 (s, 1H), 8.69 (d, J=8.6 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H),
8.24 (dd, J=7.4, 0.9 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.76 (ddd,
J=8.4, 6.9, 1.2 Hz, 1H), 7.70-7.63 (m, 2H), 7.13 (d, J=8.7 Hz, 1H),
6.69 (d, J=8.8 Hz, 1H), 3.78 (dd, J=6.9, 2.8 Hz, 1H), 3.69 (s, 3H),
2.55-2.47 (m, 1H), 2.25 (ddd, J=17.7, 11.3, 6.2 Hz, 1H), 1.95-1.88
(m, 1H), 1.74 (dddd, J=13.4, 8.8, 6.4, 3.2 Hz, 1H), 1.50-1.42 (m,
1H), 1.09-0.97 (m, 1H). LC/MS (APCI+) m/z 474, 476 (M+H).sup.+.
Example I-16
4-chloro-1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N-(naphthalene-1-sulfony-
l)-2,3-dihydro-1H-indene-1-carboxamide
Example I-16A
4-chloro-1-(2,2-dimethoxyethyl)-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-
-indene-1-carboxamide
[1096] Example I-8B (386 mg, 1.0 mmol) was placed under nitrogen,
dissolved into anhydrous DMI (1,3-dimethyl-2-imidazolidinone) (300
.mu.L) and anhydrous tetrahydrofuran (1.2 mL), cooled to 0.degree.
C. and treated with 1 M LiHMDS (lithium bis(trimethylsilyl)amide)
in tetrahydrofuran (2.0 mL, 2 mmol). 2-Bromo-1,1-dimethoxyethane
(235 .mu.L, 2.0 mmol) was added dropwise over eight minutes and
after twelve more minutes the cold bath was removed. The solution
was stirred at room temperature for three days and then additional
1 M LiHMDS in tetrahydrofuran (1.0 mL, 1 mmol) was added dropwise
followed by more 2-bromo-1,1-dimethoxyethane (120 .mu.L, 1.0 mmol).
The reaction mixture was stirred at room temperature for 24 hours
more and was quenched with 1 M aqueous citric acid (1 mL) and
diluted with brine (1 mL). The aqueous phase was separated and was
extracted with methyl tert-butyl ether. The combined organic phases
were dried (Na.sub.2SO.sub.4), filtered, and concentrated. The
residue was diluted with dilute brine and extracted with ethyl
acetate/methyl tert-butyl ether. The combined organic phases were
washed with dilute brine and then with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated. The residue was
mixed with silica gel, dichloromethane and heptane and placed atop
a silica column for chromatography (50 to 80% methyl tert-butyl
ether/heptane) to give the crude title compound. .sup.1H NMR (501
MHz, CD.sub.2Cl.sub.2) .delta. ppm 9.32 (bs, 1H), 8.46-8.42 (m,
2H), 8.17-8.15 (m, 1H), 8.02-7.99 (m, 1H), 7.70-7.60 (m, 3H), 7.22
(dd, J=8.0, 0.9 Hz, 1H), 7.08-7.04 (m, 1H), 6.91-6.88 (m, 1H), 4.08
(t, J=5.6 Hz, 1H), 3.13 (s, 3H), 3.11 (s, 3H), 2.89-2.80 (m, 2H),
2.37 (ddd, J=13.2, 8.4, 6.9 Hz, 1H), 2.09-2.02 (m, 3H). MS (ESI-)
m/z 472 (M-H).sup.-.
Example I-16B
4-chloro-1-[2-(3,3-difluoropyrrolidin-1-yl)ethyl]-N-(naphthalene-1-sulfony-
l)-2,3-dihydro-1H-indene-1-carboxamide
[1097] Example I-16A (29 mg, .ltoreq.60 .mu.mol) was dissolved into
tetrahydrofuran (300 .mu.L), treated with two drops of 2 M aqueous
HCl, stirred at room temperature for 20 minutes and concentrated.
The residue was dissolved into buffer (300 .mu.L) (prepared from
3.6 g sodium acetate trihydrate, 4.6 mL acetic acid and sufficient
methanol to bring the total volume to 100 mL) with
3,3-difluoropyrrolidine hydrochloride (12 mg, 84 .mu.mol), and
treated with sodium cyanoborohydride (6 mg, 95 .mu.mol) and stirred
at room temperature for 16 hours. The reaction mixture was diluted
with N,N-dimethylformamide and methanol and purified by
reverse-phase HPLC [Waters XBridge.TM. C18 5 .mu.m OBD column,
30.times.100 mm, flow rate 40 mL/minute, 5-70% gradient of
acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate,
adjusted to pH 10 with ammonium hydroxide)] to give the title
compound. .sup.1H NMR (400 MHz, CD.sub.2Cl.sub.2) .delta. ppm
8.70-8.66 (m, 1H), 8.41-8.38 (m, 1H), 8.09 (d, J=8.2 Hz, 1H),
8.01-7.97 (m, 1H), 7.76-7.71 (m, 1H), 7.68-7.62 (m, 1H), 7.58-7.53
(m, 1H), 7.12-7.08 (m, 1H), 6.86-6.81 (m, 1H), 6.62 (d, J=7.6 Hz,
1H), 3.32-2.99 (m, 4H), 2.82-2.76 (m, 2H), 2.68-2.47 (m, 5H),
1.94-1.83 (m, 3H). MS (ESI+) m/z=519 (M+H).sup.+.
Example I-17
(1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide
Example I-17A
4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxylic acid
[1098] A solution of 1 M lithium bis(trimethylsilyl)amide in
tetrahydrofuran (12.71 mL, 12.71 mmol) was cooled to 0.degree. C.
under N.sub.2, treated dropwise with a solution of
4-chloro-2,3-dihydro-1H-indene-1-carboxylic acid (1 g, 5.09 mmol)
in tetrahydrofuran (10 mL), and stirred at 0.degree. C. for 15
minutes. The mixture was treated portionwise over 10 minutes with
ethyl iodide (0.658 mL, 8.14 mmol), stirred at room temperature for
15 minutes, heated to 50.degree. C. for 75 minutes, cooled, and
treated with 3 M aqueous NaOH (3.39 mL, 10.17 mmol). The mixture
was stirred for 1 hour, concentrated to remove most of the
tetrahydrofuran, and partitioned between methyl tert-butyl ether
(100 mL) and 1 M aqueous HCl (40 mL). The layers were separated,
and the aqueous layer was extracted with methyl tert-butyl ether
(2.times.30 mL). The combined methyl tert-butyl ether layers were
washed with brine, dried (MgSO.sub.4), filtered, and concentrated.
The residue was chromatographed on silica gel, eluting with a
gradient of 20 to 50% 200:1:1 ethyl acetate:HCOOH:H.sub.2O in
heptanes to provide the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.28 (d, J=7.5 Hz, 1H), 7.23-7.20 (m, 1H),
7.15 (t, J=7.7 Hz, 1H), 3.07 (dt, J=16.1, 8.0 Hz, 1H), 2.96 (ddd,
J=16.6, 8.9, 4.6 Hz, 1H), 2.72 (ddd, J=13.2, 8.7, 4.6 Hz, 1H), 2.20
(dq, J=14.7, 7.4 Hz, 1H), 2.01 (ddd, J=13.2, 8.8, 7.4 Hz, 1H), 1.76
(dq, J=14.8, 7.4 Hz, 1H), 0.92 (t, J=7.4 Hz, 3H).
Example I-17B
(S)-4-chloro-1-ethyl-N--((S)-2-hydroxy-1-phenylethyl)-2,3-dihydro-1H-inden-
e-1-carboxamide
[1099] A solution of Example I-17A (0.29 g, 1.291 mmol) in
dichloromethane (5 mL) was cooled to 0.degree. C., and treated all
at once with oxalyl chloride (0.565 mL, 6.45 mmol). The mixture was
treated with 1 drop of N,N-dimethylformamide, stirred at room
temperature for 45 minutes, and concentrated. The residue was
dissolved in dichloromethane (.about.2 mL) and added dropwise to a
0.degree. C. solution of (S)-(+)-2-phenylglycinol (0.266 g, 1.936
mmol) and triethylamine (0.360 mL, 2.58 mmol) in dichloromethane (3
mL). The mixture was stirred at room temperature for 30 minutes and
was concentrated. The residue was partitioned between ethyl acetate
(50 mL) and 1 M aqueous HCl (.about.25 mL). The material that was
present between the layers was isolated by filtration. The material
was determined to be a mixture of the desired products. The layers
of the filtrate were separated, and the aqueous layer was extracted
with ethyl acetate (2.times.30 mL). The combined ethyl acetate
layers were washed with brine, dried (MgSO.sub.4), filtered, and
concentrated. The residue was combined with the material isolated
by filtration and was dissolved in dichloromethane (75 mL). Silica
gel (3 g) was added, and the mixture was concentrated to dryness.
The silica gel suspension of the crude product was purified by
silica gel chromatography, eluting with a gradient of 25 to 100%
methyl tert-butyl ether in heptanes to provide the title compound
as the first diastereomer to elute from the column. .sup.1H NMR
(501 MHz, CDCl.sub.3) .delta. ppm 7.42-7.31 (m, 4H), 7.29-7.21 (m,
4H), 6.27 (d, J=6.8 Hz, 1H), 5.13-5.09 (m, 1H), 3.88-3.80 (m, 2H),
3.14-3.03 (m, 2H), 2.65 (ddd, J=13.7, 8.1, 5.7 Hz, 1H), 2.41 (t,
J=6.0 Hz, 1H), 2.25 (ddd, J=13.2, 8.3, 7.3 Hz, 1H), 2.12 (dq,
J=14.8, 7.4 Hz, 1H), 2.01 (dq, J=14.7, 7.4 Hz, 1H), 0.92 (t, J=7.4
Hz, 3H). LC/MS (APCI+) m/z 344 (M+H).sup.+.
Example I-17C
(S)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxylic acid
[1100] A solution of Example I-17B (200 mg, 0.582 mmol) in ethylene
glycol (4 mL) was treated with 4 mL of a 10% w/v KOH solution in
water (3916 mg, 6.98 mmol), heated to 130.degree. C. for 6 hours,
cooled, and partitioned between methyl tert-butyl ether (25 mL) and
water (25 mL). The methyl tert-butyl ether layer was discarded. The
aqueous layer was acidified with 6 M aqueous HCl and was extracted
with methyl tert-butyl ether. The organic layer was washed with 0.1
M aqueous HCl (25 mL), washed with brine, dried (MgSO.sub.4),
filtered, and concentrated to provide the title compound.
Example I-17D
(1S)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide
[1101] To a solution of Example I-17C (95 mg, 0.42 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161
mg, 0.84 mmol) and 4-dimethylaminopyridine (56 mg, 0.46 mmol) in
anhydrous dichloromethane (1.0 mL) was added
naphthalene-1-sulfonamide (95 mg, 0.46 mmol). The mixture was
stirred for 16 hours at room temperature. The reaction mixture was
concentrated and purified by reverse-phase HPLC (Waters XBridge.TM.
C18 5 .mu.m OBD column, 30.times.100 mm, flow rate 40 mL/minute, 20
to 100% gradient of acetonitrile in 0.1% aqueous trifluoroacetic
acid) to provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.11 (bs, 1H), 8.59 (d, J=8.3 Hz,
1H), 8.30-8.26 (m, 2H), 8.12-8.08 (m, 1H), 7.73-7.64 (m, 3H),
7.25-7.19 (m, 2H), 7.17-7.12 (m, 1H), 2.84-2.68 (m, 2H), 2.31 (ddd,
J=13.0, 8.5, 6.3 Hz, 1H), 2.06-1.91 (m, 2H), 1.65 (dq, J=14.6, 7.3
Hz, 1H), 0.45 (t, J=7.3 Hz, 3H). MS (ESI+) m/z=414 (M+H).sup.+.
Example I-18
(1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide
Example I-18A
(R)-4-chloro-1-ethyl-N--((S)-2-hydroxy-1-phenylethyl)-2,3-dihydro-1H-inden-
e-1-carboxamide
[1102] The title compound was prepared as described in Example
I-17B, and was isolated as the second diastereomer to elute from
the column. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.33-7.20
(m, 6H), 7.12-7.08 (m, 2H), 6.23 (d, J=6.7 Hz, 1H), 5.04-5.00 (m,
1H), 3.88-3.74 (m, 2H), 2.97 (t, J=7.3 Hz, 2H), 2.57-2.47 (m, 2H),
2.15 (dt, J=13.2, 7.7 Hz, 1H), 2.02 (dtt, J=21.3, 14.4, 7.4 Hz,
2H), 0.89 (t, J=7.4 Hz, 3H). LC/MS (APCI+) m/z 344 (M+H).sup.+.
Example I-18B
(R)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-carboxylic acid
[1103] A solution of
(R)-4-chloro-1-ethyl-N--((S)-2-hydroxy-1-phenylethyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide (200 mg, 0.582 mmol) in ethylene glycol (4 mL) was
treated with 4 mL of a 10% w/v KOH solution in water (3916 mg, 6.98
mmol). The mixture was heated to 130.degree. C. for 3 hours,
cooled, and partitioned between methyl tert-butyl ether (25 mL) and
water (25 mL). The methyl tert-butyl ether layer was discarded. The
aqueous layer was acidified with 6 M aqueous HCl and extracted with
methyl tert-butyl ether. The organic layer was washed with 0.1 M
aqueous HCl (25 mL), washed with brine, dried (MgSO.sub.4),
filtered, and concentrated to provide the title compound.
Example I-18C
(1R)-4-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide
[1104] To a solution of Example I-18B (95 mg, 0.42 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161
mg, 0.84 mmol) and 4-dimethylaminopyridine (56 mg, 0.46 mmol) in
anhydrous dichloromethane (1.0 mL) was added
naphthalene-1-sulfonamide (95 mg, 0.46 mmol). The mixture was
stirred for 16 hours at room temperature. The reaction mixture was
concentrated and purified by reverse-phase HPLC (Waters XBridge.TM.
C18 5 urn OBD column, 30.times.100 mm, flow rate 40 mL/minute, 20%
to 100% gradient of acetonitrile in 0.1% aqueous trifluoroacetic
acid) to provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.11 (bs, 1H), 8.59 (d, J=8.3 Hz,
1H), 8.30-8.26 (m, 2H), 8.11-8.08 (m, 1H), 7.73-7.64 (m, 3H),
7.25-7.19 (m, 2H), 7.17-7.12 (m, 1H), 2.84-2.68 (m, 2H), 2.31 (ddd,
J=13.0, 8.5, 6.3 Hz, 1H), 2.05-1.91 (m, 2H), 1.65 (dq, J=14.5, 7.3
Hz, 1H), 0.45 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 414 (M+H).sup.+.
Example I-19
4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide
Example I-19A
4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonitrile
[1105] In a 50 mL round bottom flask,
4-bromo-7-methoxy-2,3-dihydro-1H-inden-1-one (0.977 g, 4.05 mmol)
(CAS#5411-61-0, Aldrich) and TOSMIC (toluenesulfonylmethyl
isocyanide, 1.029 g, 5.27 mmol) were dissolved in dimethoxyethane
(20 mL). The reaction was cooled under nitrogen to -8.degree. C.
with an ice/acetone/dry ice bath. Solid potassium tert-butoxide
(1.046 g, 9.32 mmol) was added in portions keeping the internal
temperature <-5.degree. C. over about an hour. The reaction was
allowed to slowly warm to room temperature for 16 hours. The
solvent was removed in vacuo and the crude material was quenched
with water (30 mL). The aqueous layer was extracted with ether
(4.times.50 mL) and the organics were washed with brine, dried
(Na.sub.2SO.sub.4), and filtered. The solvent was removed in vacuo
and the crude material was chromatographed using a 40 g silica gel
cartridge with 1-50% ethyl acetate/hexanes to give the title
compound. .sup.1H NMR (400 MHz, Chloroform-d) .delta. 7.40 (dd,
J=8.7, 0.7 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H ppm), 4.23-4.17 (m, 1H),
3.89 (s, 3H), 3.24-3.11 (m, 1H), 3.06-2.95 (m, 1H), 2.61-2.42 (m,
2H).
Example I-19B
4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid
[1106] Example I-19A (1.3 g, 5.16 mmol) was dissolved in ethanol
(17.2 mL). A solution of sodium hydroxide (2.06 g, 51.6 mmol) in
17.2 mL of water was added, and the resulting mixture was heated at
80.degree. C. for 16 hours. The reaction was cooled in an ice bath
and was acidified with 6 M aqueous HCl (11 mL) to pH .about.2. The
resulting precipitate was filtered and washed with water to give
the title compound. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 7.38 (d, J=8.6 Hz, 1H), 6.79 (d,
J=8.7 Hz, 1H), 3.97 (dd, J=9.4, 4.5 Hz, 1H), 3.74 (s, 3H), 2.95
(ddd, J=16.1, 8.7, 7.2 Hz, 1H), 2.85 (ddd, J=16.3, 9.0, 4.8 Hz,
1H), 2.39 (dtd, J=13.1, 9.2, 7.2 Hz, 1H), 2.15 (tt, J=8.6, 4.5 Hz,
1H). MS (ESI+) m/z 271 (M+H.sup.+) --Br doublet.
Example I-19C
4-bromo-7-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide
[1107] Example I-19B (154 mg, 0.568 mmol),
naphthalene-1-sulfonamide (118 mg, 0.568 mmol),
((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diamine
hydrochloride (218 mg, 1.136 mmol) and N,N-dimethylpyridin-4-amine
(76 mg, 0.625 mmol) were dissolved in dimethylacetamide (2.5 mL).
The reaction was stirred at room temperature for 2 hours. The
reaction was quenched with water (10 mL) and diluted with ethyl
acetate (75 mL). The organics were washed with water and brine,
dried over sodium sulfate, filtered, and concentrated. The crude
material was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide the title compound. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm 9.65 (s, 1H), 8.47 (dt, J=7.4, 1.0 Hz,
1H), 8.43-8.35 (m, 1H), 8.12-8.05 (m, 1H), 7.97-7.88 (m, 1H),
7.62-7.51 (m, 3H), 7.32 (d, J=8.6 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H),
4.03 (dd, J=9.0, 1.8 Hz, 1H), 3.95 (s, 3H), 2.91-2.70 (m, 2H), 2.54
(ddt, J=12.8, 7.6, 2.3 Hz, 1H), 2.17-1.96 (m, 1H). MS (APCI+) m/z
462 (M+H.sup.+).
Example I-20
(6S)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][1-
,3]dioxole-6-carboxamide
[1108] Into a 4 mL vial was weighed
(6S)-6-methyl-7,8-dihydrocyclopenta[g][1,3]benzodioxole-6-carboxylic
acid (9.03 mg, 0.036 mmol). A stock solution of
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.27 M in dichloromethane, 300 .mu.L, 0.08 mmol,
2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.15 M in
dichloromethane, 300 .mu.L, 0.05 mmol, 1.1 equivalents) was added.
A slurry of naphthalene-1-sulfonamide (0.15 M in dichloromethane,
3000, 0.04 mmol, 1.0 equivalent) was added and the reaction stirred
for 16 hours at room temperature. The solvent was removed under a
stream of nitrogen. The residue was reconstituted in acetonitrile
and was purified using preparative reverse phase HPLC/MS method
TFA8 to provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.59-8.51 (m,
1H), 8.27 (t, J=7.2 Hz, 2H), 8.14-8.07 (m, 1H), 7.75-7.65 (m, 3H),
6.63 (d, J=7.9 Hz, 1H), 6.50 (d, J=7.9 Hz, 1H), 5.96-5.90 (m, 2H),
2.76-2.63 (m, 1H), 2.63-2.55 (m, 1H), 2.46-2.34 (m, 1H), 1.88-1.76
(m, 1H), 1.28 (s, 3H). MS (APCI+) m/z 410.0 (M+H).sup.+.
Example I-21
(6R)-6-methyl-N-(naphthalene-1-sulfonyl)-7,8-dihydro-2H,6H-indeno[4,5-d][1-
,3]dioxole-6-carboxamide
[1109] Into a 4 mL vial was weighed
(6R)-6-methyl-7,8-dihydrocyclopenta[g][1,3]benzodioxole-6-carboxylic
acid (9.03 mg, 0.036 mmol). A stock solution of
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.27 M in dichloromethane, 300 .mu.L, 0.08 mmol,
2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.15 M in
dichloromethane, 300 .mu.L, 0.05 mmol, 1.1 equivalents) was added.
A slurry of naphthalene-1-sulfonamide (0.15 M in dichloromethane,
3000, 0.04 mmol, 1.0 equivalent) was added and the reaction stirred
for 16 hours at room temperature. The solvent was removed under a
stream of nitrogen. The residue was reconstituted in acetonitrile
and purified using preparative reverse phase HPLC/MS method TFA8 to
provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.59-8.51 (m,
1H), 8.31-8.23 (m, 2H), 8.15-8.06 (m, 1H), 7.76-7.64 (m, 3H), 6.63
(d, J=7.9 Hz, 1H), 6.50 (d, J=7.9 Hz, 1H), 5.96-5.90 (m, 2H),
2.76-2.63 (m, 1H), 2.63-2.54 (m, 1H), 2.46-2.34 (m, 1H), 1.88-1.76
(m, 1H), 1.28 (s, 3H). MS (APCI+) m/z 410.0 (M+H).sup.+.
Example I-22
(1S)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1110] Into a 4 mL vial was weighed
(1S)-6-methoxy-1-methyl-indane-1-carboxylic acid (16.4 mg, 0.079
mmol). A stock solution of
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.39 M in dichloromethane, 400 .mu.L, 0.16 mmol,
2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.22 M in
dichloromethane, 400 .mu.L, 0.088 mmol, 1.1 equivalents) was added.
A slurry of naphthalene-1-sulfonamide (0.20 M in dichloromethane,
400 .mu.L, 0.08 mmol, 1.0 equivalent) was added and the reaction
stirred for 16 hours at room temperature. The solvent was removed
under a stream of nitrogen. The residue was reconstituted in
acetonitrile and purified using preparative reverse phase HPLC/MS
method TFA8 to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm
8.61-8.53 (m, 1H), 8.31-8.23 (m, 2H), 8.14-8.05 (m, 1H), 7.73-7.63
(m, 3H), 7.03 (d, J=8.3 Hz, 1H), 6.71 (dd, J=8.2, 2.5 Hz, 1H), 6.66
(d, J=2.4 Hz, 1H), 3.62 (s, 3H), 2.74-2.62 (m, 1H), 2.63-2.54 (m,
1H), 2.44-2.32 (m, 1H), 1.87-1.75 (m, 1H), 1.33 (s, 3H). MS (APCI+)
m/z 396.1 (M+H).sup.+.
Example I-23
(1R)-6-methoxy-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1111] Into a 4 mL vial was weighed
(1R)-6-methoxy-1-methyl-indane-1-carboxylic acid (16.4 mg, 0.079
mmol). A stock solution of
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.39 M in dichloromethane, 400 .mu.L, 0.16 mmol,
2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.22 M in
dichloromethane, 400 .mu.L, 0.088 mmol, 1.1 equivalents) was added.
A slurry of naphthalene-1-sulfonamide (0.20 M in dichloromethane,
400 .mu.L, 0.08 mmol, 1.0 equivalent) was added and the reaction
stirred for 16 hours at room temperature. The solvent was removed
under a stream of nitrogen. The residue was reconstituted in
acetonitrile and was purified using preparative reverse phase
HPLC/MS method TFA8 to provide the title compound. .sup.1H NMR (400
MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm
8.60-8.53 (m, 1H), 8.31-8.23 (m, 2H), 8.14-8.05 (m, 1H), 7.73-7.63
(m, 3H), 7.03 (d, J=8.2 Hz, 1H), 6.71 (dd, J=8.2, 2.5 Hz, 1H), 6.66
(d, J=2.5 Hz, 1H), 3.62 (s, 3H), 2.74-2.54 (m, 2H), 2.44-2.32 (m,
1H), 1.87-1.75 (m, 1H), 1.34 (s, 3H). MS (APCI+) m/z 396.1
(M+H).sup.+.
Example I-24
N-(naphthalene-1-sulfonyl)-6,7,8,9-tetrahydro-2H-naphtho[1,2-d][1,3]dioxol-
e-6-carboxamide
[1112] Into a 4 mL vial was weighed
6,7,8,9-tetrahydro-naphtho[1,2-d][1,3]dioxole-6-carboxylic acid
(17.5 mg, 0.079 mmol). A stock solution of
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.39 M in dichloromethane, 400 .mu.L, 0.16 mmol,
2.0 equivalents), and N,N-dimethylpyridin-4-amine (0.22 M in
dichloromethane, 400 .mu.L, 0.088 mmol, 1.1 equivalents) was added.
A slurry of naphthalene-1-sulfonamide (0.20 M in dichloromethane,
400 .mu.L, 0.08 mmol, 1.0 equivalent) was added and the reaction
stirred for 16 hours at room temperature. The solvent was removed
under a stream of nitrogen. The residue was reconstituted in
acetonitrile and was purified using preparative reverse phase
HPLC/MS method TFA8 to provide the title compound. .sup.1H NMR (400
MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm
8.68-8.61 (m, 1H), 8.32-8.23 (m, 2H), 8.17-8.10 (m, 1H), 7.86-7.79
(m, 1H), 7.78-7.71 (m, 1H), 7.68 (t, J=7.8 Hz, 1H), 6.34 (d, J=8.0
Hz, 1H), 6.12 (d, J=8.0 Hz, 1H), 5.88 (d, J=10.9 Hz, 2H), 3.65 (t,
J=6.1 Hz, 1H), 2.48-2.35 (m, 2H), 1.79-1.60 (m, 2H), 1.52-1.30 (m,
2H). MS (APCI+) m/z 410.0 (M+H).sup.+.
Example I-26
(1S)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
[1113] Into a 4 mL vial was added
7-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (67.2 mg,
0.319 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,-
3-diamine hydrochloride (122 mg, 0.638 mmol), and
N,N-dimethylpyridin-4-amine (42.9 mg, 0.351 mmol) in
dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (66.1 mg, 0.319
mmol) was added neat and the mixture was stirred at room
temperature for 16 hours. The solvent was removed under a stream of
nitrogen. The residue was reconstituted in acetonitrile and
purified using preparative reverse phase HPLC/MS method TFA8 to
provide the racemate of title compound. The material was separated
by chiral preparative SFC chromatography using a CHIRALPAK OJ-H,
column size 21.times.250 mm, 5 micron, serial Number:
OJH0SAND002-011141, using a concentration of 15 mg/mL in methanol
at a flow rate of 56 g/minute CO.sub.2 and UV monitoring at 220 nm
to provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.50-8.41 (m,
1H), 8.33-8.25 (m, 2H), 8.10 (dd, J=7.3, 1.9 Hz, 1H), 7.74-7.61 (m,
3H), 7.58-7.51 (m, 1H), 7.37-7.22 (m, 3H), 7.16 (td, J=7.8, 1.4 Hz,
1H), 6.97-6.91 (m, 2H), 6.89-6.81 (m, 1H), 6.76 (d, J=8.1 Hz, 1H),
4.99 (d, J=9.5 Hz, 1H), 4.36 (d, J=9.6 Hz, 1H). MS (APCI+) m/z
430.0 (M+H).sup.+.
Example I-27
(1R)-7-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
[1114] Example I-27 was isolated as the second enantiomer from the
preparative SFC separation described in Example I-26. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
ppm 8.50-8.41 (m, 1H), 8.33-8.25 (m, 2H), 8.10 (dd, J=7.3, 1.9 Hz,
1H), 7.74-7.61 (m, 3H), 7.58-7.51 (m, 1H), 7.37-7.22 (m, 3H), 7.16
(td, J=7.8, 1.4 Hz, 1H), 6.97-6.91 (m, 2H), 6.89-6.81 (m, 1H), 6.76
(d, J=8.1 Hz, 1H), 4.99 (d, J=9.5 Hz, 1H), 4.36 (d, J=9.6 Hz, 1H).
MS (APCI+) m/z 400 (M+H).sup.+.
Example I-28
4-bromo-1-ethyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1115] To a cooled (ice bath) solution of Example I-19B (30 mg,
0.065 mmol) in tetrahydrofuran (0.5 mL),
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.029 mL) and
iodoethane (0.012 mL, 0.143 mmol) was added a solution of 1 M
lithium bis(trimethylsilyl)amide (0.196 mL, 0.196 mmol) in
tetrahydrofuran dropwise. The reaction mixture was stirred in the
cold bath for five minutes before the bath was removed. Stirring
was continued at room temperature. After 40 minutes, additional
iodoethane (0.012 mL, 0.143 mmol) and 1 M lithium
bis(trimethylsilyl)amide (0.196 mL, 0.196 mmol) in tetrahydrofuran
were added. After the mixture had been stirred 5 hours total, the
reaction was quenched with 1 M aqueous citric acid (300 .mu.L). The
organics were separated and the aqueous layer was extracted with 1
mL of ethyl acetate. The combined organics were dried in a vacuum
oven and the crude material was purified by reverse-phase
preparative HPLC on a Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100
.ANG. AXIA.TM. column (30 mm.times.150 mm). A gradient of
acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0
minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0
minutes linear gradient 95-10% A) to give the title compound.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 9.71 (s, 1H), 8.50
(dd, J=7.4, 1.3 Hz, 1H), 8.41-8.32 (m, 1H), 8.11 (d, J=8.3 Hz, 1H),
7.94 (dd, J=7.2, 2.1 Hz, 1H), 7.65-7.59 (m, 1H), 7.59-7.51 (m, 2H),
7.39 (d, J=8.7 Hz, 1H), 6.71 (d, J=8.7 Hz, 1H), 3.93 (s, 3H),
2.83-2.58 (m, 3H), 2.16 (dq, J=14.7, 7.4 Hz, 1H), 1.82-1.66 (m,
2H), 0.46 (t, J=7.5 Hz, 3H). MS (ESI+) m/z 488 (M+H).sup.+.
Example I-29
4-chloro-1-(cyclopropylmethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide
[1116] To a solution of Example I-8B (15 mg, 0.04 mmol, 1.0
equivalent) in 30 .mu.l of 1,3-dimethyl-2-imidazolidinone and 200
.mu.l of tetrahydrofuran was added LiHMDS (lithium
bis(trimethylsilyl)amide) (1 M in tetrahydrofuran, 120 .mu.L, 0.12
mmol, 3.0 equivalents) at 0.degree. C. over 5 minutes. After 10
minutes (bromomethyl)cyclopropane (12.1 mg, 0.09 mmol, 2.3
equivalents) was added in 200 .mu.l of tetrahydrofuran. The
reaction was degassed, flushed with N.sub.2 and allowed to stir at
0.degree. C. for another 10 minutes, and stirred at room
temperature for 2 hours. The reaction was purified via preparative
reverse phase HPLC/MS method TFA8 to afford the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.63-8.56 (m, 1H), 8.22-8.17 (m, 2H), 8.06-8.01
(m, 1H), 7.65-7.60 (m, 3H), 7.24-7.07 (m, 3H), 2.83-2.72 (m, 2H),
2.46-2.31 (m, 1H), 2.10 (s, 1H), 1.96-1.86 (m, 1H), 1.53-1.48 (m,
1H), 0.25-0.20 (m, 1H), 0.14-0.07 (m, 2H), -0.15--0.20 (m, 2H). MS
(APCI+) m/z 440.0 (M+H).sup.+.
Example I-30
1-butyl-4-chloro-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide
[1117] To a solution of Example I-8B (15 mg, 0.04 mmol, 1.0
equivalent) in 30 .mu.l of DMI (1,3-dimethyl-2-imidazolidinone) and
200 .mu.l of tetrahydrofuran was added LiHMDS (lithium
bis(trimethylsilyl)amide) (1 M in tetrahydrofuran, 120 .mu.L, 0.12
mmol, 3.0 equivalents) at 0.degree. C. over 5 minutes. After 10
minutes bromobutane (12.3 mg, 0.09 mmol, 2.3 equivalents) was added
in 200 .mu.l of tetrahydrofuran. The reaction was degassed, flushed
with N.sub.2, was allowed to stir at 0.degree. C. for another 10
minutes, and stirred at room temperature for 2 hours. The reaction
mixture was purified via preparative reverse phase HPLC/MS method
TFA8 to afford the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.62 (d, J=8.0
Hz, 1H), 8.25-8.20 (m, 2H), 8.09-8.04 (m, 1H), 7.68-7.63 (m, 3H),
7.33-7.26 (m, 1H), 7.19 (dt, J=15.3, 7.7 Hz, 2H), 2.76 (s, 2H),
2.48-2.29 (m, 1H), 2.06-1.95 (m, 1H), 1.89 (s, 1H), 1.54-1.49 (m,
1H), 1.07-0.95 (m, 2H), 0.73-0.68 (m, 2H), 0.57 (t, J=7.3 Hz, 3H).
MS (APCI+) m/z 442.0 (M+H).sup.+.
Example I-31
4-chloro-1-ethyl-N-(8-hydroxynaphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1118] Example I-17A (17.3 mg, 0.08 mmol, 1.0 equivalent), EDC HCl
(N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride) (29.6
mg, 0.15 mmol, 2.0 equivalents) and DMAP (4-dimethylaminopyridine)
(10.4 mg, 0.08 mmol, 1.1 equivalents) were dissolved in
dichloromethane (0.3 mL). The mixture was added to a solution of
8-hydroxynaphthalene-1-sulfonamide (20.0 mg, 0.09 mmol, 1.2
equivalents) in dichloromethane (0.3 mL). The reaction was stirred
for 16 hours at room temperature. The solvent was removed under a
stream of N.sub.2. The residue was reconstituted in acetonitrile
and was purified using preparative reverse phase HPLC/MS method
TFA10 to afford the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.31 (dd, J=7.5,
1.3 Hz, 1H), 8.16 (dd, J=8.4, 1.3 Hz, 1H), 7.63-7.51 (m, 2H), 7.47
(t, J=7.8 Hz, 1H), 7.33-7.18 (m, 3H), 7.14 (dd, J=7.5, 1.4 Hz, 1H),
2.91-2.71 (m, 2H), 2.49-2.37 (m, 1H), 2.11-1.97 (m, 2H), 1.82-1.68
(m, 1H), 0.61 (t, J=7.3 Hz, 3H). MS (APCI+) m/z 430.0
(M+H).sup.+.
Example I-32
8-bromo-5-ethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide
Example I-32A
8-bromo-5-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide
[1119] A solution of
8-bromo-5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide (Example I-15, 500 mg, 1.054 mmol) in
dichloromethane (15 mL) under N.sub.2 at 0.degree. C. was treated
dropwise with 1 M BBr.sub.3 in dichloromethane (3162 .mu.l, 3.16
mmol), stirred at 0.degree. C. for 1 hour, stirred at room
temperature for 1 hour, cooled to 0.degree. C., diluted with
dichloromethane (80 mL), treated with 0.5 M aqueous HCl (100 mL),
and transferred to a separatory funnel. The aqueous layer was
extracted with dichloromethane (30 mL). The combined
dichloromethane layers were treated with methanol (.about.10 mL) to
dissolve some precipitate that had formed. The homogenous solution
was dried (MgSO.sub.4), filtered, and concentrated. The residue was
treated with dichloromethane (.about.20 mL) and heated to dissolve
part of the material on the sides of the flask and was allowed to
stand at room temperature for 16 hours. The material was collected
by filtration to provide the title compound. The filtrate was
concentrated and the residue was taken up in dichloromethane
(.about.3 mL) and the resulting material was collected by
filtration to provide additional title compound. The combined
material was dried under vacuum with heating (50.degree. C.) for
.about.30 minutes to provide the title compound. .sup.1H NMR (400
MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.67 (s, 1H), 9.51
(bs, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.24 (dd,
J=7.4, 1.2 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.75 (ddd, J=8.5, 6.9,
1.4 Hz, 1H), 7.70-7.63 (m, 2H), 6.94 (d, J=8.6 Hz, 1H), 6.53 (d,
J=8.6 Hz, 1H), 3.75 (dd, J=6.3, 2.4 Hz, 1H), 2.52-2.44 (m, 1H),
2.22 (ddd, J=17.5, 11.2, 6.1 Hz, 1H), 1.90 (d, J=12.7 Hz, 1H), 1.73
(dddd, J=13.5, 9.0, 6.5, 3.2 Hz, 1H), 1.49-1.40 (m, 1H), 1.10-0.97
(m, 1H). MS (ESI+) m/z 460,462 (M+H).sup.+.
Example I-32B
8-bromo-5-ethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide
[1120] A solution of Example I-32A
(8-bromo-5-hydroxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthal-
ene-1-carboxamide) (15 mg, 0.033 mmol) in N,N-dimethylformamide
(0.3 mL) was treated with ethyl iodide (15.80 .mu.l, 0.196 mmol),
treated with cesium carbonate (53.1 mg, 0.163 mmol), stirred at
room temperature for 30 minutes, and filtered. The filtrate was
directly purified by reverse-phase HPLC [Waters XBridge.TM. RP18
column, 5 .mu.m, 30.times.100 mm, flow rate 40 mL/minute, 5-40%
(over 15 minutes) gradient of acetonitrile in 0.1% TFA] to afford
the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.71 (s, 1H), 8.69 (d, J=8.6 Hz,
1H), 8.28 (d, J=8.3 Hz, 1H), 8.24 (dd, J=7.4, 1.1 Hz, 1H), 8.11 (d,
J=7.9 Hz, 1H), 7.76 (ddd, J=8.5, 6.9, 1.3 Hz, 1H), 7.70-7.62 (m,
2H), 7.10 (d, J=8.7 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 3.99-3.86 (m,
2H), 3.78 (dd, J=6.2, 2.3 Hz, 1H), 2.56-2.49 (m, 1H), 2.25 (ddd,
J=17.7, 11.3, 6.2 Hz, 1H), 1.91 (d, J=12.3 Hz, 1H), 1.74 (tdd,
J=13.5, 6.5, 2.5 Hz, 1H), 1.50-1.42 (m, 1H), 1.26 (t, J=6.9 Hz,
3H), 1.09-0.96 (m, 1H). MS (APCI+) m/z 488,490 (M+H).sup.+.
Example I-33
8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide
[1121] In a 4 mL vial was added
8-bromo-5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide (Example I-15, 35 mg, 0.074 mmol) and PEPPSI
IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (6.35 mg, 7.38 .mu.mol) in tetrahydrofuran (0.5
mL). Cyclobutylzinc(II) bromide (0.738 mL, 0.369 mmol) was added.
The reaction was stirred at room temperature for 3 hours, and
heated at 60.degree. C. for 16 hours. The sample was directly
purified using preparative HPLC/MS TFA8 to afford the title
compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.76 (d, J=8.7
Hz, 1H), 8.38-8.23 (m, 2H), 8.23-8.08 (m, 1H), 7.93-7.82 (m, 1H),
7.82-7.73 (m, 1H), 7.73-7.58 (m, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.74
(d, J=8.6 Hz, 1H), 3.73 (d, J=3.4 Hz, 1H), 3.70 (s, 3H), 2.68-2.57
(m, 2H), 2.37-2.22 (m, 1H), 2.21-2.11 (m, 1H), 2.03-1.90 (m, 1H),
1.84-1.49 (m, 4H), 1.41 (q, J=9.5, 9.0 Hz, 1H), 1.31-0.95 (m, 3H).
MS (APCI+) m/z 450.0 (M+H).sup.+.
Example I-34
8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide
Example I-34A
8-chloro-1-ethyl-1,2,3,4-tetrahydronaphthalene-1-carbonitrile
[1122] To a cooled (ice bath) solution of
8-chloro-1,2,3,4-tetrahydronaphthalene-1-carbonitrile (514 mg, 2.68
mmol, Example I-2A) and ethyl iodide (0.650 mL, 8.05 mmol) in
tetrahydrofuran (2 mL) was added 1 M potassium tert-butoxide in
tetrahydrofuran (2.68 mL, 2.68 mmol). The ice bath was removed.
N,N-Dimethylformamide (1.5 mL) was added until everything
dissolved. After 1 hour, additional 1 M potassium tert-butoxide in
tetrahydrofuran (2.68 mL, 2.68 mmol) was added and the reaction was
stirred at room temperature for 18 hours. The reaction was quenched
with water, diluted with methyl tert-butyl ether (90 mL), and
acidified with 1 M aqueous HCl (.about.2 mL). The methyl tert-butyl
ether layer was separated, dried over sodium sulfate, filtered,
concentrated and chromatographed using a 12 g silica gel cartridge
eluting with 5-50% ethyl acetate in heptane over 20 minutes to
provide the title compound. .sup.1H NMR (400 MHz, Chloroform-d)
.delta. ppm 7.28 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.7 Hz, 1H), 7.06
(dq, J=7.6, 1.1 Hz, 1H), 2.92-2.77 (m, 2H), 2.44-2.32 (m, 1H),
2.32-2.18 (m, 2H), 1.95-1.73 (m, 3H), 1.11 (t, J=7.4 Hz, 3H).
Example I-34B
8-chloro-1-ethyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide
[1123] Example I-34A (0.550 g, 2.503 mmol) was dissolved in ethanol
(5 mL). A solution of sodium hydroxide (0.778 g, 19.45 mmol) in
water (5.00 mL) was added, and the resulting mixture was heated at
80.degree. C. for 72 hours. The solvent was reduced in volume and
the resulting aqueous layer was diluted with water (10 mL) and
extracted with 100 mL of methyl tert-butyl ether. The extracts were
dried over sodium sulfate, and filtered. The solvent was removed in
vacuo to provide the title compound. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm 7.30-7.22 (m, 1H), 7.18-7.12 (m, 1H),
7.07 (td, J=7.5, 1.3 Hz, 1H), 5.26 (s, 2H), 2.90-2.80 (m, 2H),
2.45-2.33 (m, 1H), 2.32-2.21 (m, 2H), 1.97-1.73 (m, 3H), 1.12 (t,
J=7.4 Hz, 3H). MS (ESI+) 238 m/z (M+H.sup.+).
Example I-34C
8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide
[1124] Example I-34B (0.541 g, 2.276 mmol) was dissolved in
tetrahydrofuran (2.5 mL) and sodium hydride (0.182 g, 4.55 mmol) as
a 60% dispersion in mineral oil was added in portions. After
stirring at room temperature for 60 minutes, naphthalene-1-sulfonyl
chloride (0.516 g, 2.276 mmol) was added in portions. The reaction
was warmed at 30.degree. C. for 2 hours. The solvent was reduced
under a stream of nitrogen. The reaction was diluted with methyl
tert-butyl ether and quenched with 1 mL of 1 N aqueous HCl and
water (1 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated. The residue was triturated with 50%
methyl tert-butyl ether/heptanes and the resulting precipitate was
washed with heptanes to give the title compound. .sup.1H NMR (500
MHz, Chloroform-d) .delta. ppm 8.57 (dt, J=7.4, 1.0 Hz, 1H),
8.43-8.33 (m, 1H), 8.19-8.13 (m, 1H), 8.04-7.94 (m, 1H), 7.88 (s,
1H), 7.71-7.57 (m, 3H), 7.20-7.06 (m, 2H), 7.00 (dd, J=7.6, 1.6 Hz,
1H), 2.86 (dt, J=16.4, 5.3 Hz, 1H), 2.79-2.70 (m, 1H), 2.37-2.26
(m, 1H), 1.96 (ddd, J=13.9, 10.3, 3.6 Hz, 1H), 1.91-1.68 (m, 4H),
0.62-0.49 (m, 3H). MS (APCI+) m/z 428 (M+H.sup.+).
Example I-35
4-chloro-N-(naphthalene-1-sulfonyl)-1-{[6-(trifluoromethyl)pyridin-2-yl]me-
thyl}-2,3-dihydro-1H-indene-1-carboxamide
[1125] To a solution of Example I-8B (20 mg, 0.05 mmol, 1.0
equivalent) in 30 .mu.l of DMI (1,3-dimethyl-2-imidazolidinone) and
200 .mu.l of tetrahydrofuran was added LiHMDS (lithium
bis(trimethylsilyl)amide) (1 M in tetrahydrofuran, 155 .mu.L, 0.15
mmol, 3.0 equivalents) at 0.degree. C. over 5 minutes. After 10
minutes, 2-(chloromethyl)-6-(trifluoromethyl)pyridine (23.3 mg,
0.12 mmol, 2.3 equivalents) was added in 200 .mu.l of
tetrahydrofuran. The reaction was degassed, flushed with N.sub.2
and allowed to stir at 0.degree. C. for another 10 minutes, and
stirred at room temperature for 2 hours. The reaction was purified
via preparative reverse phase HPLC/MS method TFA6. Impurities were
present after TFA purification and the sample was purified via
preparative reverse phase HPLC/MS method AA6 to afford the title
compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.61 (d, J=8.5
Hz, 1H), 8.15 (d, J=7.3 Hz, 1H), 8.07 (d, J=8.3 Hz, 1H), 7.96 (d,
J=8.1 Hz, 1H), 7.60-7.51 (m, 3H), 7.50-7.42 (m, 2H), 7.14-7.05 (m,
3H), 7.04-6.96 (m, 1H), 3.56 (d, J=13.9 Hz, 1H), 3.15 (d, J=14.1
Hz, 1H), 2.82-2.70 (m, 1H), 2.51-2.36 (m, 2H), 2.19-2.08 (m, 1H).
MS (APCI+) m/z 544.9 (M+H).sup.+.
Example I-36
4-chloro-1-[(6-chloropyridin-3-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3-d-
ihydro-1H-indene-1-carboxamide
[1126] To a solution of Example I-8B (20 mg, 0.05 mmol, 1.0
equivalent) in 30 .mu.l of DMI (1,3-dimethyl-2-imidazolidinone) and
200 .mu.l of tetrahydrofuran was added LiHMDS (1 M in
tetrahydrofuran, 155 .mu.L, 0.15 mmol, 3.0 equivalents) at
0.degree. C. over 5 minutes. After 10 minutes,
2-chloro-5-(chloromethyl)pyridine (18.8 mg, 0.12 mmol, 2.3
equivalents) was added in 200 .mu.l of tetrahydrofuran. The
reaction was degassed, flushed with N.sub.2, allowed to stir at
0.degree. C. for another 10 minutes, and stirred at room
temperature for 2 hours. The reaction was purified via preparative
reverse phase HPLC/MS method TFA6. Impurities were present after
TFA purification and the sample was purified via preparative
reverse phase HPLC/MS method AA6 to afford the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.66 (d, J=8.5 Hz, 1H), 8.12-8.05 (m, 1H), 7.99
(d, J=8.3 Hz, 1H), 7.95-7.85 (m, 2H), 7.55-7.45 (m, 2H), 7.45-7.36
(m, 1H), 7.23 (dd, J=8.3, 2.5 Hz, 1H), 7.12 (d, J=7.5 Hz, 2H),
7.09-7.00 (m, 1H), 6.92 (d, J=8.2 Hz, 1H), 3.30 (d, J=13.6 Hz, 1H),
2.84 (d, J=13.6 Hz, 1H), 2.81-2.71 (m, 1H), 2.52-2.40 (m, 2H),
1.90-1.78 (m, 1H). MS (APCI+) m/z 510.9 (M+H).sup.+.
Example I-37
4-chloro-1-[(6-methoxypyridin-2-yl)methyl]-N-(naphthalene-1-sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide
[1127] To a solution of Example I-8B (20 mg, 0.05 mmol, 1.0
equivalent) in 30 .mu.l of DMI (1,3-dimethyl-2-imidazolidinone) and
200 .mu.l of tetrahydrofuran was added LiHMDS (1 M in
tetrahydrofuran, 155 .mu.L, 0.15 mmol, 3.0 equivalents) at
0.degree. C. over 5 minutes. After 10 minutes,
2-(chloromethyl)-6-methoxypyridine (18.8 mg, 0.12 mmol, 2.3
equivalents) was added in 200 .mu.l of tetrahydrofuran. The
reaction was degassed, flushed with N.sub.2, allowed to stir at
0.degree. C. for another 10 minutes, and stirred at room
temperature for 2 hours. The reaction was purified via preparative
reverse phase HPLC/MS method TFA6. Impurities were present after
TFA purification and the sample was purified via preparative
reverse phase HPLC/MS method AA6 to afford the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.73 (d, J=8.7 Hz, 1H), 8.05-7.98 (m, 1H), 7.90
(d, J=8.2 Hz, 1H), 7.88-7.82 (m, 1H), 7.49-7.41 (m, 2H), 7.40-7.31
(m, 1H), 7.26 (dd, J=7.3, 1.4 Hz, 1H), 7.23-7.15 (m, 1H), 7.08-6.95
(m, 2H), 6.46 (d, J=7.3 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 3.63 (s,
3H), 3.38 (d, J=13.6 Hz, 1H), 2.98 (d, J=13.6 Hz, 1H), 2.82-2.69
(m, 1H), 2.65-2.53 (m, 1H), 2.44-2.33 (m, 1H), 2.08-1.96 (m, 1H).
MS (APCI+) m/z 506.9 (M+H).sup.+.
Example I-38
4-chloro-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide
[1128] To a solution of Example I-8B (20 mg, 0.05 mmol, 1.0
equivalent) in 30 .mu.l of DMI (1,3-dimethyl-2-imidazolidinone) and
200 .mu.l of tetrahydrofuran was added LiHMDS (1 M in
tetrahydrofuran, 155 .mu.L, 0.15 mmol, 3.0 equivalents) at
0.degree. C. over 5 minutes. After 10 minutes, methyliodide (16.9
mg, 0.12 mmol, 2.3 equivalents) was added in 200 .mu.l of
tetrahydrofuran. The reaction was degassed, flushed with N.sub.2,
allowed to stir at 0.degree. C. for another 10 minutes, and stirred
at room temperature for 2 hours. The reaction was purified via
preparative reverse phase HPLC/MS method TFA8. Impurities were
present after TFA purification and the sample was purified via
preparative reverse phase HPLC/MS method AA6 to afford the title
compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.65 (d, J=7.2
Hz, 1H), 8.11 (dd, J=25.8, 7.7 Hz, 2H), 7.97 (d, J=8.0 Hz, 1H),
7.60-7.51 (m, 3H), 7.16-7.09 (m, 1H), 7.08-6.95 (m, 2H), 2.78 (t,
J=7.3 Hz, 2H), 2.52-2.45 (m, 1H), 1.85-1.73 (m, 1H), 1.30 (s, 3H).
MS (APCI+) m/z 400.0 (M+H).sup.+.
Example I-39
4-chloro-N-(5-chloronaphthalene-1-sulfonyl)-1-ethyl-2,3-dihydro-1H-indene--
1-carboxamide
[1129] Into a 4 mL vial was weighed Example I-17A (30.0 mg, 0.13
mmol). A stock solution of
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.26 M in dichloromethane, 1.0 mL, 0.26 mmol, 2.0
equivalents), and N,N-dimethylpyridin-4-amine (0.15 M in
dichloromethane, 1.0 mL, 0.15 mmol, 1.1 equivalents) was added.
5-Chloronaphthalene-1-sulfonamide (32.3 mg, 0.13 mmol, 1.0
equivalent) was added and the reaction was stirred for 16 hours at
room temperature. The solvent was removed under a stream of
nitrogen. The residue was reconstituted in acetonitrile and was
purified using preparative reverse phase HPLC/MS method TFA8 to
provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.63-8.53 (m,
2H), 8.41-8.34 (m, 1H), 7.91-7.82 (m, 2H), 7.73-7.64 (m, 1H),
7.27-7.10 (m, 3H), 2.86-2.71 (m, 2H), 2.37-2.27 (m, 1H), 2.07-1.88
(m, 2H), 1.70-1.56 (m, 1H), 0.48 (t, J=7.3 Hz, 3H). MS (APCI+) m/z
447.9 (M+H).sup.+.
Example I-40
8-bromo-N-(naphthalene-1-sulfonyl)-5-[(propan-2-yl)oxy]-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide
[1130] A solution of Example I-32A
(8-bromo-5-hydroxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthal-
ene-1-carboxamide) (14.7 mg, 0.032 mmol) in N,N-dimethylformamide
(0.2 mL) was treated with 2-bromopropane (18 mg, 0.146 mmol),
treated with cesium carbonate (60 mg, 0.184 mmol), stirred at room
temperature for 30 minutes, heated to 50.degree. C. for 30 minutes,
cooled, diluted with N,N-dimethylformamide, filtered, and directly
purified the filtrate by reverse-phase HPLC [Waters XBridge.TM.
RP18 column, 5 .mu.m, 30.times.100 mm, flow rate 40 mL/minute,
5-40% (over 15 minutes) gradient of acetonitrile in 0.1% TFA] to
afford the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.71 (s, 1H), 8.68 (d, J=8.3 Hz,
1H), 8.28 (d, J=8.2 Hz, 1H), 8.23 (dd, J=7.4, 1.1 Hz, 1H), 8.11 (d,
J=7.9 Hz, 1H), 7.75 (ddd, J=8.5, 7.0, 1.3 Hz, 1H), 7.70-7.62 (m,
2H), 7.08 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.9 Hz, 1H), 4.48 (p, J=6.0
Hz, 1H), 3.77 (dd, J=6.1, 2.2 Hz, 1H), 2.54-2.46 (m, 1H), 2.22
(ddd, J=17.7, 11.3, 6.1 Hz, 1H), 1.94-1.87 (m, 1H), 1.79-1.69 (m,
1H), 1.50-1.42 (m, 1H), 1.21-1.17 (m, 6H), 1.09-0.96 (m, 1H). MS
(APCI+) m/z 502, 504 (M+H).sup.+.
Example I-41
5-bromo-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide
Example I-41A
5-bromo-8-methoxy-3,4-dihydronaphthalene-1-carbonitrile
[1131] A flask containing 1.6 M n-butyllithium in hexanes (4.66 mL,
7.46 mmol) was cooled to -78.degree. C. under N.sub.2 and treated
dropwise with a solution of trimethylsilyl cyanide (1 mL, 7.46
mmol) in tetrahydrofuran (5 mL). The mixture was allowed to warm to
room temperature and was stirred for 1 hour. The mixture was
diluted with heptanes and the material was collected by filtration
to provide a material which contained LiCN. A solution of
5-bromo-8-methoxy-3,4-dihydronaphthalen-1(2H)-one (CAS#77259-96-2)
(0.4 g, 1.568 mmol) in N,N-dimethylformamide (1.5 mL) was cooled to
0.degree. C., treated with diethyl cyanophosphonate (0.476 mL, 3.14
mmol), and treated with 20 mg of the LiCN containing material from
above. The mixture was stirred at room temperature for 90 minutes.
The mixture was diluted with methyl tert-butyl ether (60 mL),
washed with water (once with 30 mL, and once with 15 mL), washed
with brine, dried (MgSO.sub.4), filtered, and concentrated. The
residue was dissolved in toluene (10 mL), treated with
para-toluenesulfonic acid monohydrate (0.030 g, 0.157 mmol), heated
to 120.degree. C. for 3 hours, cooled, and partitioned between
methyl tert-butyl ether (50 mL) and saturated aqueous NaHCO.sub.3
solution (.about.15 mL). The methyl tert-butyl ether layer was
washed with brine, dried (MgSO.sub.4), filtered, and concentrated.
The residue was chromatographed on silica gel, eluting with 15%
ethyl acetate in heptanes to provide the title compound. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.45 (d, J=8.9 Hz, 1H), 6.97
(t, J=5.1 Hz, 1H), 6.72 (d, J=8.9 Hz, 1H), 3.89 (s, 3H), 2.92-2.82
(m, 2H), 2.41 (td, J=8.1, 5.2 Hz, 2H).
Example I-41B
5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile
[1132] A mixture of Example I-41A
(5-bromo-8-methoxy-3,4-dihydronaphthalene-1-carbonitrile) (0.33 g,
1.249 mmol) in ethanol (10 mL) was treated with NaBH.sub.4 (0.284
g, 7.50 mmol) and the mixture was heated to reflux for 20 minutes.
The mixture was cooled and concentrated. The residue was
partitioned between methyl tert-butyl ether (50 mL) and 1 M aqueous
HCl (25 mL). The methyl tert-butyl ether layer was washed with
brine, dried (MgSO.sub.4), filtered, and concentrated. The residue
was chromatographed on silica gel, eluting with 15% ethyl acetate
in heptane to provide the title compound. .sup.1H NMR (501 MHz,
CDCl.sub.3) .delta. ppm 7.48 (d, J=8.8 Hz, 1H), 6.65 (d, J=8.8 Hz,
1H), 4.10 (dd, J=5.4, 2.5 Hz, 1H), 3.89 (s, 3H), 2.94 (ddd, J=17.9,
5.3, 1.9 Hz, 1H), 2.57 (ddd, J=17.9, 11.4, 6.4 Hz, 1H), 2.31-2.24
(m, 1H), 2.09-1.92 (m, 2H), 1.79 (tdd, J=13.2, 5.5, 3.1 Hz,
1H).
Example I-41C
5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide
[1133] A suspension of Example I-41B
(5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile)
(101 mg, 0.380 mmol) in ethanol (1.2 mL) was treated with 3 M
aqueous NaOH (1265 .mu.l, 3.80 mmol) and heated to 80.degree. C.
for 16 hours. The mixture was cooled to room temperature and
treated with a stream of N.sub.2 to remove the ethanol. The residue
was diluted with water (.about.3 mL). The material was collected by
filtration, washed with water and dried under vacuum with heating
(50.degree. C.) for 30 minutes to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 7.42
(d, J=8.7 Hz, 1H), 7.16 (bs, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.70 (bs,
1H), 3.71 (s, 3H), 3.68-3.65 (m, 1H), 2.73-2.63 (m, 1H), 2.56-2.45
(m, 1H), 1.99-1.90 (m, 1H), 1.81-1.65 (m, 3H). MS (APCI+) m/z
284,286 (M+H).sup.+.
Example I-41D
5-bromo-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-
-1-carboxamide
[1134] A solution of Example I-41C
(5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide) (19
mg, 0.067 mmol) in tetrahydrofuran (0.5 mL) was treated with a 60%
dispersion of sodium hydride in mineral oil (5.88 mg, 0.147 mmol),
stirred at room temperature for 45 minutes, cooled to 0.degree. C.,
treated with a solution of 1-naphthalenesulfonyl chloride (16.67
mg, 0.074 mmol) in tetrahydrofuran (0.2 mL), stirred at room
temperature for 10 minutes, heated to 68.degree. C. for 75 minutes,
cooled to 0.degree. C., treated with acetic acid (5 drops), and
concentrated with a stream of N.sub.2. The residue was diluted with
N,N-dimethylformamide to .about.1 mL volume, and was directly
purified by reverse-phase HPLC [Waters XBridge.TM. RP18 column, 5
.mu.m, 30.times.100 mm, flow rate 40 mL/minute, 5-40% (over 15
minutes) gradient of acetonitrile in 0.1% TFA] to afford the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.52 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H),
8.24 (dd, J=7.4, 1.1 Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.84-7.79 (m,
1H), 7.71 (t, J=7.5 Hz, 1H), 7.69-7.64 (m, 1H), 7.34 (d, J=8.8 Hz,
1H), 6.55 (d, J=8.8 Hz, 1H), 3.72-3.68 (m, 1H), 2.95 (s, 3H),
2.55-2.37 (m, 2H), 1.82-1.65 (m, 2H), 1.47 (s, 1H), 1.32 (d, J=3.4
Hz, 1H). MS (APCI+) m/z 474,476 (M+H).sup.+.
Example I-42
4-chloro-1-ethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide
[1135] Example I-17A (50 mg, 0.223 mmol) was combined with a
mixture of
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (85 mg, 0.445 mmol) and
N,N-dimethylpyridin-4-amine (29.9 mg, 0.245 mmol) in
dichloromethane (2.5 mL). After 30 minutes, quinoline-5-sulfonamide
(46.3 mg, 0.223 mmol) (CAS#415913-05-2, Enamine) was added. The
reaction was stirred at room temperature for 16 hours. The reaction
was quenched with 1.0 mL of 2 N aqueous HCl and the mixture was put
through an aqueous/organic separator tube. The crude organic
material was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to give slightly impure product, which was subsequently
washed with methanol to provide the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.15 (s, 1H),
9.00 (dd, J=4.2, 1.6 Hz, 1H), 8.93 (dd, J=8.8, 1.5 Hz, 1H), 8.31
(d, J=7.8 Hz, 2H), 7.91 (t, J=8.0 Hz, 1H), 7.68 (dd, J=8.8, 4.2 Hz,
1H), 7.20-7.17 (m, 1H), 7.14-7.07 (m, 2H), 2.83-2.64 (m, 2H), 2.28
(ddd, J=13.1, 8.3, 6.4 Hz, 1H), 2.02-1.85 (m, 2H), 1.60 (dq,
J=14.5, 7.3 Hz, 1H), 0.43 (t, J=7.3 Hz, 3H). MS (ESI+) m/z 415
(M+H.sup.+).
Example I-43
N-(1-benzothiophene-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide
Example I-43A
benzo[b]thiophene-4-sulfonamide
[1136] A 1 M solution of di-n-butylmagnesium (4.69 mL, 4.69 mmol)
in tetrahydrofuran and 1.6 M butyllithium (2.93 mL, 4.69 mmol) in
heptanes were combined to give a thick suspension. The suspension
was cooled (dry ice/acetone, about -20.degree. C.), and a solution
of 4-bromobenzo[b]thiophene (1.00 g, 4.69 mmol) (CAS#5118-13-8,
Arkpharm) in tetrahydrofuran (5 mL) was added, keeping the internal
temperature below -10.degree. C. The reaction mixture was stirred
at -10.degree. C. for 1 hour. The cold biphasic mixture was added
to a cooled solution of sulfuryl chloride (0.875 mL, 10.79 mmol) in
toluene (12 mL) while stirring in a dry ice/acetone bath keeping
the internal temperature under 10.degree. C. The reaction was
quenched with 30 mL of ammonium hydroxide and a precipitate formed.
The solvent was reduced in vacuo and the aqueous suspension was
filtered and washed with water and ether to provide the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 8.25 (dt, J=8.2, 1.0 Hz, 1H), 7.99 (t, J=5.2 Hz, 1H), 7.93-7.88
(m, 1H), 7.85 (dd, J=7.5, 1.0 Hz, 1H), 7.52 (s, 2H), 7.48 (t, J=7.8
Hz, 1H). MS (ESI-) m/z 212 (M-H.sup.-).
Example I-43B
N-(1-benzothiophene-4-sulfonyl)-4-chloro-1-ethyl-2,3-dihydro-1H-indene-1-c-
arboxamide
[1137] Example I-17A (60 mg, 0.267 mmol) was combined with a
mixture of
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (102 mg, 0.534 mmol) and
N,N-dimethylpyridin-4-amine (35.9 mg, 0.294 mmol) in
dichloromethane (2.0 mL). After 30 minutes, Example I-43A (85 mg,
0.401 mmol) was added. The reaction was stirred at room temperature
for 16 hours. The reaction was quenched with 1.0 mL of 1 N aqueous
HCl and the organic portions were purified by reverse-phase
preparative HPLC on a Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100
.ANG. AXIA.TM. column (30 mm.times.150 mm). A gradient of
acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0
minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0
minutes linear gradient 95-10% A) to provide the title compound.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 8.20 (dd, J=7.6,
1.0 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J=5.6
Hz, 1H), 7.62 (dd, J=5.6, 0.8 Hz, 1H), 7.51 (t, J=7.9 Hz, 1H),
7.31-7.28 (m, 1H), 7.18 (t, J=7.7 Hz, 1H), 6.97 (d, J=7.4 Hz, 1H),
2.94-2.84 (m, 1H), 2.83-2.73 (m, 1H), 2.33 (ddd, J=13.9, 8.7, 5.5
Hz, 1H), 2.01 (ddd, J=13.4, 8.9, 6.5 Hz, 1H), 1.86 (dt, J=14.8, 7.3
Hz, 1H), 1.77 (dq, J=14.5, 7.4 Hz, 1H), 0.67 (t, J=7.4 Hz, 3H). MS
(APCI+) m/z 420 (M+H.sup.+).
Example I-44
4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carboxa-
mide
[1138] N,N-Dimethylpyridin-4-amine (59.5 mg, 0.487 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (170 mg, 0.885 mmol) were combined in
N,N-dimethylacetamide (2.0 mL). To the suspension was added Example
I-19B (120 mg, 0.443 mmol). After 30 minutes,
quinoline-5-sulfonamide (92 mg, 0.443 mmol) was added. The reaction
was stirred at room temperature for 18 hours. The reaction was
quenched with 1 N aqueous HCl (1 mL), put through an
aqueous/organic separator tube with dichloromethane and the
organics were purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide the title compound. .sup.1H NMR (500 MHz,
Chloroform-d) .delta. ppm 9.69 (s, 1H), 9.02 (d, J=4.1 Hz, 1H),
8.89 (ddd, J=8.8, 1.6, 0.9 Hz, 1H), 8.52 (dd, J=7.5, 1.2 Hz, 1H),
8.41 (dt, J=8.5, 1.1 Hz, 1H), 7.86 (dd, J=8.4, 7.5 Hz, 1H), 7.51
(dd, J=8.8, 4.2 Hz, 1H), 7.37 (dd, J=8.7, 0.6 Hz, 1H), 6.70 (d,
J=8.7 Hz, 1H), 4.07 (dd, J=8.9, 1.7 Hz, 1H), 4.02 (s, 3H),
2.91-2.76 (m, 2H), 2.64-2.55 (m, 1H), 2.14-2.04 (m, 1H). MS (ESI+)
m/z 462 (M+H.sup.+).
Example I-45
8-bromo-5-(2-methoxyethoxy)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide
[1139] Example I-32A (20.0 mg, 0.05 mmol, 1.0 equivalent) was
dissolved in N,N-dimethylformamide (0.4 mL). Cs.sub.2CO.sub.3 (82.2
mg, 0.25 mmol, 5.0 equivalents) was added, followed by
1-bromo-2-methoxyethane (0.4 M in N,N-dimethylformamide, 504 .mu.L,
0.20 mmol, 4.0 equivalents). The reaction was stirred for 16 hours
at 50.degree. C. The reaction was filtered and was purified using
preparative reverse phase HPLC/MS method TFA8 to afford the title
compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.71-8.64 (m,
1H), 8.32-8.21 (m, 2H), 8.15-8.08 (m, 1H), 7.81-7.74 (m, 1H),
7.73-7.61 (m, 2H), 7.11 (d, J=8.8 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H),
4.07-3.92 (m, 2H), 3.80-3.75 (m, 1H), 3.61 (t, J=4.5 Hz, 2H), 3.27
(s, 3H), 2.59-2.55 (m, 1H), 2.34-2.20 (m, 1H), 1.97-1.89 (m, 1H),
1.83-1.69 (m, 1H), 1.53-1.45 (m, 1H), 1.08-1.00 (m, 1H). MS (APCI+)
m/z 519.9 (M+H).sup.+.
Example I-46
(1S)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide
[1140] Example I-44 (43 mg) was separated by chiral preparative SFC
chromatography using a CHIRALPAK IA, column size 21.times.250 mm, 5
micron, serial Number: IA00SALC001-812121, using a concentration of
4.1 mg/mL in methanol at a flow rate of 52 g/minute CO.sub.2 and UV
monitoring at 220 nm to provide the title compound. .sup.1H NMR
(400 MHz, Chloroform-d) .delta. ppm 8.98 (dd, J=4.1, 1.6 Hz, 1H),
8.95 (d, J=8.9 Hz, 1H), 8.46-8.38 (m, 1H), 8.33 (d, J=8.4 Hz, 1H),
7.84-7.73 (m, 1H), 7.46 (dd, J=8.7, 4.2 Hz, 1H), 7.31 (d, J=8.7 Hz,
1H), 6.59 (d, J=8.6 Hz, 1H), 4.05 (dd, J=9.0, 2.7 Hz, 1H), 3.79 (s,
3H), 2.98-2.74 (m, 2H), 2.53-2.41 (m, 1H), 2.16 (dq, J=13.3, 9.0
Hz, 1H). MS (APCI+) m/z 463 (M+H.sup.+), Br doublet. R.sub.T
(chiral SFC)=9.5 minutes. The absolute structure of the title
compound was determined by X-ray crystallography.
Example I-47
(1R)-4-bromo-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide
[1141] Example I-44 (43 mg) was separated by chiral preparative SFC
chromatography using a CHIRALPAK IA, column size 21.times.250 mm, 5
micron, serial Number: IA00SALC001-812121, using a concentration of
4.1 mg/mL in methanol at a flow rate of 52 g/minute CO.sub.2 and UV
monitoring at 220 nm to provide the title compound. .sup.1H NMR
(400 MHz, Chloroform-d) .delta. ppm 8.98 (dd, J=4.2, 1.6 Hz, 1H),
8.92 (dt, J=8.8, 1.2 Hz, 1H), 8.45 (dd, J=7.5, 1.2 Hz, 1H), 8.34
(dt, J=8.3, 1.1 Hz, 1H), 7.80 (dd, J=8.5, 7.4 Hz, 1H), 7.46 (dd,
J=8.7, 4.2 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H),
4.05 (dd, J=9.0, 2.5 Hz, 1H), 3.84 (s, 3H), 2.92-2.73 (m, 2H), 2.49
(ddt, J=13.6, 8.2, 2.9 Hz, 1H), 2.13 (dq, J=13.3, 9.2 Hz, 1H). MS
(APCI+) m/z 461 (M+H).sup.+, Br doublet. R.sub.T (chiral SFC)=10.5
minutes.
Example I-48
(1S)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide
[1142] A solution of
8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide
(Example I-15C, 1.51 g, 5.31 mmol) in tetrahydrofuran (50 mL) under
N.sub.2 was treated with 60% dispersion of sodium hydride in
mineral oil (0.468 g, 11.69 mmol), stirred at room temperature for
1 hour, cooled to 0.degree. C., treated dropwise with a solution of
1-naphthylene sulfonyl chloride (1.325 g, 5.85 mmol) in
tetrahydrofuran (20 mL), stirred at room temperature for 1 hour,
and heated to reflux for 16 hours. The mixture was cooled and
concentrated to remove the majority of tetrahydrofuran. The mixture
was treated with methyl tert-butyl ether (.about.20 mL) and treated
with 1 M aqueous HCl (15 mL). The mixture was extracted with more
methyl tert-butyl ether (.about.100 mL). The organic layer was
washed with brine, dried (MgSO.sub.4), filtered, and concentrated.
The residue was treated with methyl tert-butyl ether (.about.15 mL)
and swirled. Material started to precipitate. Heptanes (30-50 mL)
were slowly added. The material was collected by filtration, washed
with cold 5:1 heptanes:methyl tert-butyl ether and dried under
vacuum with heating to 50.degree. C. for 30 minutes to provide
racemic
8-bromo-5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 12.71 (s, 1H),
8.69 (d, J=8.6 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (dd, J=7.4,
0.9 Hz, 1H), 8.11 (d, J=7.9 Hz, 1H), 7.76 (ddd, J=8.4, 6.9, 1.2 Hz,
1H), 7.70-7.63 (m, 2H), 7.13 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.8 Hz,
1H), 3.78 (dd, J=6.9, 2.8 Hz, 1H), 3.69 (s, 3H), 2.55-2.47 (m, 1H),
2.25 (ddd, J=17.7, 11.3, 6.2 Hz, 1H), 1.95-1.88 (m, 1H), 1.74
(dddd, J=13.4, 8.8, 6.4, 3.2 Hz, 1H), 1.50-1.42 (m, 1H), 1.09-0.97
(m, 1H). LC/MS (APCI+) m/z 474.1 (M+H).sup.+. The racemic material
was separated by chiral preparative SFC chromatography using a
CHIRALPAK AD-H, column size 21.times.250 mm, 5 micron, serial
Number: ADHSAMA003-810291, using a concentration of 15 mg/mL in
methanol at a flow rate of 45 g/minute CO.sub.2 and UV monitoring
at 220 nm to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm
8.70-8.62 (m, 1H), 8.30-8.19 (m, 2H), 8.13-8.06 (m, 1H), 7.79-7.72
(m, 1H), 7.70-7.60 (m, 2H), 7.12 (d, J=8.7 Hz, 1H), 6.69 (d, J=8.9
Hz, 1H), 3.67 (s, 3H), 2.50-2.44 (m, 2H), 2.31-2.17 (m, 1H),
1.95-1.87 (m, 1H), 1.76-1.71 (m, 1H), 1.49-1.44 (m, 1H), 1.06-0.98
(m, 1H). MS (APCI+) m/z 474.1 (M+H).sup.+.
Example I-49
(1R)-8-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide
[1143] Example I-49 was isolated as the second enantiomer during
the preparative SFC separation described in Example I-48. .sup.1H
NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. ppm 8.68 (d, J=8.4 Hz, 1H), 8.23-8.16 (m, 2H), 8.07 (d,
J=8.2 Hz, 1H), 7.79-7.57 (m, 3H), 7.13 (d, J=8.7 Hz, 1H), 6.68 (d,
J=8.8 Hz, 1H), 3.68 (s, 3H), 2.50-2.45 (m, 2H), 2.31-2.17 (m, 1H),
1.95-1.90 (m, 1H), 1.73-1.68 (m, 1H), 1.47-1.42 (m, 1H), 1.08-1.03
(m, 1H). MS (APCI+) m/z 474.1 (M+H).sup.+.
Example I-50
5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-
-carboxamide
Example I-50A
5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid
[1144] A solution of Example I-41B
(5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile)
(20 mg, 0.075 mmol) in ethylene glycol (0.3 mL) was treated with
50% aqueous KOH solution (230 mg, 2.050 mmol), heated to
150.degree. C. for 2 hours, heated to 170.degree. C. for 3 hours,
cooled to room temperature and partitioned between methyl
tert-butyl ether (.about.30 mL) and 1 M aqueous HCl (.about.10 mL).
The methyl tert-butyl ether layer was washed with 0.1 M aqueous HCl
(.about.10 mL), washed with brine, dried (MgSO.sub.4), filtered,
and concentrated to provide the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 7.43 (d, J=8.7 Hz, 1H), 6.62 (d, J=8.7
Hz, 1H), 3.91-3.88 (m, 1H), 3.79 (s, 3H), 2.84 (dt, J=17.5, 5.2 Hz,
1H), 2.64 (dt, J=17.6, 7.4 Hz, 1H), 2.20-2.11 (m, 1H), 2.02-1.91
(m, 1H), 1.88-1.80 (m, 2H).
Example I-50B
5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-
-carboxamide
[1145] To a solution of Example I-50A
(5-bromo-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid)
(20.5 mg, 0.072 mmol), EDC
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (27.6
mg, 0.144 mmol) and 4-dimethylaminopyridine (9.66 mg, 0.079 mmol)
in dichloromethane (0.3 mL) was added quinoline-5-sulfonamide
(16.47 mg, 0.079 mmol). The mixture was stirred at room temperature
for 16 hours, and concentrated with a stream of N.sub.2. The
residue was diluted with N,N-dimethylformamide and was directly
purified by reverse-phase HPLC [Waters XBridge.TM. RP18 column, 5
.mu.m, 30.times.100 mm, flow rate 40 mL/minute, 5-95% gradient of
acetonitrile in 0.1% TFA] to afford the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.63 (s, 1H),
9.11-9.05 (m, 2H), 8.36 (d, J=8.4 Hz, 1H), 8.32 (dd, J=7.4, 1.0 Hz,
1H), 7.93 (dd, J=8.3, 7.7 Hz, 1H), 7.85 (dd, J=8.7, 4.2 Hz, 1H),
7.35 (d, J=8.8 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 3.70-3.67 (m, 1H),
2.98 (s, 3H), 2.58-2.38 (m, 2H), 1.84-1.74 (m, 1H), 1.72-1.64 (m,
1H), 1.56-1.46 (m, 1H), 1.40-1.28 (m, 1H). MS (APCI+) m/z 475,477
(M+H).sup.+.
Example I-51
(1S)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
[1146] Example I-19C (70 mg) was separated by chiral preparative
SFC chromatography using a Whelk-O (S,S), column size 21.times.250
mm, 5 micron, serial Number: 43170, using a concentration of 6.9
mg/mL in methanol at a flow rate of 25 g/minute CO.sub.2 and UV
monitoring at 220 nm to provide the title compound. .sup.1H NMR
(501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.58 (s, 1H),
8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.25 (d,
J=7.5 Hz, 1H), 8.15-8.04 (m, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.73-7.65
(m, 2H), 7.28 (dd, J=8.6, 0.7 Hz, 1H), 6.58 (d, J=8.7 Hz, 1H), 4.03
(dd, J=9.2, 5.6 Hz, 1H), 3.11 (s, 3H), 2.74 (t, J=7.5 Hz, 2H),
2.32-2.19 (m, 1H), 1.82 (dq, J=13.3, 7.0 Hz, 1H). MS (APCI+) m/z
460 (M+H.sup.+), Br doublet; R.sub.T (chiral SFC)=4.4 minutes.
Example I-52
(1R)-4-bromo-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
[1147] Example I-19C was separated by chiral preparative SFC
chromatography using a Whelk-O (S,S), column size 21.times.250 mm,
5 micron, serial Number: 43170, using a concentration of 6.9 mg/mL
in methanol at a flow rate of 25 g/minute CO.sub.2 and UV
monitoring at 220 nm to provide the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.57 (s, 1H),
8.65 (d, J=8.5 Hz, 1H), 8.28 (d, J=8.4 Hz, 1H), 8.25 (d, J=7.4 Hz,
1H), 8.13 (d, J=8.1 Hz, 1H), 7.78 (t, J=7.4 Hz, 1H), 7.69 (dt,
J=12.3, 7.9 Hz, 2H), 7.28 (d, J=8.6 Hz, 1H), 6.58 (d, J=8.7 Hz,
1H), 4.03 (dd, J=9.1, 5.6 Hz, 1H), 3.11 (s, 3H), 2.74 (t, J=7.5 Hz,
2H), 2.30-2.20 (m, 1H), 1.82 (dq, J=13.1, 7.1 Hz, 1H). MS (APCI+)
m/z 460 (M+H).sup.+, Br doublet; R.sub.T (chiral SFC)=5.2
minutes.
Example I-53
4-bromo-7-ethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide
Example I-53A
4-bromo-7-hydroxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide
[1148] A solution of Example I-19C (350 mg, 0.760 mmol) in
dichloromethane (7 mL) under nitrogen at 0.degree. C. was treated
dropwise with 1 M boron tribromide in dichloromethane (2.243 mL,
2.243 mmol). The reaction was stirred at 0.degree. C. for 30
minutes, allowed to stir at room temperature for 3 hours, cooled to
0.degree. C., diluted with dichloromethane (10 mL), and treated
with 1 M aqueous HCl (4 mL). The organics were separated. The
aqueous layer was extracted with dichloromethane (30 mL). The
combined dichloromethane layers were treated with methanol
(.about.1.5 mL) to dissolve some precipitate that had formed. The
solution was dried (MgSO.sub.4), filtered, and concentrated. The
residual material was chromatographed using a 12 g silica gel
cartridge with 100% ethyl acetate to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.48
(s, 1H), 9.74 (s, 1H), 8.67-8.58 (m, 1H), 8.29 (d, J=8.3 Hz, 1H),
8.25 (dd, J=7.3, 1.2 Hz, 1H), 8.12 (dd, J=7.7, 1.4 Hz, 1H),
7.82-7.72 (m, 1H), 7.72-7.59 (m, 2H), 7.14 (d, J=8.5 Hz, 1H), 6.50
(d, J=8.5 Hz, 1H), 4.07 (dd, J=9.3, 4.6 Hz, 1H), 2.74-2.55 (m, 2H),
2.24-2.10 (m, 1H), 1.70 (d, J=5.0 Hz, 1H). MS (APCI+) m/z 446.0
(M+H).sup.+.
Example I-53B
4-bromo-7-ethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide
[1149] A solution of Example I-53A (40 mg, 0.090 mmol) in
N,N-dimethylformamide (0.5 mL) was treated with ethyl iodide (43.5
.mu.l, 0.538 mmol) and treated with cesium carbonate (146 mg, 0.448
mmol). The mixture was stirred at room temperature for 16 hours.
The crude material was purified by reverse-phase preparative HPLC
on a Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM.
column (30 mm.times.150 mm). A gradient of acetonitrile (A) and
0.1% trifluoroacetic acid in water (B) was used, at a flow rate of
50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide the title compound. .sup.1H NMR (501 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.52 (s, 1H), 8.63 (dd,
J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.3 Hz, 1H), 8.27 (dd, J=7.4, 1.3
Hz, 1H), 8.15-8.12 (m, 1H), 7.78 (dd, J=7.0, 1.5 Hz, 1H), 7.77-7.75
(m, OH), 7.72-7.66 (m, 2H), 7.28 (dd, J=8.7, 0.7 Hz, 1H), 6.61 (d,
J=8.6 Hz, 1H), 4.05 (dd, J=9.3, 5.8 Hz, 1H), 3.64-3.51 (m, 2H),
2.75 (t, J=7.5 Hz, 2H), 2.26 (ddt, J=13.1, 9.3, 7.4 Hz, 1H), 1.78
(dtd, J=13.3, 7.5, 5.8 Hz, 1H), 0.72 (t, J=7.0 Hz, 3H). MS (APCI+)
m/z 474 (M+H).sup.+.
Example I-54
4-bromo-N-(naphthalene-1-sulfonyl)-7-[propan-2-yl)oxy]-2,3-dihydro-1H-inde-
ne-1-carboxamide
[1150] A solution of Example I-53A (40 mg, 0.090 mmol) in
N,N-dimethylformamide (0.5 mL) was treated with 2-iodopropane (53.8
.mu.l, 0.538 mmol) and treated with cesium carbonate (146 mg, 0.448
mmol). The mixture was stirred at room temperature for 16 hours.
The crude material was purified by reverse-phase preparative HPLC
on a Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM.
column (30 mm.times.150 mm). A gradient of acetonitrile (A) and
0.1% trifluoroacetic acid in water (B) was used, at a flow rate of
50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.49 (s, 1H), 8.66 (dd,
J=8.7, 1.0 Hz, 1H), 8.34-8.24 (m, 2H), 8.13 (dd, J=8.2, 1.3 Hz,
1H), 7.82-7.72 (m, 1H), 7.72-7.60 (m, 2H), 7.27 (d, J=8.6 Hz, 1H),
6.66 (d, J=8.7 Hz, 1H), 4.35 (p, J=6.0 Hz, 1H), 4.02 (dd, J=9.5,
5.2 Hz, 1H), 2.75 (t, J=7.5 Hz, 2H), 2.23 (ddt, J=13.2, 9.5, 7.7
Hz, 1H), 1.77 (dtd, J=12.8, 7.2, 5.1 Hz, 1H), 0.91 (d, J=6.1 Hz,
3H), 0.62 (d, J=6.0 Hz, 3H). MS (APCI+) m/z 488 (M+H).sup.+.
Example I-55
4-bromo-7-(cyclopropylmethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide
[1151] A solution of Example I-53A (40 mg, 0.090 mmol) in
N,N-dimethylformamide (0.5 mL) was treated with
(iodomethyl)cyclopropane (98 mg, 0.538 mmol), treated with cesium
carbonate (146 mg, 0.448 mmol), and stirred at room temperature for
16 hours. The crude material was purified by reverse-phase
preparative HPLC on a Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100
.ANG. AXIA.TM. column (30 mm.times.150 mm). A gradient of
acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0
minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0
minutes linear gradient 95-10% A) to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.52
(s, 1H), 8.64 (dd, J=8.7, 1.1 Hz, 1H), 8.32-8.24 (m, 2H), 8.17-8.09
(m, 1H), 7.77 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.72-7.64 (m, 2H),
7.27 (dd, J=8.7, 0.6 Hz, 1H), 6.62 (d, J=8.7 Hz, 1H), 4.08 (dd,
J=9.4, 5.3 Hz, 1H), 3.45 (dd, J=10.5, 7.1 Hz, 1H), 3.37 (dd,
J=10.5, 6.4 Hz, 1H), 2.73 (ddd, J=8.8, 6.6, 2.9 Hz, 2H), 2.26 (dtd,
J=13.2, 8.8, 6.7 Hz, 1H), 1.83-1.68 (m, 1H), 0.67-0.51 (m, 1H),
0.31-0.17 (m, 2H), 0.08--0.03 (m, 2H). MS (APCI+) m/z 500
(M+H).sup.+.
Example I-56
8-bromo-5-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-
-carboxamide
Example I-56A
8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid
[1152] A mixture of Example I-15C,
(8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide)
(154 mg, 0.542 mmol) in ethylene glycol (.about.4 mL) was treated
with 85% KOH pellets (400 mg, 6.06 mmol), heated to 220.degree. C.
for 4.5 hours, cooled and partitioned between methyl tert-butyl
ether (30 mL) and 1 M aqueous HCl (15 mL). The layers were
separated and the aqueous layer was extracted with methyl
tert-butyl ether (30 mL). The combined organic layers were washed
with 0.1 M aqueous HCl, washed with brine, dried (MgSO.sub.4),
filtered, and concentrated. The residue was chromatographed on
silica gel, eluting with a gradient of 10% to 50%[200:1:1 ethyl
acetate:HCOOH:H.sub.2O] in heptanes to provide the title compound.
.sup.1H NMR (500 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 7.39
(d, J=8.7 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 3.78 (s, 4H), 2.72 (dd,
J=5.3, 18.1 Hz, 1H), 2.42 (ddd, J=6.3, 11.5, 17.9 Hz, 1H),
2.17-2.12 (m, 1H), 1.86-1.77 (m, 2H), 1.56-1.46 (m, 1H).
Example I-56B
8-bromo-5-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-
-carboxamide
[1153] To a mixture of Example I-56A
(8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid)
(56 mg, 0.196 mmol), EDC
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (75
mg, 0.393 mmol) and DMAP (4-dimethylaminopyridine) (26.4 mg, 0.216
mmol) in dichloromethane (1 mL) was added quinoline-5-sulfonamide
(45.0 mg, 0.216 mmol). The mixture was stirred at room temperature
for 16 hours, and concentrated with a stream of N.sub.2. The
residue was diluted with N,N-dimethylformamide and directly
purified by reverse-phase HPLC [Waters XBridge.TM. RP18 column, 5
.mu.m, 30.times.100 mm, flow rate 40 mL/minute, 5-95% gradient of
acetonitrile in 0.1% TFA] to afford the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.80 (s, 1H),
9.05-9.02 (m, 2H), 8.32 (d, J=8.5 Hz, 1H), 8.28 (dd, J=1.3, 7.5 Hz,
1H), 7.88 (dd, J=7.4, 8.4 Hz, 1H), 7.78-7.74 (m, 1H), 7.10 (d,
J=8.7 Hz, 1H), 6.67 (d, J=8.8 Hz, 1H), 3.74 (dd, J=2.6, 6.5 Hz,
1H), 3.66 (s, 3H), 2.54-2.45 (m, 1H), 2.23 (ddd, J=6.2, 11.3, 17.7
Hz, 1H), 1.91-1.84 (m, 1H), 1.74 (tdd, J=2.8, 6.5, 13.5 Hz, 1H),
1.53-1.44 (m, 1H), 1.12-0.99 (m, 1H). MS (ESI+) m/z 475, 477
(M+H).sup.+.
Example I-57
5-methoxy-8-(4-methylphenyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide
[1154] p-Tolylboronic acid (12.9 mg, 0.09 mmol, 1.5 equivalents)
and PdCl.sub.2(dppf)
([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 5%
w/w on glass beads 92.6 mg, 0.006 mmol, 0.1 equivalents) were
weighed into a 4 mL vial. Example I-15D (30.0 mg, 0.06 mmol, 1.0
equivalent) in dioxane (1 mL) was added, followed by the addition
of Cs.sub.2CO.sub.3 (2 M in H.sub.2O, 94 .mu.L, 0.18 mmol, 3.0
equivalents). The reaction was capped and heated to 80.degree. C.
for 16 hours. The reaction was filtered, the filtrate was
concentrated and the residue was purified using preparative reverse
phase HPLC/MS method TFA8. After purification with TFA8 method, the
sample was impure and was repurified using preparative reverse
phase HPLC/MS method AA8 to afford the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
ppm 8.85-8.58 (m, 1H), 8.26-7.90 (m, 3H), 7.72-7.38 (m, 3H),
6.93-6.68 (m, 6H), 3.75 (s, 3H), 3.18 (m, 1H), 2.44 (s, 2H), 2.23
(s, 3H), 2.10-1.95 (m, 2H), 1.32 (d, J=52.4 Hz, 3H). MS (APCI+) m/z
486.0 (M+H).sup.+.
Example I-58
4-bromo-7-(difluoromethoxy)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide
[1155] To a 50 mL flask was added potassium hydroxide (37.7 mg,
0.672 mmol) in acetonitrile (0.7 mL) and water (0.700 mL). The
mixture was stirred at room temperature until the material was in
solution. The reaction was cooled to 0.degree. C. and Example I-53A
(60 mg, 0.134 mmol) was added slowly. Diethyl
(bromodifluoromethyl)phosphonate (0.072 mL, 0.403 mmol) was added
dropwise. The mixture was stirred at 0.degree. C. for 10 minutes,
and the reaction was allowed to warm to room temperature over 4
hours. Aqueous HCl (1 N, 1 mL) was added and the mixture was
extracted with 3.times.5 mL of ethyl acetate. The organic layer was
dried over sodium sulfate, filtered, and concentrated in vacuo. The
residue was purified via a 12 g cartridge eluting with a gradient
of 0-6% methanol/dichloromethane over a period of 12 minutes to
provide the title compound. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.72 (s, 1H), 8.63 (dd, J=8.6, 1.1
Hz, 1H), 8.24 (dd, J=20.3, 7.8 Hz, 2H), 8.11 (d, J=8.1 Hz, 1H),
7.74 (d, J=8.0 Hz, 1H), 7.66 (dt, J=15.6, 7.7 Hz, 2H), 7.43 (d,
J=8.6 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.82 (t, J=73.8 Hz, 1H),
4.12 (bs, 1H), 2.82-2.66 (m, 2H), 2.29 (dq, J=16.9, 8.8 Hz, 1H),
1.77 (bs, 1H). MS (APCI+) m/z 496 (M+H.sup.+).
Example I-59
4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide
[1156] A suspension of Example I-19C (30 mg, 0.065 mmol), copper(I)
chloride (112 mg, 1.129 mmol) in dimethyl acetamide (0.5 mL) was
purged with nitrogen and heated at 150.degree. C. for 5 hours. The
reaction was cooled, filtered, and washed with ethyl acetate. The
filtrate was acidified with 0.5 mL 1 N aqueous HCl. Water (3 mL)
was added and the mixture was extracted with 3.times.15 mL of ethyl
acetate. The combined organics were concentrated in vacuo and the
residue was chromatographed using a 12 g silica gel cartridge with
0-100% ethyl acetate/heptanes over a period of 10 minutes to
provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.57 (s, 1H), 8.73-8.61 (m, 1H),
8.30 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.4, 1.3 Hz, 1H), 8.17-8.08 (m,
1H), 7.79 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.75-7.60 (m, 2H), 7.15
(d, J=8.6 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 4.02 (m, 1H), 3.10 (s,
3H), 2.77 (t, J=7.5 Hz, 2H), 2.36-2.20 (m, 1H), 1.83 (ddd, J=13.6,
7.7, 5.8 Hz, 1H). MS (APCI+) m/z 416 (M+H.sup.+).
Example I-60
(1S)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide
[1157] Into a 4 mL vial was weighed
8-bromo-5-methoxy-N-(naphthalen-1-ylsulfonyl)-1,2,3,4-tetrahydronaphthale-
ne-1-carboxamide (Example I-15, 115 mg, 0.242 mmol) and
Pd(dppf)Cl.sub.2
([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 19.80
mg, 0.024 mmol) in tetrahydrofuran (0.5 mL). Cyclobutylzinc(II)
bromide (0.5 M in tetrahydrofuran, 1.5 mL, 0.750 mmol) was added.
The reaction was heated to 50.degree. C. for 16 hours. The reaction
mixture was filtered and was purified using preparative HPLC/MS
method TFA8 to afford a racemic mixture. The mixture was separated
by chiral preparative SFC chromatography using a CHIRALPAK IC,
column size 21.times.250 mm, 5 micron, serial Number:
IC00SALK014-812151, using a concentration of 21.5 mg/mL in methanol
at a flow rate of 49 g/minutes CO.sub.2 and UV monitoring at 220 nm
to provide the title compound. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.74 (dd, J=8.6,
1.0 Hz, 1H), 8.30-8.21 (m, 2H), 8.13 (d, J=8.2 Hz, 1H), 7.89-7.78
(m, 1H), 7.78-7.67 (m, 1H), 7.64 (t, J=7.8 Hz, 1H), 6.88 (d, J=8.5
Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 3.67 (s, 3H), 2.72-2.55 (m, 1H),
2.51-2.47 (m, 2H), 2.33-2.18 (m, 1H), 2.18-2.03 (m, 1H), 2.03-1.83
(m, 1H), 1.80-1.45 (m, 4H), 1.45-1.30 (m, 1H), 1.30-0.93 (m, 3H).
MS (APCI+) m/z 450.0 (M+H).sup.+.
Example I-61
(1R)-8-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydron-
aphthalene-1-carboxamide
[1158] Example I-61 was isolated as the second enantiomer to elute
from the preparative SFC separation described in Example I-60.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.74 (dd, J=8.6, 1.0 Hz, 1H), 8.39-8.17 (m, 2H),
8.13 (d, J=8.3 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.72 (t, J=7.5 Hz,
1H), 7.64 (t, J=7.8 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.70 (d, J=8.6
Hz, 1H), 3.67 (s, 3H), 2.65-2.58 (m, 1H), 2.51-2.44 (m, 2H),
2.33-2.21 (m, 1H), 2.17-2.06 (m, 1H), 2.01-1.88 (m, 1H), 1.79-1.33
(m, 5H), 1.30-0.96 (m, 3H). MS (APCI+) m/z 450.0 (M+H).sup.+.
Example I-62
(1S)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthal-
ene-1-carboxamide
[1159] The material from Example I-50 was separated by
Supercritical Fluid Chromatography (SFC) using a 21.times.250 mm
Chiralpak IC chiral column eluting with 30% methanol in liquid
CO.sub.2 to provide the title compound as the first peak to elute
from the column. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6)
.delta. ppm 12.62 (s, 1H), 9.09 (s, 2H), 8.34 (d, J=8.5 Hz, 1H),
8.30 (dd, J=1.2, 7.4 Hz, 1H), 7.92 (dd, J=7.4, 8.4 Hz, 1H), 7.83
(dd, J=4.3, 8.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.56 (d, J=8.8 Hz,
1H), 3.70-3.66 (m, 1H), 3.00 (s, 3H), 2.57-2.37 (m, 2H), 1.83-1.64
(m, 2H), 1.56-1.45 (m, 1H), 1.39-1.29 (m, 1H). MS (ESI+) m/z
475,477 (M+H).sup.+.
Example I-63
(1R)-5-bromo-8-methoxy-N-(quinoline-5-sulfonyl)-1,2,3,4-tetrahydronaphthal-
ene-1-carboxamide
[1160] The material from Example I-50 was separated by
Supercritical Fluid Chromatography (SFC) using a 21.times.250 mm
Chiralpak IC chiral column eluting with 30% methanol in liquid
CO.sub.2 to provide the title compound as the second peak to elute
from the column. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6)
.delta. ppm 12.62 (s, 1H), 9.10-9.05 (m, 2H), 8.34 (d, J=8.4 Hz,
1H), 8.30 (dd, J=1.2, 7.5 Hz, 1H), 7.92 (dd, J=7.5, 8.4 Hz, 1H),
7.83 (dd, J=4.3, 8.6 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 6.56 (d,
J=8.8 Hz, 1H), 3.68 (t, J=5.6 Hz, 1H), 3.00 (s, 3H), 2.57-2.38 (m,
2H), 1.83-1.66 (m, 2H), 1.55-1.46 (m, 1H), 1.40-1.29 (m, 1H). MS
(ESI+) m/z 475,477 (M+H).sup.+.
Example I-64
(1S)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphtha-
lene-1-carboxamide
[1161] Example I-34C (120 mg) was separated by chiral preparative
SFC chromatography using a CHIRALPAK IC, column size 21.times.250
mm, 5 micron, serial Number: IC00SALK014-812151, using a
concentration of 25 mg/mL in methanol/dichloromethane 1:1 at a flow
rate of 48 g/minutes CO.sub.2 and UV monitoring at 220 nm to
provide the title compound. .sup.1H NMR (501 MHz, Chloroform-d)
.delta. ppm 8.57 (dd, J=7.4, 1.2 Hz, 1H), 8.39 (dd, J=7.9, 1.7 Hz,
1H), 8.16 (dd, J=8.1, 1.2 Hz, 1H), 8.01-7.96 (m, 1H), 7.89 (s, 1H),
7.68-7.58 (m, 3H), 7.14 (t, J=7.7 Hz, 1H), 7.10 (dd, J=7.6, 1.4 Hz,
1H), 7.01 (dd, J=7.7, 1.5 Hz, 1H), 2.85 (dt, J=16.4, 5.4 Hz, 1H),
2.74 (ddd, J=16.3, 8.9, 5.0 Hz, 1H), 2.33 (dq, J=15.2, 7.6 Hz, 1H),
1.97 (ddd, J=14.0, 10.3, 3.7 Hz, 1H), 1.92-1.69 (m, 4H), 0.56 (t,
J=7.5 Hz, 3H). MS (ESI+) m/z 428 (M+H.sup.+). R.sub.T (chiral
SFC)=3.0 minutes. The absolute structure of the title compound was
determined by X-ray crystallography.
Example I-65
(1R)-8-chloro-1-ethyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphtha-
lene-1-carboxamide
[1162] Example I-34C (120 mg) was separated by chiral preparative
SFC chromatography using a CHIRALPAK IC, column size 21.times.250
mm, 5 micron, serial Number: IC00SALK014-812151, using a
concentration of 25 mg/mL in methanol/dichloromethane 1:1 at a flow
rate of 48 g/minute CO.sub.2 and UV monitoring at 220 nm to provide
the title compound. .sup.1H NMR (501 MHz, Chloroform-d) .delta. ppm
8.57 (dd, J=7.4, 1.2 Hz, 1H), 8.39 (dd, J=7.9, 1.7 Hz, 1H), 8.16
(dd, J=8.3, 1.2 Hz, 1H), 8.02-7.97 (m, 1H), 7.89 (s, 1H), 7.70-7.57
(m, 3H), 7.14 (t, J=7.7 Hz, 1H), 7.10 (dd, J=7.6, 1.4 Hz, 1H), 7.01
(dd, J=7.7, 1.5 Hz, 1H), 2.85 (dt, J=16.4, 5.4 Hz, 1H), 2.74 (ddd,
J=16.3, 8.9, 5.0 Hz, 1H), 2.33 (dq, J=15.2, 7.6 Hz, 1H), 1.97 (ddd,
J=14.0, 10.3, 3.7 Hz, 1H), 1.92-1.69 (m, 4H), 0.56 (t, J=7.5 Hz,
3H). MS (ESI+) m/z 428 (M+H.sup.+). R.sub.T (chiral SFC)=5.0
minutes.
Example I-66
4-chloro-1-ethyl-N-(1-methyl-1H-indole-7-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
Example I-66A
1-methyl-1H-indole-7-sulfonamide
[1163] Into a 4 mL vial was added 2 mL concentrated NH.sub.4OH.
1-Methyl-1H-indole-7-sulfonyl chloride (104 mg, 0.45 mmol) in 1 mL
tetrahydrofuran was added to the vigorously stirred concentrated
NH.sub.4OH. The reaction was stirred for 2 hours, concentrated
under a stream of nitrogen, and dried in a vacuum oven to provide
the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 7.77 (dd, J=7.9, 1.1 Hz, 1H), 7.66
(dd, J=7.6, 1.1 Hz, 1H), 7.39 (d, J=3.2 Hz, 1H), 7.09 (t, J=7.7 Hz,
1H), 6.58 (d, J=3.1 Hz, 1H), 4.10 (s, 3H).
Example I-66B
4-chloro-1-ethyl-N-(1-methyl-1H-indole-7-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1164] 1-Methyl-1H-indole-7-sulfonamide (22.46 mg, 0.11 mmol, 1.2
equivalents) was weighed into a 4 mL vial. Example I-17A (20.0 mg,
0.09 mmol, 1.0 equivalent), EDC HCl
((1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 34.0
mg, 0.18 mmol, 2.0 equivalents) and DMAP (4-dimethylaminopyridine)
(11.9 mg, 0.10 mmol, 1.1 equivalents) were dissolved in
dichloromethane (0.5 mL) and was added to the vial containing
1-methyl-1H-indole-7-sulfonamide. The reaction was stirred
overnight at room temperature. The solvent was removed under a
stream of nitrogen and the residue was reconstituted in methanol
and was purified using preparative reverse phase HPLC/MS method
TFA6 to afford the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 7.90 (dd, J=7.9,
1.2 Hz, 1H), 7.77 (dd, J=7.8, 1.2 Hz, 1H), 7.37 (d, J=3.2 Hz, 1H),
7.31-7.23 (m, 1H), 7.23-7.11 (m, 3H), 6.64 (d, J=3.2 Hz, 1H), 4.00
(s, 3H), 2.85 (t, J=7.3 Hz, 2H), 2.52-2.40 (m, 1H), 2.12-1.97 (m,
2H), 1.80-1.66 (m, 1H), 0.65 (t, J=7.3 Hz, 3H). MS (APCI+) m/z
417.1 (M+H).sup.+.
Example I-67
5-methoxy-8-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide
[1165] In a 4 mL vial was weighed Example I-15D (25 mg, 0.05 mmol,
1.0 equivalent) and Pd(dppf)Cl.sub.2
([1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), 3.86
mg, 0.005 mmol, 0.1 equivalents) in tetrahydrofuran (0.5 mL).
Isobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.32 mL, 0.750
mmol) was added. The reaction was heated to 50.degree. C. for 16
hours. The sample was directly purified using preparative reverse
phase HPLC/MS method TFA8 to afford the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
ppm 8.67 (d, J=8.7 Hz, 1H), 8.33-8.21 (m, 2H), 8.13 (d, J=8.1 Hz,
1H), 7.84-7.75 (m, 1H), 7.75-7.61 (m, 2H), 6.73 (d, J=8.4 Hz, 1H),
6.66 (d, J=8.4 Hz, 1H), 3.81 (dd, J=6.0, 2.6 Hz, 1H), 3.67 (s, 3H),
2.50-2.44 (m, 1H), 2.33-2.19 (m, 1H), 1.95-1.76 (m, 2H), 1.75-1.60
(m, 2H), 1.51-1.36 (m, 2H), 1.08-1.00 (m, 1H), 0.59 (d, J=6.6 Hz,
3H), 0.48 (d, J=6.4 Hz, 3H). MS (APCI+) m/z 452.1 (M+H).sup.+.
Example I-68
8-methoxy-5-(2-methylpropyl)-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydro-
naphthalene-1-carboxamide
[1166] Into a 4 mL vial was weighed Example I-15D (25 mg, 0.05
mmol, 1.0 equivalent) and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (4.53 mg, 0.005 mmol, 0.1 equivalents) in
tetrahydrofuran (0.5 mL). Isobutylzinc(II) bromide (0.5 M in
tetrahydrofuran, 0.32 mL, 0.750 mmol) was added. The reaction was
stirred for 16 hours at room temperature. The sample was directly
purified using preparative reverse phase HPLC/MS method TFA8 to
afford the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.69 (d, J=8.7
Hz, 1H), 8.33-8.21 (m, 2H), 8.18-8.10 (m, 1H), 7.87-7.78 (m, 1H),
7.77-7.63 (m, 2H), 6.84 (d, J=8.3 Hz, 1H), 6.47 (d, J=8.3 Hz, 1H),
3.73-3.65 (m, 1H), 2.90 (s, 3H), 2.54-2.36 (m, 2H), 2.27 (d, J=7.0
Hz, 2H), 1.87-1.73 (m, 1H), 1.70-1.57 (m, 2H), 1.52-1.32 (m, 2H),
0.85-0.77 (m, 6H). MS (APCI+) m/z 452.1 (M+H).sup.+.
Example I-69
5-cyclobutyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphth-
alene-1-carboxamide
[1167] Into a 4 mL vial was weighed Example I-15D (25 mg, 0.05
mmol, 1.0 equivalent) and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) 4.53 mg, 0.005 mmol, 0.1 equivalents) in
tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.5 M in
tetrahydrofuran, 0.32 mL, 0.750 mmol) was added. The reaction was
stirred for 16 hours at room temperature. The sample was directly
purified using preparative reverse phase HPLC/MS method TFA8 to
afford the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.73-8.65 (m,
1H), 8.32-8.21 (m, 2H), 8.14 (d, J=8.2 Hz, 1H), 7.82 (ddd, J=8.5,
6.9, 1.4 Hz, 1H), 7.77-7.62 (m, 2H), 6.96 (d, J=8.4 Hz, 1H), 6.51
(d, J=8.4 Hz, 1H), 3.71-3.63 (m, 1H), 3.41 (p, J=9.1, 8.6 Hz, 1H),
2.91 (s, 3H), 2.47-2.28 (m, 2H), 2.25-2.12 (m, 2H), 1.99-1.81 (m,
3H), 1.81-1.60 (m, 3H), 1.49-1.25 (m, 2H). MS (APCI+) m/z 450.0
(M+H).sup.+.
Example I-70
5-chloro-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide
Example I-70A
8-hydroxy-3,4-dihydronaphthalen-1(2H)-one
[1168] Naphthalene-1,8-diol (10 g, 62 mmol) (CAS#569-42-6) and
ethanol (10 mL) were added to 10% Pd/C, dry (0.518 g, 0.487 mmol)
in a 250 mL SS pressure bottle under argon. The mixture was shaken
for 24 hours at 60 psi hydrogen at 60.degree. C. and another 24
hours at room temperature at 60 psi hydrogen. The mixture was
concentrated, and filtered through silica with 10% methyl
tert-butyl ether/heptanes to provide the crude title compound which
was used without further purification.
Example I-70B
8-methoxy-3,4-dihydronaphthalen-1(2H)-one
[1169] Potassium hydroxide (3.65 g, 65 mmol) was ground in a
mortar, transferred to a round-bottomed flask and heated in
dimethyl sulfoxide (65 mL) at 60.degree. C. for about 15 minutes.
The mixture was cooled to near 0.degree. C., placed under a stream
of nitrogen, and treated with Example I-70A (8.11 g, 17 mmol) in
dimethyl sulfoxide (10 mL) with a dimethyl sulfoxide (5 mL) rinse.
The reaction flask was removed from the bath and the mixture was
stirred 40 minutes before the flask was placed back into the ice
water bath. Iodomethane (3.4 mL, 55 mmol) was added dropwise, the
flask was again removed from the bath and the reaction mixture was
stirred at room temperature for 30 minutes before the contents were
poured into ice water (400 mL). The mixture was extracted with 1:1
methyl tert-butyl ether/heptane (2.times.200 mL). The combined
extracts were washed with brine, dried (Na.sub.2SO.sub.4),
filtered, concentrated and chromatographed on silica (20 to 80%
methyl tert-butyl ether/heptane) to give crude material which was
chromatographed on silica (0 to 10% ethyl acetate/dichloromethane)
to give the title compound. MS (ESI+) m/z=177 (M+H).sup.+.
Example I-70C
8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carbaldehyde
[1170] To a suspension of methoxymethyl)triphenylphosphonium
chloride (1.40 g, 4.08 mmol) in anhydrous tetrahydrofuran (6.0 mL)
under nitrogen and at room temperature was added 1 M potassium
tert-butoxide (4.0 mL, 4.0 mmol) dropwise. The resulting reaction
mixture was stirred for 20 minutes before a solution of the Example
I-70B (599 mg, 3.40 mmol) in tetrahydrofuran (5.0 mL) was added
dropwise over 7 minutes. The resulting reaction mixture was stirred
40 minutes. Aqueous HCl (3 M, 5.0 mL) was added and stirring at
room temperature was continued for 16 hours. The reaction mixture
was concentrated and the mixture was extracted with 3.times.50 mL
of methyl tert-butyl ether. The combined organic phases were washed
with dilute hydrochloric acid and with brine, dried
(Na.sub.2SO.sub.4), filtered, concentrated and chromatographed on
silica (20 to 60% CHCl.sub.3/heptane) to give the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 9.60 (d, J=1.9 Hz,
1H), 7.18 (dd, J=8.2, 7.7 Hz, 1H), 6.79-6.76 (m, 1H), 6.74 (d,
J=8.2 Hz, 1H), 3.80 (s, 3H), 3.79-3.75 (m, 1H), 2.81-2.69 (m, 2H),
2.20-2.12 (m, 1H), 1.87-1.64 (m, 3H). MS (ESI+) m/z 191
(M+H).sup.+.
Example I-70D
8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid
[1171] To a solution of Example 70C (38 mg, 0.20 mmol) in acetone
(2.0 mL) at 0.degree. C. was added dropwise a 2.0 M solution of
chromium trioxide in aqueous sulfuric acid (440 .mu.L, 0.88 mmol)
over six minutes. The cold solution was for stirred 30 minutes,
removed from the bath and after 10 minutes quenched with
isopropanol (220 .mu.L). After two minutes, the suspension was
filtered through diatomaceous earth with a thorough ethyl acetate
rinse. The filtrate was concentrated and chromatographed on silica
(67% to 100% methyl tert-butyl ether/heptane) to give the crude
product which was purified by reverse-phase HPLC [Waters
XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm, flow rate 40
mL/minute, 10 to 60% gradient of acetonitrile in 0.1% aqueous TFA]
to give the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 11.95 (s, 1H), 7.11 (dd, J=8.2, 7.7
Hz, 1H), 6.74 (dd, J=8.2, 1.0 Hz, 1H), 6.69 (dd, J=7.7, 1.0 Hz,
1H), 3.71 (s, 3H), 3.65 (dd, J=6.5, 4.8 Hz, 1H), 2.75-2.61 (m, 2H),
2.01-1.86 (m, 2H), 1.71-1.64 (m, 2H). MS (ESI+) m/z 229
(M+Na).sup.+.
Example I-70E
5-chloro-8-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic
acid
[1172] To a solution of Example I-70D (26 mg, 0.14 mmol) in
anhydrous dichloromethane (500 .mu.L) at 0.degree. C. was carefully
added sulfuryl chloride (15.5 .mu.L, 0.19 mmol). The resulting
solution was stirred cold about 15 minutes and another 90 minutes
at room temperature. The suspension was cooled back towards
0.degree. C., quenched with 0.5 M aqueous Na.sub.2S.sub.2O.sub.3
(0.2 mL), stirred another ten minutes, diluted with brine (0.2 mL)
and extracted thrice with methyl tert-butyl ether. The combined
extracts were dried (Na.sub.2SO.sub.4), filtered, concentrated and
purified by reverse-phase HPLC [Waters XBridge.TM. C18 5 .mu.m OBD
column, 30.times.100 mm, flow rate 40 mL/minute, 10 to 60% gradient
of acetonitrile in 0.1% aqueous TFA] to give the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.14
(s, 1H), 7.29 (d, J=8.7 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 3.73 (s,
3H), 3.71 (dd, J=6.5, 4.0 Hz, 1H), 2.73 (ddd, J=17.6, 5.2, 4.7 Hz,
1H), 2.56 (ddd, J=17.6, 9.8, 5.8 Hz, 1H), 2.04-1.97 (m, 1H),
1.89-1.73 (m, 2H), 1.70-1.60 (m, 1H). MS (ESI+) m/z=241
(M+H).sup.+.
Example I-70F
5-chloro-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide
[1173] To a solution of Example I-70E (21 mg, 87 .mu.mol, EDAC
(1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 33
mg, 0.17 mmol) and DMAP (4-dimethylaminopyridine) (12 mg, 98
.mu.mol in anhydrous dichloromethane (250 .mu.L) was added
naphthalene-1-sulfonamide (21 mg, 0.10 mmol). The solution was
stirred for 90 minutes, concentrated and purified by reverse-phase
HPLC [Waters XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm,
flow rate 40 mL/minute, 20 to 80% gradient of acetonitrile in 0.1%
aqueous TFA] to give the title compound. .sup.1H NMR (500 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.54 (s, 1H), 8.69 (dd,
J=8.6, 1.1 Hz, 1H), 8.31-8.28 (m, 1H), 8.24 (dd, J=7.4, 1.3 Hz,
1H), 8.16-8.13 (m, 1H), 7.82 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.72
(ddd, J=8.1, 6.9, 1.1 Hz, 1H), 7.67 (dd, J=8.2, 7.4 Hz, 1H), 7.18
(d, J=8.8 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 3.72-3.68 (m, 1H), 2.94
(s, 3H), 2.58-2.51 (m, 1H), 2.44 (ddd, J=17.4, 9.0, 5.6 Hz, 1H),
1.83-1.74 (m, 1H), 1.74-1.67 (m, 1H), 1.53-1.45 (m, 1H), 1.37-1.27
(m, 1H). MS (ESI+) m/z=430 (M+H).sup.+.
Example I-71
(1S)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1174] Example I-59 (60 mg) was separated by chiral preparative SFC
chromatography using a CHIRALPAK IC, column size 21.times.250 mm, 5
micron, serial Number: IC00SALK014-812151, using a concentration of
5.9 mg/mL in methanol/dichloromethane 1:1 at a flow rate of 49
g/minutes CO.sub.2 and UV monitoring at 220 nm to provide the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.57 (s, 1H), 8.65 (dd, J=8.6, 1.1 Hz, 1H), 8.29 (d, J=8.2 Hz,
1H), 8.25 (dd, J=7.4, 1.2 Hz, 1H), 8.14 (dd, J=8.2, 1.3 Hz, 1H),
7.79 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.64 (m, 2H), 7.15 (d,
J=8.6 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 4.01 (dd, J=9.2, 5.6 Hz,
1H), 3.11 (s, 3H), 2.77 (t, J=7.5 Hz, 2H), 2.36-2.22 (m, 1H),
1.90-1.74 (m, 1H). MS (APCI+) m/z 416 (M+H.sup.+). R.sub.T (chiral
SFC)=5.4 minutes.
Example I-72
(1R)-4-chloro-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1175] Example I-59 (60 mg) was separated by chiral preparative SFC
chromatography using a CHIRALPAK IC, column size 21.times.250 mm, 5
micron, serial Number: IC00SALK014-812151, using a concentration of
5.9 mg/mL in methanol/dichloromethane 1:1 at a flow rate of 49
g/minute CO.sub.2 and UV monitoring at 220 nm to provide the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.57 (s, 1H), 8.65 (dd, J=8.6, 1.1 Hz, 1H), 8.29 (d, J=8.2 Hz,
1H), 8.25 (dd, J=7.4, 1.2 Hz, 1H), 8.14 (dd, J=8.2, 1.3 Hz, 1H),
7.79 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.64 (m, 2H), 7.15 (d,
J=8.6 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 4.01 (dd, J=9.2, 5.6 Hz,
1H), 3.11 (s, 3H), 2.77 (t, J=7.5 Hz, 2H), 2.36-2.22 (m, 1H),
1.90-1.74 (m, 1H). MS (APCI+) m/z 416 (M+H).sup.+. R.sub.T (chiral
SFC)=6.3 minutes.
Example I-73
5,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide
Example I-73A
5,8-dimethoxy-3,4-dihydronaphthalene-1-carbonitrile
[1176] A flask containing 1.6 M n-butyllithium in hexanes (4.66 mL,
7.46 mmol) was cooled to -78.degree. C. under N.sub.2 and treated
dropwise with a solution of trimethylsilyl cyanide (1 mL, 7.46
mmol) in tetrahydrofuran (5 mL). The mixture was allowed to warm to
room temperature and was stirred for 1 hour. The mixture was
diluted with heptanes and the material was collected by filtration
to provide a material which contained LiCN. A solution of
5,8-dimethoxy-3,4-dihydronaphthalen-1(2H)-one (CAS#1015-55-0)
(0.153 g, 0.742 mmol) in N,N-dimethylformamide (1 mL) was cooled to
0.degree. C., treated with diethyl cyanophosphonate (0.225 mL,
1.484 mmol), treated with 20 mg of the LiCN containing material
from above, stirred at room temperature for 90 minutes, treated
with an additional 20 mg of the LiCN containing material from above
and stirred at room temperature for 3 days. The mixture was
partitioned between methyl tert-butyl ether (30 mL) and water. The
methyl tert-butyl ether layer was washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue was dissolved
in toluene (.about.5 mL), treated with para-toluenesulfonic acid
monohydrate (0.014 g, 0.074 mmol) and heated to 120.degree. C. for
3 hours. The mixture was cooled, diluted with methyl tert-butyl
ether (30 mL), washed with aqueous NaHCO.sub.3 solution (10 mL),
washed with brine, dried (MgSO.sub.4), filtered, and concentrated.
The residue was chromatographed on silica gel, eluting with a
gradient of 10% to 30% (over 9 minutes) ethyl acetate in heptanes
to provide the title compound. .sup.1H NMR (501 MHz, CDCl.sub.3)
.delta. ppm 6.95 (t, J=5.1 Hz, 1H), 6.83 (d, J=9.0 Hz, 1H), 6.76
(d, J=9.0 Hz, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 2.76 (t, J=8.1 Hz,
2H), 2.38-2.33 (m, 2H).
Example I-73B
5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile
[1177] A solution of Example I-73A
(5,8-dimethoxy-3,4-dihydronaphthalene-1-carbonitrile) (0.16 g,
0.743 mmol) in ethanol (10 mL) was treated with NaBH.sub.4 (0.169
g, 4.46 mmol), heated to 80.degree. C. for 20 minutes, cooled and
partitioned between methyl tert-butyl ether (.about.50 mL) and 1 M
aqueous HCl (.about.25 mL). The layers were separated and the
aqueous layer was extracted with methyl tert-butyl ether (.about.25
mL). The combined methyl tert-butyl ether layers were concentrated
to provide the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 6.74 (d, J=8.8 Hz, 1H), 6.68 (d, J=8.9 Hz, 1H),
4.10-4.07 (m, 1H), 3.85 (s, 3H), 3.78 (s, 3H), 2.93-2.85 (m, 1H),
2.47 (ddd, J=6.3, 11.1, 17.8 Hz, 1H), 2.29-2.22 (m, 1H), 2.04-1.86
(m, 2H), 1.80 (tdd, J=3.0, 5.4, 12.7 Hz, 1H).
Example I-73C
5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid
[1178] A solution of Example I-73B
(5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-1-carbonitrile) (0.132
g, 0.608 mmol) in ethylene glycol (10 mL) was treated with 45% w/v
KOH in water (5 mL, 44.1 mmol), heated to 170.degree. C. for 16
hours, heated for an additional 8 hours, cooled and partitioned
between methyl tert-butyl ether (75 mL) and 1 M aqueous HCl (75
mL). The layers were separated and the aqueous layer was extracted
with methyl tert-butyl ether (.about.50 mL). The combined methyl
tert-butyl ether layers were washed with 0.1 M aqueous HCl
(.about.25 mL), washed with brine, dried (MgSO.sub.4), filtered,
and concentrated to provide the title compound. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 6.71 (d, J=8.8 Hz, 1H), 6.66 (d, J=8.9
Hz, 1H), 3.88 (t, J=5.7 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 2.77
(dt, J=5.4, 17.7 Hz, 1H), 2.57 (ddd, J=6.2, 8.7, 17.7 Hz, 1H),
2.18-2.10 (m, 1H), 1.96 (dddd, J=3.4, 6.4, 9.9, 13.2 Hz, 1H),
1.89-1.72 (m, 2H).
Example I-73D
5,8-dimethoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-c-
arboxamide
[1179] To a solution of Example I-73C
(5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid)
(20.5 mg, 0.087 mmol), EDC
(1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) (33.3
mg, 0.174 mmol) and DMAP (4-dimethylaminopyridine) (11.66 mg, 0.095
mmol) in dichloromethane (1 mL) was added naphthalene-1-sulfonamide
(19.78 mg, 0.095 mmol). The mixture was stirred at room temperature
for 16 hours, concentrated with a stream of N.sub.2, diluted with
N,N-dimethylformamide and directly purified by reverse-phase HPLC
[Waters XBridge.TM. RP18 column, 5 .mu.m, 30.times.100 mm, flow
rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA] to
afford the title compound. .sup.1H NMR (500 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.45 (s, 1H), 8.69 (dd, J=1.0, 8.7
Hz, 1H), 8.28 (d, J=8.3 Hz, 1H), 8.24 (dd, J=1.2, 7.4 Hz, 1H), 8.13
(d, J=8.0 Hz, 1H), 7.81 (ddd, J=1.4, 6.9, 8.5 Hz, 1H), 7.71 (ddd,
J=1.1, 6.8, 8.1 Hz, 1H), 7.66 (dd, J=7.4, 8.2 Hz, 1H), 6.64 (d,
J=8.9 Hz, 1H), 6.47 (d, J=8.9 Hz, 1H), 3.66 (t, J=5.8 Hz, 1H), 3.64
(s, 3H), 2.89 (s, 3H), 2.43 (dt, J=5.4, 17.5 Hz, 1H), 2.32 (ddd,
J=5.7, 9.0, 17.5 Hz, 1H), 1.79-1.71 (m, 1H), 1.68-1.62 (m, 1H),
1.45-1.37 (m, 1H), 1.34-1.25 (m, 1H). MS (ESI+) m/z 426
(M+H).sup.+.
Example I-74
4-chloro-1-ethyl-N-(1-methyl-1H-indole-4-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1180] Example I-17A (25.0 mg, 0.11 mmol, 1.0 equivalent), EDC HCl
(1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride,
42.3 mg, 0.22 mmol, 2.0 equivalents) and DMAP
(4-dimethylaminopyridine) (14.95 mg, 0.12, mmol, 1.1 equivalents)
were dissolved in CH.sub.2Cl.sub.2 (1.0 mL) and added to a vial
containing 1-methyl-1H-indole-4-sulfonamide (28.1 mg, 0.13 mmol,
1.2 equivalents). The reaction was stirred for 16 hours at room
temperature. The solvent was removed under a stream of N.sub.2,
dissolved in dimethyl sulfoxide, and purified using preparative
reverse phase HPLC/MS method TFA8 to afford the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 7.63 (d, J=8.1 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H),
7.35 (d, J=2.9 Hz, 1H), 7.21 (t, J=7.9 Hz, 1H), 7.17-7.12 (m, 2H),
7.11-7.04 (m, 1H), 6.78 (dd, J=3.1, 0.9 Hz, 1H), 3.80 (s, 3H), 2.78
(t, J=7.4 Hz, 2H), 2.50-2.38 (m, 1H), 2.01-1.87 (m, 2H), 1.75-1.61
(m, 1H), 0.61 (t, J=7.4 Hz, 3H). MS (APCI+) m/z 417.0
(M+H).sup.+.
Example I-75
7-methoxy-4-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide
[1181] A solution of Example I-19C (35 mg, 0.076 mmol), potassium
carbonate (42.0 mg, 0.304 mmol), trimethylboroxine (0.043 mL, 0.304
mmol) in 1,4-dioxane (0.7 mL) and water (0.12 mL) was degassed with
bubbling nitrogen.
1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (24.84 mg, 0.030 mmol) was added and the
mixture was heated at 90.degree. C. with stirring for 16 hours. The
reaction was quenched with water (1 mL), acidified with 1 N aqueous
HCl (0.1 mL), and extracted with dichloromethane (2 mL). The layers
were separated, the solvent was evaporated in vacuo and the
resulting residue was chromatographed using a 12 g silica gel
cartridge with 0-100% ethyl acetate/heptanes over a period of 10
minutes to give crude product (12 mg) which was purified by
reverse-phase preparative HPLC on a Phenomenex.RTM. Luna.RTM. C8(2)
5 .mu.m 100 .ANG. AXIA.TM. column (30 mm.times.150 mm). A gradient
of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0
minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0
minutes linear gradient 95-10% A) to provide the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.47
(s, 1H), 8.67 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.26
(dd, J=7.4, 1.2 Hz, 1H), 8.13 (dt, J=8.2, 0.9 Hz, 1H), 7.85-7.77
(m, 1H), 7.74-7.64 (m, 2H), 6.88 (d, J=8.2 Hz, 1H), 6.48 (d, J=8.2
Hz, 1H), 3.95 (dd, J=9.1, 5.6 Hz, 1H), 3.08 (s, 3H), 2.66 (td,
J=7.3, 3.2 Hz, 2H), 2.27-2.13 (m, 1H), 2.05 (s, 3H), 1.85-1.72 (m,
1H). MS (APCI+) m/z 396 (M+H.sup.+).
Example I-76
4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
[1182] Into a 4 mL vial was added Example I-19C (100 mg, 0.217
mmol) and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (17.74 mg, 0.022 mmol) in tetrahydrofuran (0.5
mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.869
mL, 0.434 mmol) was added. The reaction was stirred for 16 hours at
room temperature. The sample was directly purified using
preparative HPLC/MS method TFA8 to afford the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.68 (d, J=8.7 Hz, 1H), 8.39-8.31 (m, 1H), 8.29
(dd, J=7.4, 1.3 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.84 (ddd, J=8.5,
6.9, 1.4 Hz, 1H), 7.79-7.68 (m, 2H), 7.02 (d, J=8.3 Hz, 1H), 6.59
(d, J=8.3 Hz, 1H), 3.95 (dd, J=9.1, 5.5 Hz, 1H), 3.40 (p, J=8.6 Hz,
1H), 3.13 (s, 3H), 2.69 (t, J=7.6 Hz, 2H), 2.31-2.16 (m, 3H),
2.04-1.86 (m, 3H), 1.86-1.67 (m, 2H). MS (APCI+) m/z 436.1
(M+H).sup.+.
Example I-77
4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide
[1183] Into a 4 mL vial was added Example I-44 (30 mg, 0.065 mmol)
and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (5.31 mg, 6.50 .mu.mol) in tetrahydrofuran (0.5
mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.520
mL, 0.260 mmol) was added. The reaction was stirred for 16 hours at
room temperature. The sample was directly purified using
preparative HPLC/MS method TFA8 to afford the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 9.12 (dd, J=4.2, 1.6 Hz, 1H), 9.11-9.04 (m, 1H),
8.45-8.35 (m, 2H), 7.99 (dd, J=8.5, 7.5 Hz, 1H), 7.87 (dd, J=8.8,
4.2 Hz, 1H), 7.03 (d, J=8.3 Hz, 1H), 6.59 (d, J=8.4 Hz, 1H), 3.94
(dd, J=9.1, 5.8 Hz, 1H), 3.47-3.34 (m, 1H), 3.12 (s, 3H), 2.71 (s,
2H), 2.35-2.16 (m, 3H), 2.05-1.91 (m, 3H), 1.91-1.72 (m, 2H). MS
(APCI+) m/z 437.1 (M+H).sup.+.
Example I-78
4-bromo-N-(imidazo[1,2-a]pyridine-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-ind-
ene-1-carboxamide
Example I-78A
imidazo[1,2-a]pyridine-5-sulfonamide
[1184] Di-n-butylmagnesium (2.74 mL, 2.74 mmol, 1 M in
tetrahydrofuran) and n-butyllithium (0.365 mL, 0.914 mmol, 2.5 M in
hexanes) were combined. The mixture was cooled (ice/acetone bath at
-10.degree. C.) and 3 mL of tetrahydrofuran was added. A solution
of 5-bromoimidazo[1,2-a]pyridine (0.450 g, 2.284 mmol)
(CAS#69214-09-1) in tetrahydrofuran (9 mL) was added dropwise. The
reaction was stirred at -10.degree. C. for a total of 2 hours. The
cold mixture was added to a cooled solution of sulfuryl chloride
(0.426 mL, 5.25 mmol) in tetrahydrofuran (3 mL) while stirring in a
dry ice/acetone bath keeping the internal temperature below
-10.degree. C. The cold bath was removed and the reaction was
allowed to warm up to room temperature. The crude sulfonyl chloride
suspension was filtered and the material was added to a rapidly
stirring solution of ammonium hydroxide. The solvent was reduced
and the crude material was filtered. The material was filtered,
washed with water, and dried under reduced pressure to provide the
title compound. .sup.1H NMR (500 MHz, dimethyl sulfoxide-d.sub.6)
.delta. ppm 8.31-8.15 (m, 2H), 7.90 (d, J=9.0 Hz, 1H), 7.83 (d,
J=1.3 Hz, 1H), 7.56 (dd, J=7.1, 1.1 Hz, 1H), 7.49-7.39 (m, 1H),
7.19-7.08 (m, 1H).
Example I-78B
4-bromo-N-(imidazo[1,2-a]pyridine-5-sulfonyl)-7-methoxy-2,3-dihydro-1H-ind-
ene-1-carboxamide
[1185] Example I-19B (50 mg, 0.184 mmol),
N,N-dimethylpyridin-4-amine (24.78 mg, 0.203 mmol), and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (70.7 mg, 0.369 mmol) were combined in
N,N-dimethylacetamide (1 mL). After 30 minutes, Example I-78A (41
mg, 0.208 mmol) was added. The reaction was stirred at room
temperature for 18 hours. The reaction was quenched with 0.5 mL of
water and 10 drops of 1 M aqueous HCl, and put through an
aqueous/organic extractor tube with dichloromethane (2.times.1 mL).
The solvent was removed and the crude material was purified by
reverse-phase preparative HPLC on a Phenomenex.RTM. Luna.RTM. C8(2)
5 .mu.m 100 .ANG. AXIA.TM. column (30 mm.times.150 mm). A gradient
of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0
minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0
minutes linear gradient 95-10% A) to provide crude title compound.
The crude material was triturated with 0.5 mL of dichloromethane
and the solvent was removed to provide the title compound as a
trifluoroacetic acid salt. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 8.34 (dd, J=1.8, 0.8 Hz, 1H), 8.12
(d, J=1.7 Hz, 1H), 8.05 (dt, J=9.0, 1.0 Hz, 1H), 7.82 (dd, J=7.3,
1.1 Hz, 1H), 7.73 (dd, J=9.0, 7.2 Hz, 1H), 7.29 (d, J=8.7 Hz, 1H),
6.63 (d, J=8.7 Hz, 1H), 3.94 (dd, J=9.2, 5.3 Hz, 1H), 3.30 (s, 3H),
2.79 (qdd, J=16.0, 8.7, 6.0 Hz, 2H), 2.29 (dtd, J=13.1, 9.0, 6.5
Hz, 1H), 1.92 (ddt, J=13.0, 8.8, 5.6 Hz, 1H). MS (APCI+) 451 m/z
(M+H).sup.+.
Example I-79
2-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trien-
e-7-carboxamide
Example I-79A
2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid
[1186] A solution of Example I-102K
(2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile)
(0.63 g, 2.65 mmol) in ethanol (10.58 mL) was treated with a
solution of potassium hydroxide (0.742 g, 13.23 mmol) in water
(2.65 mL). The mixture was heated at 80.degree. C. for 5 hours,
cooled to 0.degree. C., and acidified with 6 M aqueous HCl to pH
.about.2. The resulting precipitate was collected by filtration,
washed with water, and dried in a vacuum oven provide the title
compound. .sup.1H NMR (400 MHz, CDCL.sub.3) .delta. ppm 7.28 (d,
J=8.9 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 4.32 (dd, J=2.6, 5.6 Hz,
1H), 3.84 (s, 3H), 3.44 (dd, J=5.6, 14.2 Hz, 1H), 3.33 (dd, J=2.6,
14.2 Hz, 1H).
Example I-79B
2-bromo-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5-trien-
e-7-carboxamide
[1187] A solution of Example I-79A
(2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid) (12 mg, 0.047 mmol) in dichloromethane was treated with
oxalyl chloride (20.43 .mu.l, 0.233 mmol), treated with a catalytic
amount of N,N-dimethylformamide, stirred at room temperature for
.about.30 minutes and concentrated with a stream of N.sub.2. The
residue was dissolved in dichloromethane (.about.0.3 mL) and added
to a 0.degree. C. solution of naphthalene-1-sulfonamide (12.58 mg,
0.061 mmol), triethylamine (13.01 .mu.l, 0.093 mmol) and DMAP
(4-dimethylaminopyridine) (0.570 mg, 4.67 .mu.mol) in
dichloromethane (.about.0.2 mL). The mixture was stirred for 2
hours, and concentrated with a stream of N.sub.2. The residue was
dissolved in N,N-dimethylformamide (.about.1 mL) and was directly
purified by reverse-phase HPLC [Waters XBridge.TM. RP18 column, 5
.mu.m, 30.times.100 mm, flow rate 40 mL/minute, 5-95% gradient of
acetonitrile in 0.1% TFA] to afford the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.87 (s, 1H),
8.61 (d, J=8.7 Hz, 1H), 8.33-8.28 (m, 2H), 8.14 (d, J=8.0 Hz, 1H),
7.79 (ddd, J=1.5, 6.9, 8.6 Hz, 1H), 7.74-7.67 (m, 2H), 7.23 (d,
J=8.9 Hz, 1H), 6.60 (d, J=8.9 Hz, 1H), 4.38 (dd, J=2.4, 5.7 Hz,
1H), 3.34 (s, 3H), 3.25 (dd, J=6.3, 7.9 Hz, 1H), 2.69 (dd, J=2.5,
14.2 Hz, 1H). MS (ESI+) m/z 446,448 (M+H).sup.+.
Example I-80
(1S)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide
[1188] Into a 4 mL vial was weighed Example I-19 (100 mg, 0.217
mmol) and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (17.74 mg, 0.022 mmol) in tetrahydrofuran (0.5
mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.869
mL, 0.434 mmol) was added. The reaction was stirred for 16 hours at
room temperature, and directly purified using preparative reverse
phase HPLC/MS method TFA8 to afford the racemate of the title
compound. The racemate was separated by chiral preparative SFC
chromatography using a CHIRALPAK AD-H, column size 21.times.250 mm,
5 micron, serial Number: ADH0SAMA003-810291, using a concentration
of 12 mg/mL in methanol at a flow rate of 48 g/minutes CO.sub.2 and
UV monitoring at 220 nm to provide the title compound. .sup.1H NMR
(501 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
ppm 8.66 (d, J=8.6 Hz, 1H), 8.32-8.23 (m, 2H), 8.14 (d, J=8.2 Hz,
1H), 7.84-7.76 (m, 1H), 7.76-7.65 (m, 2H), 6.99 (d, J=8.4 Hz, 1H),
6.56 (d, J=8.4 Hz, 1H), 3.92 (dd, J=9.1, 5.6 Hz, 1H), 3.37 (p,
J=8.7 Hz, 1H), 3.11 (s, 3H), 2.73-2.59 (m, 2H), 2.28-2.14 (m, 3H),
2.01-1.84 (m, 3H), 1.82-1.68 (m, 2H). MS (APCI+) m/z 436.1
(M+H).sup.+.
Example I-81
(1R)-4-cyclobutyl-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide
[1189] Example I-81 was isolated as the second enantiomer during
the preparative SFC separation described in Example I-80. .sup.1H
NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. ppm 8.67 (d, J=8.5 Hz, 1H), 8.20-8.15 (m, 2H), 8.06 (d,
J=8.0 Hz, 1H), 7.76-7.50 (m, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.55 (d,
J=8.4 Hz, 1H), 3.88-3.77 (m, 1H), 3.35 (q, J=8.9 Hz, 1H), 3.18 (s,
3H), 2.64 (q, J=7.9 Hz, 2H), 2.23-2.09 (m, 3H), 2.02-1.65 (m, 5H).
MS (APCI+) m/z 436.1 (M+H).sup.+.
Example I-82
8-cyclobutyl-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-ca-
rboxamide
[1190] Into a 4 mL vial was added
8-chloro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (68 mg,
0.323 mmol) and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (27.8 mg, 0.032 mmol) in tetrahydrofuran (1 mL).
Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 2.58 mL,
1.291 mmol) was added. The reaction was heated at 50.degree. C. for
16 hours. The reaction was purified using preparative reverse phase
HPLC/MS method TFA1 to provide
8-cyclobutyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid. Into
a 4 mL vial was added
8-cyclobutyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (24
mg, 0.104 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (40.0 mg, 0.208 mmol), and
N,N-dimethylpyridin-4-amine (14.00 mg, 0.115 mmol) in
dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (23.76 mg,
0.115 mmol) was added. The reaction was stirred for 16 hours at
room temperature. The solvent was removed under a stream of N.sub.2
and the residue was redissolved in methanol. The reaction was
purified using preparative reverse phase HPLC/MS method TFA8 to
afford the title compound. .sup.1H NMR (500 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.71 (dd, J=8.7,
1.0 Hz, 1H), 8.32-8.19 (m, 2H), 8.13 (dd, J=8.1, 1.1 Hz, 1H), 7.85
(ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.73 (ddd, J=8.2, 6.9, 1.1 Hz, 1H),
7.64 (dd, J=8.3, 7.3 Hz, 1H), 7.02 (t, J=7.6 Hz, 1H), 6.89 (d,
J=7.6 Hz, 1H), 6.85-6.77 (m, 1H), 2.62-2.52 (m, 4H), 2.15-2.05 (m,
1H), 1.96-1.87 (m, 1H), 1.85-1.72 (m, 1H), 1.70-1.42 (m, 3H), 1.36
(q, J=9.3 Hz, 1H), 1.28-1.04 (m, 2H), 1.03-0.90 (m, 1H). MS (APCI+)
m/z 420.1 (M+H).sup.+.
Example I-83
7-cyclobutyl-1-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-c-
arboxamide
[1191] Into a 4 mL vial was added
7-chloro-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (37 mg,
0.176 mmol) and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (15.11 mg, 0.018 mmol) in tetrahydrofuran (0.5
mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 1.4 mL,
0.70 mmol) was added. The reaction was heated at 50.degree. C. for
16 hours. The reaction was purified using preparative reverse phase
HPLC/MS method TFA1 to provide
7-cyclobutyl-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid. Into
a 4 mL vial was added
7-cyclobutyl-1-methyl-2,3-dihydro-1H-indene-1-carboxylic acid (10
mg, 0.043 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (16.65 mg, 0.087 mmol), and
N,N-dimethylpyridin-4-amine (5.84 mg, 0.048 mmol) in
dichloromethane (0.5 mL). Naphthalene-1-sulfonamide (9.90 mg, 0.048
mmol) was added. The reaction was stirred for 16 hours at room
temperature. The solvent was removed under a stream of N.sub.2 and
the residue was redissolved in methanol. The reaction was purified
using preparative reverse phase HPLC/MS method TFA8 to afford the
title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.70 (d, J=9.5
Hz, 1H), 8.27 (dd, J=7.4, 1.3 Hz, 1H), 8.17 (d, J=8.2 Hz, 1H),
8.09-7.94 (m, 1H), 7.68-7.50 (m, 3H), 7.26-7.08 (m, 2H), 6.98 (dd,
J=7.1, 1.3 Hz, 1H), 3.16-3.05 (m, 1H), 2.81 (dd, J=9.0, 5.7 Hz,
2H), 2.28-1.40 (m, 8H), 1.22 (s, 3H). MS (APCI+) m/z 420.1
(M+H).sup.+.
Example I-84
(1R)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
Example I-84A
(S)-7-bromo-4-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid
[1192] To a solution of
(S)-4-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (450 mg,
2.341 mmol) in methanol (5 mL) and water (1.5 mL) at room
temperature was added dibromine (0.180 mL, 3.51 mmol) dropwise. The
mixture was stirred for 1 hour. The solvent was removed and water
(2 mL) was added. The mixture was extracted with dichloromethane,
and the combined organic layers were concentrated in vacuo. The
mixture was purified by chromatography using a 24 g silica gel
cartridge with a gradient of 0-100% ethyl acetate/heptanes over a
period of 10 minutes to provide the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.39 (s, 1H),
7.33 (d, J=8.6 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 3.91 (dd, J=9.6,
3.3 Hz, 1H), 3.78 (s, 3H), 2.95-2.87 (m, 2H), 2.41 (dq, J=13.2, 9.1
Hz, 1H), 2.17 (dddd, J=13.2, 7.5, 4.5, 3.3 Hz, 1H). MS (APCI+) m/z
271 (M+H).sup.+.
Example I-84B
7-bromo-4-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide
[1193] Example I-84A (0.41 g, 1.512 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (0.580 g, 3.02 mmol) and
N,N-dimethylpyridin-4-amine (0.203 g, 1.664 mmol) were dissolved in
N,N-dimethylacetamide (6.7 mL). The reaction was stirred at room
temperature for 20 minutes and naphthalene-1-sulfonamide (0.313 g,
1.512 mmol) was added. After 16 hours, the N,N-dimethylacetamide
was evaporated in vacuo. The residue was quenched with 1 N aqueous
HCl (2.4 mL) to pH-2, and extracted with 50 mL dichloromethane. The
solvent was evaporated in vacuo. The residue was purified by
chromatography, eluting on a 24 g silica gel cartridge with a
gradient of 0-100% ethyl acetate/heptanes over a period of 20
minute to provide the title compound. .sup.1H NMR (501 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.72 (s, 1H), 8.67 (dd,
J=8.7, 1.0 Hz, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.5, 1.3
Hz, 1H), 8.14-8.09 (m, 1H), 7.76 (ddd, J=8.5, 6.9, 1.4 Hz, 1H),
7.71-7.62 (m, 2H), 7.09 (d, J=8.7 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H),
3.97 (dd, J=9.7, 4.1 Hz, 1H), 3.70 (s, 3H), 2.77 (ddd, J=16.5, 9.2,
4.3 Hz, 1H), 2.72-2.62 (m, 1H), 2.37-2.27 (m, 1H), 1.82 (ddt,
J=13.1, 8.7, 4.3 Hz, 1H). MS (APCI+) m/z 460 (M+H.sup.+).
Example I-84C
(1R)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
[1194] Example I-84B (42 mg) was separated by chiral preparative
SFC chromatography using a Whelk-O (S,S), column size 21.times.250
mm, 5 micron, serial Number: 43170, using a concentration of 4.2
mg/mL in methanol/dichlromethane 1:1 at a flow rate of 64 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.70
(s, 1H), 8.66 (dd, J=8.6, 1.0 Hz, 1H), 8.28-8.19 (m, 2H), 8.12-8.04
(m, 1H), 7.73 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.68-7.56 (m, 2H),
7.08 (d, J=8.6 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 3.94 (dd, J=9.7,
4.0 Hz, 1H), 3.68 (s, 3H), 2.77-2.58 (m, 2H), 2.29 (dtd, J=13.3,
9.4, 7.6 Hz, 1H), 1.81 (ddt, J=13.1, 8.6, 4.2 Hz, 1H). MS (APCI+)
m/z 460 (M+H.sup.+), Br doublet. R.sub.T (chiral SFC)=12.6
minutes.
Example I-85
(1S)-7-bromo-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
[1195] Example I-84B (42 mg) was separated by chiral preparative
SFC chromatography using a Whelk-O (S,S), column size 21.times.250
mm, 5 micron, serial Number: 43170, using a concentration of 4.2
mg/mL in methanol/dichlromethane 1:1 at a flow rate of 64 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.70
(s, 1H), 8.66 (dd, J=8.5, 1.0 Hz, 1H), 8.28-8.14 (m, 2H), 8.13-8.04
(m, 1H), 7.73 (ddd, J=8.4, 6.8, 1.4 Hz, 1H), 7.65 (q, J=7.5 Hz,
2H), 7.07 (d, J=8.6 Hz, 1H), 6.68 (d, J=8.6 Hz, 1H), 3.94 (dd,
J=9.9, 4.0 Hz, 1H), 3.68 (s, 3H), 2.75 (ddd, J=16.4, 9.2, 4.3 Hz,
1H), 2.66 (dt, J=16.3, 8.1 Hz, 1H), 2.33-2.23 (m, 1H), 1.81 (ddt,
J=13.0, 8.5, 4.2 Hz, 1H). MS (APCI+) m/z 460 (M+H.sup.+), Br
doublet. R.sub.T (chiral SFC)=14.3 minutes.
Example I-86
(1R)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
Example I-86A
7-chloro-4-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide
[1196] A suspension of Example I-84B (100 mg, 0.217 mmol),
copper(I) chloride (373 mg, 3.76 mmol) in N,N-dimethylacetamide
(DMA) (0.9 mL) was purged with nitrogen and heated at 150.degree.
C. for 5 hours. The reaction was cooled, filtered, and washed with
ethyl acetate. The filtrate was acidified with 1.5 mL 1 N aqueous
HCl. Water (3 mL) was added and the mixture was extracted with
ethyl acetate. The solvent was evaporated in vacuo and the residue
was chromatographed using a 12 g silica gel cartridge with 0-100%
ethyl acetate/heptanes over a period of 10 minutes to afford the
title compound. .sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6)
.delta. ppm 12.73 (s, 1H), 8.66 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d,
J=8.2 Hz, 1H), 8.26 (dd, J=7.4, 1.3 Hz, 1H), 8.12 (dt, J=8.1, 0.9
Hz, 1H), 7.76 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.71-7.64 (m, 2H),
6.96 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.03 (dd, J=9.5,
4.8 Hz, 1H), 3.70 (s, 3H), 2.78-2.62 (m, 2H), 2.31 (dtd, J=13.2,
9.3, 6.9 Hz, 1H), 1.81 (ddt, J=13.5, 8.7, 5.1 Hz, 1H). MS (APCI+)
m/z 416 (M+H.sup.+).
Example I-86B
(1R)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1197] Example I-86A (39 mg) was separated by chiral preparative
SFC chromatography using a ChiralPak AD-H column size 21.times.250
mm, 5 micron, serial Number: ADHSAMA003-810291, using a
concentration of 3.9 mg in methanol at a flow rate of 48 g/minutes
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.73
(s, 1H), 8.66 (dd, J=8.6, 1.1 Hz, 1H), 8.29-8.20 (m, 2H), 8.11 (dd,
J=8.3, 1.4 Hz, 1H), 7.75 (ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.71-7.61
(m, 2H), 6.96 (d, J=8.7 Hz, 1H), 6.75 (d, J=8.7 Hz, 1H), 4.01 (dd,
J=9.5, 4.7 Hz, 1H), 3.70 (s, 3H), 2.79-2.62 (m, 2H), 2.30 (dtd,
J=13.2, 9.2, 7.0 Hz, 1H), 1.82 (ddt, J=13.4, 8.6, 5.1 Hz, 1H). MS
(APCI+) m/z 416 (M+H).sup.+. R.sub.T (chiral SFC)=2.85 minutes.
Example I-87
(1S)-7-chloro-4-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1198] Example I-86A (39 mg) was separated by chiral preparative
SFC chromatography using a ChiralPak AD-H column size 21.times.250
mm, 5 micron, serial Number: ADHSAMA003-810291, using a
concentration of 3.9 mg in methanol at a flow rate of 48 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.73
(s, 1H), 8.66 (dd, J=8.7, 1.1 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.25
(dd, J=7.4, 1.2 Hz, 1H), 8.13-8.07 (m, 1H), 7.75 (ddd, J=8.5, 6.8,
1.4 Hz, 1H), 7.70-7.62 (m, 2H), 6.96 (d, J=8.7 Hz, 1H), 6.75 (d,
J=8.6 Hz, 1H), 4.02 (dd, J=9.5, 4.7 Hz, 1H), 3.70 (s, 3H),
2.78-2.63 (m, 2H), 2.31 (dtd, J=13.2, 9.2, 6.9 Hz, 1H), 1.82 (ddt,
J=13.4, 8.6, 5.0 Hz, 1H). MS (APCI+) m/z 416 (M+H.sup.+). R.sub.T
(chiral SFC)=3.3 minutes.
Example I-88
5-cyclopropyl-8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronapht-
halene-1-carboxamide
[1199] Into a 4 mL vial was added Example I-41 (20 mg, 0.042 mmol)
and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (3.63 mg, 4.22 .mu.mol) in tetrahydrofuran (0.5
mL). Cyclopropylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.253
mL, 0.126 mmol) was added. The reaction was stirred at room
temperature for 2 hours, at which point there was minimal
conversion. Cyclopropylzinc(II) bromide (0.5 M in tetrahydrofuran,
0.253 mL, 0.126 mmol) was added and the reaction was stirred for 16
hours at room temperature. The sample was directly purified using
preparative HPLC/MS method TFA8 to afford the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.70 (d, J=8.6 Hz, 1H), 8.31-8.21 (m, 2H), 8.13
(d, J=8.2 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76-7.69 (m, 1H), 7.67
(t, J=7.8 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.44 (d, J=8.5 Hz, 1H),
3.68 (t, J=5.7 Hz, 1H), 2.91 (s, 3H), 2.73-2.63 (m, 1H), 2.63-2.56
(m, 1H), 1.81-1.74 (m, 1H), 1.73-1.62 (m, 2H), 1.53-1.46 (m, 1H),
1.40-1.36 (m, 1H), 0.84-0.72 (m, 2H), 0.46-0.34 (m, 2H). MS (APCI+)
m/z 436.1 (M+H).sup.+.
Example I-89
(1S)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide
Example I-89A
4,7-dimethoxy-2,3-dihydro-1H-indene-1-carbonitrile
[1200] In a 100 mL round bottom flask
4,7-dimethoxy-2,3-dihydro-1H-inden-1-one (1 g, 5.20 mmol)
(CAS#52428-09-8, Aldrich) and
1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TOSMIC, 1.016 g, 5.20
mmol) were dissolved in dimethoxyethane (15 mL) and methanol (0.358
mL, 8.84 mmol). The reaction was cooled to 0.degree. C. in an ice
bath under nitrogen. Solid potassium tert-butoxide (1.168 g, 10.41
mmol) was added in portions over 0.5 hour. The reaction was allowed
to warm to room temperature over 1.5 hours, and heated at
42.degree. C. for 1.5 hours. The solvent was removed in vacuo and
the crude material was quenched with water (30 mL). The aqueous
layer was extracted with ether (4.times.50 mL) and the organic
suspension was filtered through diatomaceous earth. The filtered
material was washed with ether. The solvent was removed in vacuo
and the crude material was chromatographed using a 24 g silica gel
cartridge with a gradient 0-100% ethyl acetate/heptanes over a
period of 20 minutes to provide the title compound. .sup.1H NMR
(501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 6.87 (dd, J=8.8,
0.6 Hz, 1H), 6.85-6.81 (m, 1H), 4.32 (ddd, J=9.1, 4.7, 0.7 Hz, 1H),
3.78 (s, 3H), 3.74 (s, 3H), 2.99-2.89 (m, 1H), 2.88-2.79 (m, 1H),
2.49-2.42 (m, 1H), 2.28 (ddt, J=13.4, 8.6, 4.9 Hz, 1H).
Example I-89B
4,7-dimethoxy-2,3-dihydro-1H-indene-1-carboxylic acid
[1201] Example I-89A (0.33 g, 1.624 mmol) was dissolved in ethanol
(5.41 mL). A solution of sodium hydroxide (0.649 g, 16.24 mmol) in
5.4 mL of water was added, and the resulting mixture was heated at
80.degree. C. After 16 hours, the reaction was cooled in an ice
bath and acidified with 6 M aqueous HCl (3.5 mL) to pH-2. The
resulting precipitate was filtered and washed with water to provide
the title compound. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.08 (s, 1H), 6.75 (d, J=8.7 Hz,
1H), 6.71 (d, J=8.8 Hz, 1H), 3.85 (dd, J=9.2, 4.6 Hz, 1H), 3.72 (s,
3H), 3.68 (s, 3H), 2.86 (ddd, J=15.8, 8.6, 7.0 Hz, 1H), 2.77 (ddd,
J=16.0, 8.9, 4.9 Hz, 1H), 2.34 (dtd, J=12.9, 9.1, 7.0 Hz, 1H), 2.11
(ddt, J=13.3, 8.7, 4.8 Hz, 1H). MS (ESI+) m/z 223 (M+H.sup.+).
Example I-89C
4,7-dimethoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxam-
ide
[1202] N,N-Dimethylpyridin-4-amine (43.2 mg, 0.354 mmol), and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (123 mg, 0.643 mmol) were combined in
N,N-dimethylacetamide (1.2 mL). To the suspension was added Example
I-89B (71.5 mg, 0.322 mmol). After 30 minutes,
naphthalene-1-sulfonamide (60 mg, 0.290 mmol) was added. The
reaction was stirred at room temperature for 18 hours. The
N,N-dimethylacetamide was evaporated in vacuo. The residue was
quenched with 1 mL water and 1 N aqueous citric acid (24 drops) to
pH .about.4, extracted with dichloromethane and chromatographed
using a 12 g silica gel cartridge, eluting with 0-100% ethyl
acetate/heptanes over a period of 20 minutes to provide the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.45 (s, 1H), 8.63 (dd, J=8.7, 1.1 Hz, 1H), 8.25 (d, J=8.4 Hz,
1H), 8.21 (dd, J=7.4, 1.2 Hz, 1H), 8.12-8.07 (m, 1H), 7.75 (ddd,
J=8.5, 6.8, 1.4 Hz, 1H), 7.69-7.60 (m, 2H), 6.62 (d, J=8.7 Hz, 1H),
6.48 (d, J=8.8 Hz, 1H), 3.90 (dd, J=9.0, 5.6 Hz, 1H), 3.61 (s, 3H),
3.04 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 2.24-2.12 (m, 1H), 1.82-1.70
(m, 1H). MS (APCI+) m/z 412 (M+H.sup.+).
Example I-89D
(1S)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide
[1203] Example I-89C (33 mg) was separated by chiral preparative
SFC chromatography using a ChiralPak AD-H column size 21.times.250
mm, 5 micron, serial Number: ADHSAMA003-810291, using a
concentration of 8.2 mg in methanol at a flow rate of 48 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.45
(s, 1H), 8.63 (dd, J=8.7, 1.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.21
(dd, J=7.4, 1.2 Hz, 1H), 8.12-8.07 (m, 1H), 7.75 (ddd, J=8.5, 6.8,
1.4 Hz, 1H), 7.69-7.60 (m, 2H), 6.62 (d, J=8.7 Hz, 1H), 6.48 (d,
J=8.8 Hz, 1H), 3.90 (dd, J=9.0, 5.6 Hz, 1H), 3.61 (s, 3H), 3.04 (s,
3H), 2.62 (t, J=7.4 Hz, 2H), 2.24-2.12 (m, 1H), 1.82-1.70 (m, 1H).
MS (APCI+) m/z 412 (M+H.sup.+). R.sub.T (chiral SFC)=3.0
minutes.
Example I-90
(1R)-4,7-dimethoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide
[1204] Example I-89C (33 mg) was separated by chiral preparative
SFC chromatography using a ChiralPak AD-H column size 21.times.250
mm, 5 micron, serial Number: ADHSAMA003-810291, using a
concentration of 8.2 mg in methanol at a flow rate of 48 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.45
(s, 1H), 8.63 (dd, J=8.7, 1.1 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.21
(dd, J=7.4, 1.2 Hz, 1H), 8.12-8.07 (m, 1H), 7.75 (ddd, J=8.5, 6.8,
1.4 Hz, 1H), 7.69-7.60 (m, 2H), 6.62 (d, J=8.7 Hz, 1H), 6.48 (d,
J=8.8 Hz, 1H), 3.90 (dd, J=9.0, 5.6 Hz, 1H), 3.61 (s, 3H), 3.04 (s,
3H), 2.62 (t, J=7.4 Hz, 2H), 2.24-2.12 (m, 1H), 1.82-1.70 (m, 1H).
MS (APCI+) m/z 412 (M+H.sup.+). R.sub.T (chiral SFC)=4.1
minutes.
Example I-91
(1S)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide
Example I-91A
4,7-dimethoxy-N-(quinolin-5-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamid-
e
[1205] N,N-Dimethylpyridin-4-amine (43.0 mg, 0.352 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (123 mg, 0.640 mmol) were combined in
N,N-dimethylacetamide (1.2 mL). To this suspension was added
Example I-89B (71.1 mg, 0.320 mmol). After 30 minutes,
quinoline-5-sulfonamide (60 mg, 0.288 mmol) was added. The reaction
was stirred at room temperature for 16 hours. The
N,N-dimethylacetamide was evaporated in vacuo, and the residue was
quenched with 1 N aqueous citric acid (24 drops) to pH .about.4.
The precipitate was filtered and chromatographed using a 4 g silica
gel cartridge with 0-100% ethyl acetate/heptanes over a period of 5
minutes to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.56 (s, 1H), 9.07-8.97
(m, 2H), 8.34-8.25 (m, 2H), 7.89 (dd, J=8.4, 7.4 Hz, 1H), 7.77 (dd,
J=8.8, 4.2 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 6.48 (d, J=8.7 Hz, 1H),
3.88 (dd, J=9.1, 5.6 Hz, 1H), 3.62 (s, 3H), 3.03 (s, 3H), 2.64
(ddd, J=8.5, 6.6, 4.2 Hz, 2H), 2.20 (dtd, J=13.0, 8.6, 6.5 Hz, 1H),
1.78 (ddt, J=12.4, 8.4, 6.1 Hz, 1H). MS (APCI+) m/z 413
(M+H.sup.+).
Example I-91B
(1S)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide
[1206] Example I-91A (60 mg) was separated by chiral preparative
SFC chromatography using a ChiralPak AD-H column size 21.times.250
mm, 5 micron, serial Number: ADHSAMA003-810291, using a
concentration of 6.0 mg in methanol at a flow rate of 56 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.56
(s, 1H), 9.07-8.97 (m, 2H), 8.34-8.25 (m, 2H), 7.89 (dd, J=8.4, 7.4
Hz, 1H), 7.77 (dd, J=8.8, 4.2 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 6.48
(d, J=8.7 Hz, 1H), 3.88 (dd, J=9.1, 5.6 Hz, 1H), 3.62 (s, 3H), 3.03
(s, 3H), 2.64 (ddd, J=8.5, 6.6, 4.2 Hz, 2H), 2.20 (dtd, J=13.0,
8.6, 6.5 Hz, 1H), 1.78 (ddt, J=12.4, 8.4, 6.1 Hz, 1H). MS (APCI+)
m/z 413 (M+H.sup.+). R.sub.T (chiral SFC)=2.75 minute.
Example I-92
(1R)-4,7-dimethoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-carbox-
amide
[1207] Example I-91A (60 mg) was separated by chiral preparative
SFC chromatography using a ChiralPak AD-H column size 21.times.250
mm, 5 micron, serial Number: ADHSAMA003-810291, using a
concentration of 6.0 mg in methanol at a flow rate of 56 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.56
(s, 1H), 9.07-8.97 (m, 2H), 8.34-8.25 (m, 2H), 7.89 (dd, J=8.4, 7.4
Hz, 1H), 7.77 (dd, J=8.8, 4.2 Hz, 1H), 6.63 (d, J=8.7 Hz, 1H), 6.48
(d, J=8.7 Hz, 1H), 3.88 (dd, J=9.1, 5.6 Hz, 1H), 3.62 (s, 3H), 3.03
(s, 3H), 2.64 (ddd, J=8.5, 6.6, 4.2 Hz, 2H), 2.20 (dtd, J=13.0,
8.6, 6.5 Hz, 1H), 1.78 (ddt, J=12.4, 8.4, 6.1 Hz, 1H). MS (APCI+)
m/z 413 (M+H).sup.+. R.sub.T (chiral SFC)=3.3 minute.
Example I-93
(1S)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro--
1H-indene-1-carboxamide
Example I-93A
7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one
[1208] A mixture of 7-methoxy-2,3-dihydro-1H-inden-1-one
[CAS#34985-41-6](1 g, 6.17 mmol), trimethyl(trifluoromethyl)silane
(1.753 g, 12.33 mmol), silver(I) fluoride (0.196 g, 1.541 mmol) and
PhI(OAc).sub.2 ((diacetoxyiodo)benzene 3.97 g, 12.33 mmol) in
dimethyl sulfoxide (10 mL) was stirred at 45.degree. C. for 16
hours. Water (10 mL) was added. The mixture was extracted with
ethyl acetate (3.times.20 mL), and the combined extracts were
washed with brine. The organic layer was dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by
reverse-phase preparative HPLC on a Phenomenex.RTM. Luna.RTM. C8(2)
5 .mu.m 100 .ANG. AXIA.TM. column (30 mm.times.150 mm). A gradient
of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0
minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0
minutes linear gradient 95-10% A) to provide the title compound.
.sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 7.79 (dd, J=8.6,
0.8 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 4.01 (s, 3H), 3.28-3.22 (m,
2H), 2.76-2.68 (m, 2H). MS (ESI+) m/z 231.0 (M+H).sup.+.
Example I-93B
7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carbonitrile
[1209] The mixture of Example I-93A (0.290 g, 1.260 mmol) and
1-((isocyanomethyl)sulfonyl)-4-methylbenzene (TOSMIC, 0.320 g,
1.638 mmol) were dissolved in dimethoxyethane (12.60 mL). The
reaction mixture was cooled to -8.degree. C. (internal temperature)
with ice/acetone/dry ice under nitrogen. Solid potassium
tert-butoxide (0.325 g, 2.90 mmol) was added in portions keeping
the internal temperature <-5.degree. C. over about 30 minutes,
and allowed to warm to room temperature and stir for 16 hours. The
solvent was removed in vacuo and the crude residue was quenched
with water (20 mL). The aqueous layer was extracted with ether
(3.times.60 mL). The solvent was removed and the crude residue was
chromatographed using a 25 g silica gel cartridge, eluting with an
ethyl acetate in hexane at 0-50% gradient to provide the title
compound. .sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 7.57 (d,
J=8.5 Hz, 1H), 6.82 (d, J=8.5 Hz, 1H), 4.14 (dd, J=8.4, 5.3 Hz,
1H), 3.96 (s, 3H), 3.32 (dt, J=16.5, 8.1 Hz, 1H), 3.17 (dtd,
J=14.4, 6.5, 3.2 Hz, 1H), 2.66-2.46 (m, 2H). MS (APCI+) m/z 258
(M+H.sup.+).
Example I-93C
7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxylic
acid
[1210] A mixture of Example I-93B (170 mg, 0.705 mmol) and sodium
hydroxide (282 mg, 7.05 mmol) in ethanol (6 mL) was stirred at
90.degree. C. for 16 hours. The solvent was removed under reduced
pressure and water (3 mL) was added. The mixture was adjusted to pH
1.about.2 by adding 2N aqueous HCl and extracted with
dichloromethane (3.times.20 mL). The combined extracts was washed
with brine, dried over MgSO.sub.4, filtered, and concentrated. The
residue was purified via chromatography on a 12 g cartridge,
eluting with ethyl acetate/methanol (9:1) in heptanes at 0-70%
gradient to provide title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.28 (s, 1H), 7.56 (d, J=8.5 Hz,
1H), 6.98 (d, J=8.5 Hz, 1H), 3.92 (dd, J=9.4, 4.6 Hz, 1H), 3.83 (s,
3H), 3.14-2.96 (m, 2H), 2.46-2.35 (m, 1H), 2.19 (ddt, J=13.2, 8.6,
4.8 Hz, 1H). MS[APCI(+)] m/z 258 (M+H).sup.+.
Example I-93D
7-methoxy-N-(naphthalen-1-ylsulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-i-
ndene-1-carboxamide
[1211] A mixture of Example I-93C (47 mg, 0.181 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (69.3 mg, 0.361 mmol) and
N,N-dimethylpyridin-4-amine (24.27 mg, 0.199 mmol) in
dichloromethane (2 mL) was stirred at room temperature for 30
minutes. Naphthalene-1-sulfonamide (41.2 mg, 0.199 mmol) was added.
The mixture was stirred for another 2 hours. The reaction mixture
without work up was loaded on a 12 g silica gel cartridge and
chromatographed eluting with methanol in ethyl acetate (0-15%
gradient) to provide the title compound. MS [APCI(+)], m/z 450.3
(M+H.sup.+).
Example I-93E
(1S)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro--
1H-indene-1-carboxamide
[1212] Example I-93D (62 mg, 0.138 mmol) was separated via chiral
SFC using Column: ChiralPak AD-H, Column Size: 21.times.250 mm, 5
micron, Concentration: 6 mg/mL in methanol, and Co-Solvent:
methanol. The title compound was the first fraction at 3.05
minutes. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.64 (s, 1H), 8.67 (dd, J=8.6, 1.1 Hz, 1H), 8.34-8.21 (m, 2H),
8.14 (dd, J=8.3, 1.3 Hz, 1H), 7.80 (ddd, J=8.6, 6.9, 1.4 Hz, 1H),
7.75-7.63 (m, 2H), 7.45 (d, J=8.6 Hz, 1H), 6.76 (d, J=8.5 Hz, 1H),
3.98 (dd, J=9.2, 5.5 Hz, 1H), 3.17 (s, 3H), 2.90 (t, J=7.6 Hz, 2H),
2.40-2.26 (m, 1H), 1.86 (dtd, J=12.9, 7.3, 5.5 Hz, 1H). MS(ESI+)
m/z 449.9 (M+H.sup.+).
Example I-94
(1R)-7-methoxy-N-(naphthalene-1-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro--
1H-indene-1-carboxamide
[1213] The title compound was the second fraction at 4.87 minutes
during the chiral SFC separation described in Example I-93E.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.65
(s, 1H), 8.67 (dd, J=8.6, 1.0 Hz, 1H), 8.37-8.23 (m, 2H), 8.14 (dd,
J=8.2, 1.3 Hz, 1H), 7.79 (ddd, J=8.6, 6.9, 1.4 Hz, 1H), 7.76-7.61
(m, 2H), 7.45 (d, J=8.6 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 3.97 (dd,
J=9.2, 5.5 Hz, 1H), 3.18 (s, 3H), 2.90 (t, J=7.6 Hz, 2H), 2.38-2.24
(m, 1H), 1.86 (dtd, J=12.9, 7.3, 5.4 Hz, 1H). MS(ESI+) m/z 450
(M+H).sup.+.
Example I-95
(1S)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-
-indene-1-carboxamide
Example I-95A
7-methoxy-N-(quinolin-5-ylsulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide
[1214] A mixture of Example I-93C (45 mg, 0.173 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (66.3 mg, 0.346 mmol) and
N,N-dimethylpyridin-4-amine (23.24 mg, 0.190 mmol) in
dichloromethane (2 mL) was stirred at room temperature for 30
minutes. Quinoline-5-sulfonamide (39.6 mg, 0.190 mmol) was added.
The mixture was stirred for 2 hours. The reaction mixture was
purified via chromatography, eluting with methanol in ethyl acetate
at 0-15% to provide the title compound. MS [APCI(+)], m/z 451.27
(M+H).sup.+.
Example I-95B
(1S)-7-methoxy-N-(5-quinolylsulfonyl)-4-(trifluoromethyl)indane-1-carboxam-
ide
[1215] Racemic Example I-95A (60 mg, 0.133 mmol) was separated via
chiral SFC using Column: ChiralPak AD-H, Column Size: 21.times.250
mm, 5 micron, Concentration: 6 mg/mL in methanol, Co-Solvent:
methanol. The first fraction at 3.05 minute was the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.75
(s, 1H), 9.10 (dd, J=4.2, 1.6 Hz, 1H), 9.05 (dt, J=8.7, 1.3 Hz,
1H), 8.38 (dt, J=8.4, 1.1 Hz, 1H), 8.34 (dd, J=7.4, 1.3 Hz, 1H),
7.95 (dd, J=8.5, 7.4 Hz, 1H), 7.84 (dd, J=8.8, 4.2 Hz, 1H), 7.47
(d, J=8.6 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.98 (dd, J=9.2, 5.7 Hz,
1H), 3.17 (s, 3H), 2.92 (t, J=7.4 Hz, 2H), 2.36 (ddt, J=13.1, 9.3,
7.4 Hz, 1H), 1.88 (dtd, J=13.2, 7.4, 5.7 Hz, 1H). MS(ESI+) m/z
451.2 (M+H).sup.+.
Example I-96
(1R)-7-methoxy-N-(quinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-dihydro-1H-
-indene-1-carboxamide
[1216] The title compound was the second fraction at 4.87 minutes
from the chiral SFC separation described in Example I-95B. .sup.1H
NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.75 (s,
1H), 9.10 (dd, J=4.2, 1.6 Hz, 1H), 9.05 (dt, J=8.8, 1.3 Hz, 1H),
8.41-8.31 (m, 2H), 7.95 (dd, J=8.4, 7.5 Hz, 1H), 7.83 (dd, J=8.8,
4.2 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.97
(dd, J=9.2, 5.7 Hz, 1H), 3.18 (s, 3H), 2.92 (t, J=7.5 Hz, 2H), 2.35
(ddt, J=13.1, 9.5, 7.5 Hz, 1H), 1.88 (dtd, J=13.2, 7.5, 5.6 Hz,
1H). MS(ESI+) m/z 451.2 (M+H).sup.+.
Example I-97
4-chloro-1-ethyl-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
Example I-97A
1-methyl-1H-indazole-7-sulfonamide
[1217] n-Butyllithium (2.5 M in tetrahydrofuran, 0.758 mL, 1.895
mmol) and n-Bu.sub.2Mg (di-n-butyl magnesium, 1.0 M in heptane,
5.69 mL, 5.69 mmol) were charged into a nitrogen filled
three-necked flask at room temperature. A solution of
7-bromo-1-methyl-1H-indazole (1.000 g, 4.74 mmol) in
tetrahydrofuran (15 mL) was added dropwise to the n-Bu.sub.3MgLi
solution at -25.degree. C. and the mixture was stirred at
-10.degree. C. for 1 hour. The LC/MS indicated the consumption of
the reaction substrates. The resulting mixture was added to a
solution of SO.sub.2Cl.sub.2 (0.959 mL, 11.85 mmol) in toluene (10
mL) at -10.degree. C. and the mixture was stirred for 20 minutes at
-10.degree. C. The LC/MS indicated the completion of the reaction,
and that most of sulfonyl chloride product was formed. The organic
solvents were removed by rotary evaporation to give the crude
material. The crude material was used in the next step without
purification. Ammonium hydroxide (15 mL) was added to the crude
material at room temperature, and the mixture was stirred for 15
minutes. After completion, the mixture was concentrated by rotary
evaporation. The crude product was diluted with ethyl acetate (200
mL), washed with saturated NaCl solution (50 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The crude material
was purified by Combi-Flash chromatography (H.sub.2O (0.01% TFA)
(A)/Methanol (B), Gradient from 20-50% of B at 10 minute-20 minute,
and concentrated to provide the title compound. .sup.1H NMR: (400
MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 8.27 (s, 1H), 8.05
(dd, J=8.0, 0.9 Hz, 1H), 7.93 (dd, J=8.0, 0.9 Hz, 1H), 7.92 (s,
2H), 7.28 (t, J=7.7 Hz, 1H), 4.37 (s, 3H). LCMS (ESI+) m/z 212.1
(M+H).sup.+.
Example I-97B
4-chloro-1-ethyl-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1218] Example I-17A (26.6 mg, 0.12 mmol, 1.0 equivalent), EDCI HCl
(1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride,
44.9 mg, 0.24 mmol, 2.0 equivalents) and DMAP
(4-dimethylaminopyridine) (15.9 mg, 0.13 mmol, 1.1 equivalents) was
dissolved in dichloromethane (0.5 mL).
1-Methyl-1H-indazole-7-sulfonamide (25 mg, 0.12 mmol, 1.0
equivalent) in dichloromethane (0.25 mL) was added and the reaction
was stirred at room temperature for 16 hours. The solvent was
removed under a stream of N.sub.2. The residue was dissolved in
methanol and purified using preparative reverse phase HPLC/MS
method TFA6 to afford the title compound. .sup.1H NMR (501 MHz,
dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.28 (s,
1H), 8.14 (dd, J=8.0, 1.1 Hz, 1H), 8.06 (dd, J=7.5, 1.1 Hz, 1H),
7.35-7.24 (m, 2H), 7.22-7.11 (m, 2H), 4.25 (s, 3H), 2.85 (t, J=7.3
Hz, 2H), 2.47 (dt, J=13.0, 7.4 Hz, 1H), 2.09-1.98 (m, 2H),
1.76-1.65 (m, 1H), 0.62 (t, J=7.4 Hz, 3H). MS (APCI+) m/z 418.1
(M+H).sup.+.
Example I-98
4-bromo-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide
[1219] Example I-19B (32.1 mg, 0.12 mmol, 1.0 equivalent), EDCI HCl
(N-ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride) (44.9
mg, 0.24 mmol, 2.0 equivalents) and DMAP (4-dimethylaminopyridine)
(15.9 mg, 0.13 mmol, 1.1 equivalents) were dissolved in
dichloromethane (0.5 mL). 1-Methyl-1H-indazole-7-sulfonamide (25
mg, 0.12 mmol, 1.0 equivalent) in dichloromethane (0.25 mL) was
added and the reaction was stirred at room temperature for 16
hours. The solvent was removed under a stream of N.sub.2. The
residue was dissolved in methanol and purified using preparative
reverse phase HPLC/MS method TFA6 to afford the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.35 (s, 1H), 8.20 (dd, J=8.0, 1.1 Hz, 1H), 8.09
(dd, J=7.6, 1.1 Hz, 1H), 7.37-7.30 (m, 2H), 6.65 (d, J=8.8 Hz, 1H),
4.43 (s, 3H), 4.13 (dd, J=9.1, 5.9 Hz, 1H), 3.23 (s, 3H), 2.92-2.78
(m, 2H), 2.47-2.36 (m, 1H), 2.08-1.95 (m, 1H). MS (APCI+) m/z 463.9
(M+H).sup.+.
Example I-99
4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydro-1H--
indene-1-carboxamide
[1220] Into a 4 mL vial was added Example I-98 (14.5 mg, 0.031
mmol) and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II)) (2.69 mg, 3.12 .mu.mol) in tetrahydrofuran (1
mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 0.2 mL,
0.100 mmol) was added. The reaction was stirred for 16 hours at
room temperature. The sample was directly purified using
preparative HPLC/MS method TFA7 to afford the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.31 (s, 1H), 8.15 (d, J=7.9 Hz, 1H), 8.06 (d,
J=7.3 Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.01 (d, J=8.3 Hz, 1H), 6.61
(d, J=8.4 Hz, 1H), 4.43 (s, 3H), 3.96 (t, J=7.5 Hz, 1H), 3.47-3.35
(m, 1H), 3.22 (s, 3H), 2.87-2.63 (m, 2H), 2.41-2.27 (m, 1H),
2.27-2.08 (m, 2H), 2.07-1.85 (m, 4H), 1.81-1.66 (m, 1H). MS (APCI+)
m/z 440.1 (M+H).sup.+.
Example I-100
4-bromo-7-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide
Example I-100A
3-methylimidazo[1,2-a]pyridine-5-sulfonamide hydrobromic acid
[1221] 6-Aminopyridine-2-sulfonamide (53 mg, 0.306 mmol)
(CAS#75903-58-1) and 2-bromo-1,1-diethoxypropane (0.101 mL, 0.573
mmol) were combined in ethanol (0.5 mL). The mixture was heated to
reflux. The reaction was heated at reflux for 16 hours and the
solvent had evaporated. The residue was triturated with ethyl ether
and the resulting precipitate was dried under a stream of nitrogen
to provide the title compound as a hydrobromic acid salt. .sup.1H
NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 8.73 (s, 2H),
8.10 (td, J=4.5, 1.3 Hz, 2H), 8.01 (dd, J=7.4, 1.3 Hz, 1H), 7.93
(dd, J=8.9, 7.4 Hz, 1H), 2.81 (d, J=1.0 Hz, 3H). MS (ESI+) m/z 212
(M+H.sup.+).
Example I-100B
4-bromo-7-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide
[1222] N,N-Dimethylpyridin-4-amine (48.8 mg, 0.399 mmol), and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (72.9 mg, 0.380 mmol) were combined in
N,N-dimethylacetamide (0.9 mL). To the suspension was added Example
I-19B (51.6 mg, 0.190 mmol). After 30 minutes, Example I-100A (50
mg, 0.171 mmol) was added. The reaction was stirred at room
temperature for 18 hours. The N,N-dimethylacetamide was evaporated
in vacuo. The residue was quenched with 1 N aqueous citric acid (23
drops) to pH .about.4, and extracted with 2.5 mL 25% isopropyl
alcohol/dichloromethane. The solvent was evaporated in vacuo. The
residue was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A). The material was triturated with 1 mL of ether and
filtered. The material was triturated with 1 mL methanol and
filtered to provide the title compound as a trifluoroacetic acid
salt. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm
8.00-7.92 (m, 2H), 7.90 (s, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.30 (d,
J=8.6 Hz, 1H), 6.66 (d, J=8.7 Hz, 1H), 3.87 (bs, 1H), 3.44 (s, 3H),
2.94-2.72 (m, 2H), 2.85 (s, 3H), 2.30 (dtd, J=13.0, 9.0, 7.0 Hz,
1H), 2.03 (ddt, J=13.3, 9.0, 4.7 Hz, 1H). MS (APCI+) m/z 464
(M+H).sup.+.
Example I-101
4-bromo-7-methoxy-N-(2-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide
Example I-101A
2-methylimidazo[1,2-a]pyridine-5-sulfonamide, Hydrochloric Acid
[1223] 6-Aminopyridine-2-sulfonamide (50 mg, 0.289 mmol)
(CAS#75903-58-1) and 1-chloropropan-2-one (0.046 mL, 0.577 mmol)
were combined in ethanol (0.5 mL) and heated to reflux. The
reaction was heated for 16 hours and the solvent was evaporated.
The material was triturated with diethyl ether and the resulting
precipitate was dried under a stream of nitrogen to provide the
title compound as a hydrochloric acid salt. .sup.1H NMR (501 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 8.64 (s, 2H), 8.32-8.27 (m,
1H), 8.11 (dt, J=8.7, 1.1 Hz, 1H), 7.94 (dd, J=8.7, 7.4 Hz, 1H),
7.90 (dd, J=7.4, 1.4 Hz, 1H), 2.54 (d, J=1.0 Hz, 3H).
Example I-101B
4-bromo-7-methoxy-N-(2-methylimidazo[1,2-a]pyridine-5-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide
[1224] N,N-Dimethylpyridin-4-amine (43.7 mg, 0.358 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (65.4 mg, 0.341 mmol) were combined in
N,N-dimethylacetamide (0.8 mL). To the suspension was added Example
I-19B (46.2 mg, 0.170 mmol). After 30 minutes, Example I-101A (38
mg, 0.153 mmol) was added. The reaction was stirred at room
temperature for 18 hours. The N,N-dimethylacetamide was evaporated
in vacuo. The residue was quenched with 1 N aqueous citric acid (25
drops) to pH .about.4, and extracted with 2.5 mL 25% isopropyl
alcohol/dichloromethane. The solvent was evaporated in vacuo. The
residue was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A)t. The material was triturated with 1 mL of
dichloromethane, and filtered. The filtrate was concentrated to
dryness, triturated with 0.5 mL methanol, filtered, and combined
with previous filtered material to provide the title compound as a
trifluoroacetic acid salt. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 8.11 (s, 1H), 7.94-7.87 (m, 1H),
7.70 (d, J=4.9 Hz, 2H), 7.29 (d, J=8.6 Hz, 1H), 6.64 (d, J=8.6 Hz,
1H), 3.87 (bs, 1H), 3.34 (s, 1H), 2.91-2.69 (m, 2H), 2.49 (s, 3H),
2.35-2.19 (m, 1H), 1.97 (ddt, J=13.6, 9.4, 5.1 Hz, 1H). MS (APCI+)
m/z 465 (M+H).sup.+.
Example I-102
2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5--
triene-7-carboxamide
Example I-102A
5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol
[1225] A 2 L flask under an atmosphere of nitrogen was charged with
tetrahydrofuran (250 mL, 3051 mmol), cooled to 0.degree. C.,
treated dropwise with 2.5 M n-butyllithium in hexanes (77.6 mL, 194
mmol), and stirred at room temperature for 16 hours. In a separate
flask, a solution of 2,2,6,6-tetramethylpiperidine (24.2 g, 171
mmol) in tetrahydrofuran (120 mL) at 0.degree. C. under N.sub.2 was
treated dropwise with 2.5 M n-butyllithium in hexanes (69 mL, 173
mmol). The mixture was stirred at 0.degree. C. for 30 minutes. The
solution of tetrahydrofuran/n-butyllithium was cooled to
-78.degree. C. and was treated with a solution of 3-bromoanisole
(30 g, 160 mmol) in tetrahydrofuran (120 mL). The mixture was
treated dropwise over 30 minutes with the solution of lithium
tetramethylpiperidine, stirred at -78.degree. C. for 45 minutes,
treated with a solution of ammonium chloride (68.6 g, 1283 mmol) in
water (450 mL) and was allowed to stir at room temperature for 10
minutes. The mixture was concentrated to remove .about.400 mL of
tetrahydrofuran. The mixture was extracted with ethyl acetate
(3.times.200 mL). The combined ethyl acetate layers were washed
with brine, dried (MgSO.sub.4), filtered, and concentrated. The
residue was chromatographed on silica gel, eluting with a gradient
of 10% to 50% ethyl acetate in heptanes to provide the title
compound. .sup.1H NMR (501 MHz, CDCl.sub.3) .delta. ppm 7.22 (dd,
J=7.3, 8.3 Hz, 2H), 6.74-6.70 (m, 2H), 5.35 (ddd, J=1.9, 4.5, 9.6
Hz, 1H), 3.97 (s, 3H), 3.60 (dd, J=4.5, 14.4 Hz, 1H), 3.02-2.98 (m,
1H), 2.36 (d, J=9.6 Hz, 1H). MS (APCI+) m/z 151 (M+H).sup.+.
Example I-102B
5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one
[1226] A solution of oxalyl chloride (6.56 mL, 74.9 mmol) in
dichloromethane (90 mL) was cooled to -78.degree. C., treated
dropwise with a solution of dimethyl sulfoxide (10.63 mL, 150 mmol)
in dichloromethane (70 mL), stirred at -78.degree. C. for 20
minutes, treated dropwise with a solution of Example I-102A
(5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol) (7.5 g, 49.9 mmol)
in dichloromethane (70 mL), stirred at -78.degree. C. for 2 hours,
treated dropwise with triethylamine (41.8 mL, 300 mmol), and
allowed to stir at room temperature. When the mixture reached
0.degree. C., water (100 mL) was added. The mixture was transferred
to a separatory funnel, and the layers were separated. The aqueous
layer was extracted with dichloromethane (.about.100 mL). The
combined dichloromethane layers were washed with brine, dried
(MgSO.sub.4), filtered, and concentrated. The residue
chromatographed on silica gel, eluting with a gradient of 5% to 20%
ethyl acetate in heptanes to provide the title compound. .sup.1H
NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.42 (dd, J=7.1, 8.4 Hz, 1H),
7.02 (dq, J=0.7, 7.1 Hz, 1H), 6.80 (dq, J=0.7, 8.5 Hz, 1H), 4.11
(s, 3H), 3.92 (t, J=0.8 Hz, 2H).
Example I-102C
(E)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene
and
(Z)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene
[1227] A solution of (methoxymethyl)triphenylphosphonium chloride
(9.72 g, 28.3 mmol) in tetrahydrofuran (90 mL) under N.sub.2 at
room temperature was treated with 1 M potassium tert-butoxide in
tetrahydrofuran (26.3 mL, 26.3 mmol), and stirred at room
temperature for 20 minutes. The mixture was treated with a solution
of Example I-102B (5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-one)
(3 g, 20.25 mmol) in tetrahydrofuran (20 mL), stirred for 16 hours,
concentrated without heat to remove majority of tetrahydrofuran and
partitioned between methyl tert-butyl ether (100 mL) water (50 mL).
The layers were separated and the aqueous layer was extracted with
methyl tert-butyl ether (30 mL). The combined methyl tert-butyl
ether layers were washed with brine, dried (MgSO.sub.4), filtered,
concentrated, dissolved in dichloromethane (5 mL), diluted with
heptanes (.about.45 mL), and allowed to stand at room temperature
for 10 minutes. The material was removed by filtration. The
filtrate was concentrated and the residue was chromatographed on
silica gel, eluting with a gradient of 5% to 15% ethyl acetate in
heptanes to provide the less polar isomer as the first to elute,
(E)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene,
followed by the more polar isomer as the second to elute,
(Z)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene.
NMR of less polar isomer: .sup.1H NMR (501 MHz, CDCl.sub.3) .delta.
ppm 7.07 (dd, J=7.2, 8.4 Hz, 1H), 6.76 (dd, J=0.5, 7.2 Hz, 1H),
6.69 (d, J=8.4 Hz, 1H), 6.52 (t, J=1.4 Hz, 1H), 3.84 (s, 3H), 3.71
(s, 3H), 3.65-3.64 (m, 2H). LC/MS (APCI+) m/z 218
(M+CH.sub.3CN+H).sup.+. .sup.1H NMR of more polar isomer: .sup.1H
NMR (501 MHz, CDCl.sub.3) .delta. ppm 7.14 (dd, J=7.1, 8.5 Hz, 1H),
6.77 (dd, J=0.8, 7.2 Hz, 1H), 6.72 (d, J=8.4 Hz, 1H), 5.93 (t,
J=0.9 Hz, 1H), 3.89 (s, 3H), 3.76 (s, 3H), 3.45 (d, J=0.9 Hz, 2H).
LC/MS (APCI+) m/z 218 (M+CH.sub.3CN+H).sup.+.
Example I-102D
5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde
[1228] A solution of the less polar isomer from Example I-102C
((E)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene)
(1.72 g, 9.76 mmol) in tetrahydrofuran (30 mL) was treated with 3 M
aqueous HCl (25 mL) in portions over 2 minutes. The mixture was
stirred at room temperature for 2 hours, heated to 55.degree. C.
for 1 hour, cooled, diluted with water (.about.90 mL) and extracted
with methyl tert-butyl ether (twice, .about.150 mL and .about.75
mL). The combined methyl tert-butyl ether layers were washed with
brine, dried (MgSO.sub.4), filtered, and concentrated to provide
impure aldehyde. In a separate flask, a solution of more polar
isomer from Example I-102C
((Z)-2-methoxy-8-(methoxymethylene)bicyclo[4.2.0]octa-1,3,5-triene)
(0.97 g, 5.50 mmol) in tetrahydrofuran (.about.20 mL) was treated
with 3 M aqueous HCl in water (18.35 mL, 55.0 mmol) in portions
over 2 minutes. The mixture was stirred at room temperature for 2
hours, diluted with water (.about.60 mL) and extracted with methyl
tert-butyl ether (twice, .about.80 mL and .about.40 mL). The
combined methyl tert-butyl ether layers were washed with brine,
dried (MgSO.sub.4), filtered, and concentrated to provide pure
aldehyde. The impure aldehyde and pure aldehyde were combined and
chromatographed on silica gel, eluting with a gradient of 5 to 30%
ethyl acetate to provide the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 9.74 (d, J=4.0 Hz, 1H), 7.23 (t, J=8.0 Hz,
1H), 6.77-6.73 (m, 2H), 4.31-4.28 (m, 1H), 3.80 (s, 3H), 3.41 (dd,
J=5.3, 14.5 Hz, 1H), 3.33 (dd, J=2.4, 14.5 Hz, 1H).
Example I-102E
5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid
[1229] A solution of Example I-102D
(5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbaldehyde) (1.83 g,
11.28 mmol) in acetone (55 mL) was cooled to 0.degree. C. and
treated dropwise with 2 M CrO.sub.3 in aqueous H.sub.2SO.sub.4
(Aldrich catalog #758035-25ML) (11.28 mL, 22.57 mmol), stirred at
0.degree. C. for 30 minutes, quenched with the dropwise addition of
2-propanol (4.35 mL, 56.4 mmol), and stirred at room temperature
for 15 minutes. The mixture was diluted with acetone (50 mL) and
the material was removed by filtration through diatomaceous earth
and washed with acetone. The combined filtrates were concentrated
in vacuo with gentle heating (.about.30.degree. C.) to remove the
acetone. The residue was partitioned between methyl tert-butyl
ether (.about.100 mL) and water (.about.40 mL). The layers were
separated and the aqueous layer was extracted with methyl
tert-butyl ether (.about.50 mL). The combined methyl tert-butyl
ether layers were washed with brine, dried (MgSO.sub.4), filtered,
and concentrated to provide the title compound. .sup.1H NMR (501
MHz, CDCl.sub.3) .delta. ppm 7.24-7.21 (m, 1H), 6.75-6.73 (m, 2H),
4.38 (dd, J=2.4, 5.6 Hz, 1H), 3.87 (s, 3H), 3.52-3.48 (m, 1H),
3.42-3.38 (m, 1H).
Example I-102F
ethyl 5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate
[1230] A solution of Example I-102E
(5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid) (1.78
g, 9.99 mmol) in ethanol (50 mL) was treated with concentrated
H.sub.2SO.sub.4 (0.1 mL), heated to 80.degree. C. for 1 hour,
cooled, treated with NaHCO.sub.3 (.about.1 g), stirred for 5
minutes, and concentrated. The residue was partitioned between
methyl tert-butyl ether (75 mL) and water (30 mL). The methyl
tert-butyl ether layer was washed with brine, dried (MgSO.sub.4),
filtered, and concentrated to provide the title compound. .sup.1H
NMR (501 MHz, CDCl.sub.3) .delta. ppm 7.20 (t, J=7.9 Hz, 1H),
6.73-6.71 (m, 2H), 4.35 (dd, J=2.6, 5.7 Hz, 1H), 4.21 (qd, J=1.7,
7.2 Hz, 2H), 3.85 (s, 3H), 3.45 (dd, J=5.7, 14.0 Hz, 1H), 3.34 (dd,
J=2.6, 14.0 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H). MS (ESI+) m/z 248
(M+MeCN+H).sup.+.
Example I-102G
ethyl
2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate
and
ethyl
4-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate
[1231] A solution of Example I-102F (ethyl
5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate) (1.9 g,
9.21 mmol) in CH.sub.3CN (90 mL) was cooled to 0.degree. C.,
treated with a solution of N-bromosuccinimide (1.640 g, 9.21 mmol)
in CH.sub.3CN (20 mL), stirred overnight at room temperature, and
concentrated to dryness. The residue was taken up in
dichloromethane (.about.5 mL), diluted with heptanes, and was
allowed to stand at room temperature for .about.15 minutes while a
material precipitated. The material was removed by filtration and
was discarded. The filtrate was concentrated to dryness. The
residue was chromatographed on silica gel, eluting with a gradient
of 5% to 15% methyl tert-butyl ether in heptanes to provide a
mixture of ethyl
2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate and
ethyl
4-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate in a
12:1 ratio. NMR/MS of the major component, ethyl
2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate:
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. ppm 7.25 (dd, J=0.8, 8.9
Hz, 1H), 6.64-6.62 (m, 1H), 4.28 (ddd, J=0.8, 2.6, 5.7 Hz, 1H),
4.24-4.19 (m, 2H), 3.83 (s, 3H), 3.38 (ddd, J=0.8, 5.7, 14.1 Hz,
1H), 3.28 (ddd, J=0.8, 2.6, 14.1 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H).
MS (ESI+) m/z 285,287 (M+H).sup.+.
Example I-102H
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid
[1232] A solution of Example I-102G (ethyl
2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate)
(542 mg, 1.900 mmol) and
1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II)
dichloromethane complex (139 mg, 0.190 mmol) in tetrahydrofuran (5
mL) was treated with 0.5 M cyclobutylzinc bromide in
tetrahydrofuran (11.4 mL, 5.70 mmol), stirred at room temperature
for 2 hours, and partitioned between methyl tert-butyl ether (100
mL) and 1 M aqueous HCl (50 mL). The layers were separated and the
aqueous layer was extracted with methyl tert-butyl ether (50 mL).
The combined methyl tert-butyl ether layers were washed with brine,
dried (MgSO.sub.4), filtered, concentrated, and chromatographed on
silica gel, eluting with 5% methyl tert-butyl ether in heptanes
provided ethyl
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate,
with a minor impurity. .sup.1H NMR of major component, ethyl
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 6.99 (d, J=8.6 Hz,
1H), 6.67 (d, J=8.6 Hz, 1H), 4.32 (dd, J=2.6, 5.6 Hz, 1H), 4.21 (q,
J=7.1 Hz, 2H), 3.82 (s, 3H), 3.47 (dd, J=5.6, 13.8 Hz, 1H),
3.44-3.40 (m, 1H), 3.37 (dd, J=2.7, 13.8 Hz, 1H), 2.32-2.23 (m,
2H), 2.21-2.09 (m, 2H), 2.05-1.92 (m, 1H), 1.89-1.79 (m, 1H), 1.28
(t, J=7.1 Hz, 3H). A solution of ethyl
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate
(173 mg, 0.665 mmol) in tetrahydrofuran (1.5 mL) and methanol (1.5
mL) was treated with 1 M aqueous NaOH (1.5 mL), stirred at room
temperature for 30 minutes, and partitioned between methyl
tert-butyl ether (.about.75 mL) and 1 M aqueous HCl (15 mL). The
methyl tert-butyl ether layer was washed with brine, dried
(MgSO.sub.4), filtered, and concentrated to provide the
corresponding carboxylic acid,
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid, which contained an impurity. Crude
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid was dissolved in methanol (.about.5 mL), treated with 1 drop
of concentrated H.sub.2SO.sub.4, heated to 60.degree. C. for 2
hours, cooled, treated with NaHCO.sub.3 (.about.1 g), stirred for
15 minutes and concentrated. The residue was partitioned between
methyl tert-butyl ether (75 mL) and water (20 mL). The methyl
tert-butyl ether layer was washed with brine, dried (MgSO.sub.4),
filtered, concentrated and chromatographed on silica gel, eluting
with 5% methyl tert-butyl ether in heptanes to provide the pure
methyl ester, methyl
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.00 (d, J=8.7 Hz,
1H), 6.67 (d, J=8.5 Hz, 1H), 4.34 (dd, J=2.7, 5.6 Hz, 1H), 3.82 (s,
3H), 3.75 (s, 3H), 3.51-3.35 (m, 3H), 2.32-2.22 (m, 2H), 2.21-2.09
(m, 2H), 2.05-1.91 (m, 1H), 1.89-1.79 (m, 1H). Methyl
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylate
was dissolved in tetrahydrofuran (1.5 mL) and methanol (1.5 mL),
treated with 1 M aqueous NaOH (1 mL), stirred at room temperature
for 30 minutes, and partitioned between methyl tert-butyl ether
(.about.75 mL) and 1 M aqueous HCl (15 mL). The methyl tert-butyl
ether layer was washed with brine, dried (MgSO.sub.4), filtered,
and concentrated to provide the pure title compound. .sup.1H NMR
(501 MHz, CDCl.sub.3) .delta. ppm 7.01 (d, J=8.7 Hz, 1H), 6.68 (d,
J=8.6 Hz, 1H), 4.36 (dd, J=2.5, 5.6 Hz, 1H), 3.84 (s, 3H), 3.52
(dd, J=5.6, 13.8 Hz, 1H), 3.48-3.40 (m, 2H), 2.31-2.23 (m, 2H),
2.19-2.10 (m, 2H), 2.04-1.93 (m, 1H), 1.89-1.81 (m, 1H).
Example I-1021
2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol
[1233] A solution of Example I-102A
(5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol) (40 mg, 0.266 mmol)
in CH.sub.3CN (.about.0.5 mL) was treated with N-bromosuccinimide
(47.4 mg, 0.266 mmol) and stirred at room temperature for 30
minutes. The mixture was concentrated via a stream of N.sub.2,
dissolved in dichloromethane (.about.1 mL), and diluted with
heptanes. A material formed. The material was removed by filtration
and was discarded. The filtrate was concentrated and
chromatographed on silica gel, eluting with a gradient of 10% to
30% ethyl acetate in heptanes to provide the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.29-7.25 (m, 1H),
6.62 (dt, J=0.7, 8.9 Hz, 1H), 5.31 (ddd, J=1.8, 4.5, 9.3 Hz, 1H),
3.95 (s, 3H), 3.53 (ddd, J=0.7, 4.6, 14.7 Hz, 1H), 2.95 (ddd,
J=0.8, 1.9, 14.7 Hz, 1H), 2.30 (d, J=9.3 Hz, 1H).
Example I-102J
2,7-dibromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene
[1234] A solution of Example I-1021
(2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-trien-7-ol) (8.35 g,
34.6 mmol), carbon tetrabromide (14.35 g, 43.3 mmol) and
triphenylphosphine (16.80 g, 64.1 mmol) in methyl tert-butyl ether
(400 mL) was stirred overnight at room temperature. The mixture was
diluted with heptanes and the resulting material was removed by
filtration. The filtrate was concentrated to dryness and was
purified by chromatography on silica gel, eluting with a gradient
of 0% to 20% ethyl acetate in heptanes to provide the title
compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 7.32 (d,
J=8.9 Hz, 1H), 6.65 (d, J=8.9 Hz, 1H), 5.45-5.43 (m, 1H), 3.98 (s,
3H), 3.78 (ddd, J=0.8, 4.6, 15.0 Hz, 1H), 3.39 (ddd, J=0.8, 1.7,
14.9 Hz, 1H).
Example I-102K
2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile
[1235] A solution of Example I-102J
(2,7-dibromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene) (3.26 g,
11.17 mmol) in tetrahydrofuran (74.4 mL) was treated with
tetrabutylammonium cyanide (4.50 g, 16.75 mmol) and was stirred at
room temperature for 16 hours. The mixture was partitioned between
ethyl acetate (250 mL) and water (150 mL). The ethyl acetate layer
was washed with saturated aqueous NaHCO.sub.3, washed with brine,
dried (MgSO.sub.4), filtered, concentrated and chromatographed on
silica gel, eluting with a gradient of 0% to 20% ethyl acetate in
heptanes to provide the title compound. .sup.1H NMR (501 MHz,
CDCl.sub.3) .delta. ppm 7.33 (dd, J=0.8, 9.0 Hz, 1H), 6.68 (d,
J=9.0 Hz, 1H), 4.27 (ddd, J=0.8, 2.7, 5.5 Hz, 1H), 3.92 (s, 3H),
3.57 (ddd, J=0.8, 5.6, 14.3 Hz, 1H), 3.45 (ddd, J=0.8, 2.7, 14.3
Hz, 1H).
Example I-102L
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile
[1236] A mixture of Example I-102K
(2-bromo-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carbonitrile)
(0.17 g, 0.714 mmol) and
1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II)
dichloromethane complex (0.045 g, 0.056 mmol) in tetrahydrofuran
(3.57 mL) was degassed by bubbling a stream of nitrogen through the
mixture for 1 minute, treated with 0.5 M cyclobutylzinc bromide in
tetrahydrofuran (2.142 mL, 1.071 mmol), stirred for 16 hours at
room temperature under nitrogen, and quenched with saturated
aqueous ammonium chloride solution (5 mL). The mixture was
extracted with ethyl acetate (20 mL). The organic layer was washed
with saturated aqueous ammonium chloride, washed with brine, dried
(sodium sulfate), filtered, concentrated and chromatographed on
silica gel, eluting with a gradient of 0% to 20% ethyl acetate in
heptanes to provide the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.05 (d, J=8.6 Hz, 1H), 6.70 (d, J=8.7 Hz,
1H), 4.30-4.27 (m, 1H), 3.90 (s, 3H), 3.65 (dd, J=5.5, 13.9 Hz,
1H), 3.52 (dd, J=2.7, 14.0 Hz, 1H), 3.42 (p, J=8.8 Hz, 1H),
2.32-2.24 (m, 2H), 2.17-2.06 (m, 2H), 2.06-1.93 (m, 1H), 1.90-1.80
(m, 1H).
Example I-102M
2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1,3,5--
triene-7-carboxamide
[1237] A solution of Example I-102H
(2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid) (41 mg, 0.177 mmol) in dichloromethane at 0.degree. C. was
treated with oxalyl chloride (77 .mu.l, 0.883 mmol), treated with a
catalytic amount of N,N-dimethylformamide, stirred at room
temperature for 30 minutes and concentrated with a stream of
N.sub.2 for 30 minutes. The residue was dissolved in
dichloromethane (.about.0.3 mL), cooled to 0.degree. C., treated
with naphthalene-1-sulfonamide (47.6 mg, 0.229 mmol), treated with
triethylamine (49.2 .mu.L, 0.353 mmol), treated with DMAP
(4-dimethylaminopyridine) (2.156 mg, 0.018 mmol), stirred at room
temperature for 16 hours, and partitioned between ethyl acetate (35
mL) and 1 M aqueous HCl (15 mL). The ethyl acetate layer was washed
with brine, dried (MgSO.sub.4), filtered, concentrated, redissolved
in N,N-dimethylformamide (.about.1 mL) and purified by
reverse-phase HPLC [Waters XBridge.TM. RP18 column, 5 .mu.m,
30.times.100 mm, flow rate 40 mL/minute, 5-95% gradient of
acetonitrile in 0.1% TFA] to afford the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.74 (s, 1H),
8.64-8.60 (m, 1H), 8.30 (ddd, J=1.1, 4.2, 7.5 Hz, 2H), 8.13 (d,
J=8.0 Hz, 1H), 7.78 (ddd, J=1.4, 6.9, 8.6 Hz, 1H), 7.73-7.67 (m,
2H), 6.87 (d, J=8.6 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 4.35 (dd,
J=2.5, 5.7 Hz, 1H), 3.36-3.22 (m, 1H), 3.29 (s, 3H), 2.81 (dd,
J=2.5, 13.9 Hz, 1H), 2.17-2.06 (m, 2H), 2.00-1.81 (m, 4H),
1.75-1.68 (m, 1H). MS (APCI+) m/z 422 (M+H).sup.+.
Example I-103
(1R)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1238] Into a 4 mL vial was added Example I-44 (110 mg, 0.238 mmol)
and PEPPSI IPentCl
([(1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dich-
loropalladium(II))) (10.25 mg, 0.012 mmol) in tetrahydrofuran (2
mL). Cyclobutylzinc(II) bromide (0.5 M in tetrahydrofuran, 1.5 mL,
0.750 mmol) was added and the reaction was stirred for 16 hours at
room temperature. The sample was purified using preparative reverse
phase HPLC/MS method TFA7. The material was separated by chiral
preparative SFC chromatography using a CHIRALPAK AD-H, column size
21.times.250 mm, 5 micron, serial Number: ADH0SAMA003-810291, using
a concentration of 13 mg/mL in methanol at a flow rate of 56
g/minute CO.sub.2 and UV monitoring at 220 nm to provide the title
compound as the first eluent. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 9.10 (dd, J=4.2,
1.6 Hz, 1H), 9.06 (ddd, J=8.8, 1.6, 0.9 Hz, 1H), 8.39 (dt, J=8.4,
1.1 Hz, 1H), 8.36 (dd, J=7.4, 1.3 Hz, 1H), 7.97 (dd, J=8.5, 7.4 Hz,
1H), 7.84 (dd, J=8.8, 4.2 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 6.56 (d,
J=8.3 Hz, 1H), 3.91 (dd, J=9.1, 5.7 Hz, 1H), 3.43-3.32 (m, 1H),
3.09 (s, 3H), 2.75-2.61 (m, 2H), 2.32-2.12 (m, 3H), 2.01-1.85 (m,
3H), 1.84-1.67 (m, 2H). MS (APCI+) m/z 437.1 (M+H).sup.+.
Example I-104
(1S)-4-cyclobutyl-7-methoxy-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1239] Example I-104 was isolated as the second elutent during the
preparative SFC separation described in Example I-103. .sup.1H NMR
(501 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
ppm 9.12-9.01 (m, 2H), 8.40-8.29 (m, 2H), 7.94 (dd, J=8.4, 7.5 Hz,
1H), 7.81 (dd, J=8.8, 4.2 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 6.56 (d,
J=8.4 Hz, 1H), 3.89 (dd, J=9.1, 5.5 Hz, 1H), 3.46-3.26 (m, 1H),
3.11 (s, 3H), 2.77-2.60 (m, 2H), 2.30-2.12 (m, 3H), 2.04-1.84 (m,
3H), 1.84-1.63 (m, 2H). MS (APCI+) m/z 437.1 (M+H).sup.+.
Example I-105
4-bromo-N-(5-hydroxynaphthalene-1-sulfonyl)-7-methoxy-2,3-dihydro-1H-inden-
e-1-carboxamide
[1240] N,N-Dimethylpyridin-4-amine (54.7 mg, 0.448 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (68.7 mg, 0.358 mmol) were combined in
N,N-dimethylacetamide (1 mL). To the suspension was added
(S)-4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (60.7
mg, 0.224 mmol). After 30 minutes,
5-hydroxynaphthalene-1-sulfonamide (50 mg, 0.224 mmol) was added.
The reaction was heated at 70.degree. C. for 3 days. The mixture
was quenched with water (5 mL) and 1 N aqueous citric acid (0.5 mL)
to pH .about.4 and was extracted with 4 mL dichloromethane. The
solvent was evaporated in vacuo, and the residue was
chromatographed using a 12 g silica gel cartridge with 0-5%
methanol/dichloromethane over a period of 8 minutes to give crude
product which was then purified by reverse-phase preparative HPLC
on a Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM.
column (30 mm.times.150 mm). A gradient of acetonitrile (A) and
0.1% trifluoroacetic acid in water (B) was used, at a flow rate of
50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide the title compound. .sup.1H NMR (501 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.47 (s, 1H), 10.60 (s,
1H), 8.50 (d, J=8.4 Hz, 1H), 8.23 (dd, J=7.4, 1.3 Hz, 1H), 8.05
(dd, J=8.7, 0.9 Hz, 1H), 7.57 (ddd, J=10.0, 8.6, 7.5 Hz, 2H), 7.29
(d, J=8.6 Hz, 1H), 7.03 (dd, J=7.7, 0.9 Hz, 1H), 6.60 (d, J=8.7 Hz,
1H), 4.05 (dd, J=9.2, 5.6 Hz, 1H), 3.18 (s, 3H), 2.74 (td, J=8.3,
7.6, 3.3 Hz, 2H), 2.32-2.21 (m, 1H), 1.80 (dq, J=13.6, 6.6, 6.2 Hz,
1H). MS (APCI+) m/z 476 (M+H.sup.+).
Example I-106
(7S)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1-
,3,5-triene-7-carboxamide
[1241] The enantiomers from Example I-102 were separated by
Supercritical Fluid Chromatography (SFC) using a 21.times.250 mm
Whelk-O (S,S) chiral column eluting with 20% methanol in liquid
CO.sub.2 using a flow rate of 80 mL/minute to provide the title
compound as the first peak to elute form the column. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.74 (s, 1H),
8.64-8.60 (m, 1H), 8.30 (ddd, J=1.1, 4.2, 7.5 Hz, 2H), 8.13 (d,
J=8.0 Hz, 1H), 7.78 (ddd, J=1.4, 6.9, 8.6 Hz, 1H), 7.73-7.67 (m,
2H), 6.87 (d, J=8.6 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 4.35 (dd,
J=2.5, 5.7 Hz, 1H), 3.36-3.22 (m, 1H), 3.29 (s, 3H), 2.81 (dd,
J=2.5, 13.9 Hz, 1H), 2.17-2.06 (m, 2H), 2.00-1.81 (m, 4H),
1.75-1.68 (m, 1H). MS (APCI+) m/z 422 (M+H).sup.+.
Example I-107
(7R)-2-cyclobutyl-5-methoxy-N-(naphthalene-1-sulfonyl)bicyclo[4.2.0]octa-1-
,3,5-triene-7-carboxamide
[1242] The enantiomers from Example I-102 were separated by
Supercritical Fluid Chromatography (SFC) using a 21.times.250 mm
Whelk-O (S,S) chiral column eluting with 20% methanol in liquid
CO.sub.2 using a flow rate of 80 mL/minute to provide the title
compound as the second peak to elute from the column. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.74 (s, 1H),
8.64-8.60 (m, 1H), 8.30 (ddd, J=1.1, 4.2, 7.5 Hz, 2H), 8.13 (d,
J=8.0 Hz, 1H), 7.78 (ddd, J=1.4, 6.9, 8.6 Hz, 1H), 7.73-7.67 (m,
2H), 6.87 (d, J=8.6 Hz, 1H), 6.51 (d, J=8.6 Hz, 1H), 4.35 (dd,
J=2.5, 5.7 Hz, 1H), 3.36-3.22 (m, 1H), 3.29 (s, 3H), 2.81 (dd,
J=2.5, 13.9 Hz, 1H), 2.17-2.06 (m, 2H), 2.00-1.81 (m, 4H),
1.75-1.68 (m, 1H). LC/MS (APCI+) m/z 422 (M+H).sup.+.
Example I-108
(1R)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
Example I-108A
4-methoxy-7-methyl-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide
[1243] A solution of Example I-84B (80 mg, 0.174 mmol), potassium
carbonate (96 mg, 0.695 mmol), and trimethylboroxine (0.097 mL,
0.695 mmol) in 1,4-dioxane (1.6 mL) and water (0.3 mL) was degassed
with bubbling nitrogen.
1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride
dichloromethane complex (56.8 mg, 0.070 mmol) was added and the
mixture was heated at 90.degree. C. with stirring for 16 hours. The
mixture was quenched with water (1 mL) and acidified with 1 N
aqueous HCl (0.2 mL). The mixture was extracted with
dichloromethane (2 mL), and the organic layer was concentrated in
vacuo. The resulting residue was chromatographed using a 12 g
silica gel cartridge with 0-100% ethyl acetate/heptanes over a
period of 10 minutes to give crude product which was purified by
reverse-phase preparative HPLC on a Phenomenex.RTM. Luna.RTM. C8(2)
5 .mu.m 100 .ANG. AXIA.TM. column (30 mm.times.150 mm). A gradient
of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0
minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0
minutes linear gradient 95-10% A) to provide the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.70
(s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27
(dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd,
J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H),
6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H),
2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80
(dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396
(M+H.sup.+).
Example I-108B
(1R)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1244] Example I-108A (13 mg) was separated by chiral preparative
SFC chromatography using a ChiralPak AD-H column size 21.times.250
mm, 5 micron, serial Number: ADHSAMA003-810291, using a
concentration of 4.0 mg in methanol at a flow rate of 56 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.70
(s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27
(dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd,
J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H),
6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H),
2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80
(dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396
(M+H.sup.+). R.sub.T (chiral SFC)=6.0 minutes.
Example I-109
(1S)-4-methoxy-7-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1-
-carboxamide
[1245] Example I-108A (13 mg) was separated by chiral preparative
SFC chromatography using a ChiralPak AD-H column size 21.times.250
mm, 5 micron, serial Number: ADHSAMA003-810291, using a
concentration of 4.0 mg in methanol at a flow rate of 56 g/minute
CO.sub.2 and UV monitoring at 220 nm to provide the title compound.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.70
(s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27
(dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd,
J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H),
6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H),
2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80
(dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396
(M+H.sup.+). R.sub.T (chiral SFC)=5.1 minutes.
Example I-110
[1246]
4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclope-
nta[c]pyridine-7-carboxamide
Example I-110A
methyl 4-(3-ethoxy-3-oxopropyl)-2-methoxynicotinate
[1247] Methyl 4-chloro-2-methoxynicotinate (1.007 g, 4.99 mmol)
(CAS#1256826-55-7) was combined with
2-dicyclohexylphosphino-2',6'-bis(dimethylamino)-1,1'-biphenyl
(0.087 g, 0.200 mmol) and diacetoxypalladium (0.022 g, 0.100 mmol)
in toluene (10 mL) under nitrogen and then degassed with nitrogen
for 5 minutes. To this mixture was added a solution of
(3-ethoxy-3-oxopropyl)zinc(II) bromide (11.99 mL, 5.99 mmol, 0.5 M
in tetrahydrofuran), with vigorous stirring. The reaction was
stirred at room temperature for 3 hours. The mixture was adsorbed
onto silica gel and was chromatographed using a 40 g silica gel
cartridge with an ethyl acetate/hexanes solvent system to provide
the title compound. .sup.1H NMR (400 MHz, chloroform-d) .delta. ppm
8.12 (dd, J=5.3, 0.8 Hz, 1H), 6.80 (d, J=5.2 Hz, 1H), 4.15 (qd,
J=7.2, 0.9 Hz, 2H), 3.97 (d, J=0.8 Hz, 3H), 3.94 (d, J=0.8 Hz, 3H),
2.91 (t, J=7.9 Hz, 2H), 2.74-2.53 (m, 2H), 1.26 (td, J=7.2, 0.9 Hz,
3H). MS (APCI+) m/z 268 (M+H).sup.+.
Example I-110B
1-methoxy-5H-cyclopenta[c]pyridin-7(6H)-one
[1248] A solution of methyl
4-(3-ethoxy-3-oxopropyl)-2-methoxynicotinate (1.2 g, 4.49 mmol)
from Example I-110A in tetrahydrofuran (10 mL) was added to a
suspension of 60% sodium hydride (0.898 g, 22.45 mmol) in
tetrahydrofuran (10 mL) at room temperature. Once the bubbling
subsided, methanol (0.024 mL, 0.593 mmol) was added and the
reaction was heated at reflux (block was at 65.degree. C.). The
solvent was removed in vacuo. To the material was carefully added
ice and water, and the mixture was stirred until it reached room
temperature and the bubbling stopped. The reaction was placed in a
heating block at 100.degree. C. for 2 hours. The aqueous layer was
filtered, cooled and extracted with 2.times.100 mL of
dichloromethane. The combined organics were dried over sodium
sulfate and filtered. The solvent was removed in vacuo to provide
the title compound. .sup.1H NMR (501 MHz, chloroform-d) .delta. ppm
8.29 (d, J=5.2 Hz, 1H), 7.04 (dd, J=5.2, 0.9 Hz, 1H), 4.13 (s, 3H),
3.26-2.98 (m, 2H), 2.83-2.63 (m, 2H). MS (ESI+) m/z 164
(M+H).sup.+.
Example I-110C
1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carbonitrile
[1249] In a 50 mL round bottom flask
1-methoxy-5H-cyclopenta[c]pyridin-7(6H)-one (0.339 g, 2.078 mmol)
from Example I-110B and TOSMIC (toluenesulfonylmethyl isocyanide,
0.527 g, 2.70 mmol) were dissolved in dimethoxyethane (12 mL). The
reaction was cooled to -8.degree. C. (internal temperature) with
ice/acetone/dry ice under nitrogen. Potassium tert-butoxide (0.536
g, 4.78 mmol) was added in portions keeping the internal
temperature <-5.degree. C. over about an hour. The reaction was
allowed to slowly warm to room temperature over two hours. The
mixture was quenched with water (30 mL). The aqueous layer was
extracted with MTBE (methyl tert-butyl ether, 4.times.50 mL). The
solvent was removed in vacuo and the crude material was
chromatographed using a 12 g silica gel cartridge with 1-50% ethyl
acetate/hexanes to provide the title compound. .sup.1H NMR (400
MHz, chloroform-d) .delta. ppm 8.09 (dd, J=5.2, 0.7 Hz, 1H), 6.85
(d, J=5.1 Hz, 1H), 4.10 (dd, J=8.8, 5.2 Hz, 1H), 4.04 (s, 3H),
3.22-3.07 (m, 1H), 2.98 (ddd, J=16.9, 8.5, 5.4 Hz, 1H), 2.62-2.41
(m, 2H). MS (ESI+) 175 m/z (M+H.sup.+).
Example I-110D
1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic
acid
[1250]
1-Methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carbonitrile (144
mg, 0.827 mmol) from Example I-110C was dissolved in ethanol (2
mL). A solution of sodium hydroxide (231 mg, 5.79 mmol) in water
(2.000 mL) was added, and the resulting mixture was heated at
80.degree. C. for 16 hours. The solvent was reduced in volume and
the resulting mixture was acidified with acetic acid (0.379 mL,
6.61 mmol). The material was filtered. The aqueous layer was
extracted with 3.times.15 mL of methyl tert-butyl ether. The
combined extracts were dried over sodium sulfate and filtered. The
solvent removed in vacuo to provide the title compound. .sup.1H NMR
(400 MHz, Chloroform-d) .delta. ppm 8.06 (d, J=5.2 Hz, 1H), 6.87
(d, J=5.2 Hz, 1H), 4.07 (dd, J=8.9, 4.6 Hz, 1H), 4.01 (s, 3H),
3.19-3.06 (m, 1H), 2.93 (ddd, J=16.7, 8.8, 4.7 Hz, 1H), 2.58-2.38
(m, 2H). MS (ESI+) 194 m/z (M+H).sup.+.
Example I-110E
4-bromo-1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic
acid
[1251] To a mixture of
1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic acid
(Example I-110D, 50 mg, 0.259 mmol) in CS.sub.2 (5 mL) cooled in an
ice bath, was added dibromine (0.013 mL, 0.259 mmol) in CS.sub.2
(0.5 mL) slowly. The mixture was stirred overnight, and the solvent
was removed, followed by addition of water (2 mL). Methanol (0.5
mL) was added followed by addition of dibromine (0.013 mL, 0.259
mmol). After 10 minutes, the bromine color disappeared. The mixture
was purified by chromatography, eluting with ethyl acetate/methanol
(9:1) in heptane at a 0-60% gradient to provide the title compound.
MS (APCI+) m/z 272.09 (M+H).sup.+.
Example I-110F
4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]p-
yridine-7-carboxamide
[1252] A mixture of
4-bromo-1-methoxy-6,7-dihydro-5H-cyclopenta[c]pyridine-7-carboxylic
acid (50 mg, 0.184 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (70.5 mg, 0.368 mmol) and
N,N-dimethylpyridin-4-amine (24.69 mg, 0.202 mmol) in
dichloromethane (2 mL) was stirred at room temperature for 30
minutes, followed by addition of naphthalene-1-sulfonamide (45.7
mg, 0.221 mmol). The mixture was stirred at room temperature for 2
hours. The crude mixture was purified using reverse-phase HPLC
[Waters XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm, flow
rate 40 mL/minute, 20 to 90% gradient of acetonitrile in 0.1%
aqueous TFA] to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.68 (s, 1H), 8.63 (dd,
J=8.6, 1.0 Hz, 1H), 8.37-8.24 (m, 2H), 8.15 (dd, J=8.2, 1.3 Hz,
1H), 8.05 (s, 1H), 7.80 (ddd, J=8.6, 6.9, 1.5 Hz, 1H), 7.74-7.65
(m, 2H), 4.05 (dd, J=9.3, 5.7 Hz, 1H), 2.87-2.70 (m, 2H), 2.34
(dtd, J=13.2, 9.0, 6.1 Hz, 1H), 1.84 (ddt, J=12.6, 8.8, 6.3 Hz,
1H). MS (ESI+) m/z 462.9 (M+H).sup.+.
Example I-111
4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopent-
a[c]pyridine-7-carboxamide
[1253] Into a 4 mL vial was added
4-bromo-1-methoxy-N-(naphthalen-1-ylsulfonyl)-6,7-dihydro-5H-cyclopenta[c-
]pyridine-7-carboxamide (Example I-110F, 25 mg, 0.054 mmol) and Pd
PEPPSI IPentCl
([1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyrid-
yl)dichloropalladium(II), (4.43 mg, 5.42 .mu.mol) in
tetrahydrofuran (0.5 mL). Cyclobutylzinc(II) bromide (0.325 mL,
0.163 mmol) was added. The reaction was stirred overnight at room
temperature. The crude material was directly injected onto a prep
HPLC and purified using preparative reverse phase HPLC/MS method
TFA8 to provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.68-8.59 (m,
1H), 8.36 8.20 (m, 2H), 8.20-8.08 (m, 1H), 7.88-7.77 (m, 1H),
7.77-7.60 (m, 3H), 3.99-3.89 (m, 1H), 3.39 (p, J=8.9 Hz, 1H), 3.22
(s, 3H), 2.70 (t, J=7.9 Hz, 2H), 2.39-2.14 (m, 3H), 2.11-1.63 (m,
5H). MS (APCI+) m/z 437.1 (M+H).sup.+.
Example I-112
4-chloro-1-methoxy-N-(naphthalene-1-sulfonyl)-6,7-dihydro-5H-cyclopenta[c]-
pyridine-7-carboxamide
[1254] A mixture of Example I-110F (68 mg, 0.147 mmol) and copper
(I) chloride (219 mg, 2.211 mmol) in dimethylacetamide (0.5 mL) was
refluxed for overnight at 150.degree. C. The solvent was removed
and the residue was purified via chromatography on a 24 g silica
gel cartridge, eluting with methanol/ethyl acetate at 0-10%
gradient to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.65 (s, 1H), 8.60 (dd,
J=8.6, 1.1 Hz, 1H), 8.26 (ddd, J=14.8, 7.9, 1.1 Hz, 2H), 8.11 (dd,
J=8.1, 1.3 Hz, 1H), 7.93 (d, J=0.7 Hz, 1H), 7.76 (ddd, J=8.6, 6.9,
1.4 Hz, 1H), 7.72-7.61 (m, 2H), 3.99 (dd, J=9.3, 5.7 Hz, 1H), 3.19
(s, 3H), 2.87-2.70 (m, 2H), 2.32 (dtd, J=13.2, 8.9, 6.1 Hz, 1H),
1.91-1.76 (m, 1H). MS (ESI+) m/z=417.0 (M+H).
Example I-113
4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoquinolin-
e-8-carboxamide
Example I-113A
methyl 2-methoxy-4-methylnicotinate
[1255] Into a 160 mL stainless steel reactor was added
3-bromo-2-methoxy-4-methylpyridine (25 g, 121 mmol),
PdCl.sub.2(dppf)
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.771
g, 2.42 mmol), methanol (50 mL) and triethylamine (25.4 mL, 182
mmol). The reactor was degassed with nitrogen gas several times
followed by carbon monoxide. The reaction was heated to 100.degree.
C. for 10 hours at 60 psi. The reaction was vented and the mixture
was filtered. The filtrate was concentrated and was purified by
flash column chromatography, eluting with 0 to 30% ethyl acetate in
heptanes to provide the title compound. .sup.1H NMR (501 MHz,
Chloroform-d) .delta. ppm 8.08 (d, J=5.2 Hz, 1H), 6.76 (dd, J=5.3,
0.7 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 2.32 (d, J=0.6 Hz, 3H). MS
(ESI.sup.+) m/z 452.0 (M+H).sup.+.
Example I-113B
methyl
1-methoxy-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate
[1256] Methyl 2-methoxy-4-methylnicotinate (17.14 g, 95 mmol) in
tetrahydrofuran (100 mL) was added over a period of 20 minutes to a
solution of lithium diisopropylamide (31.7 mmol), which was freshly
prepared from diisobutylamine (18.36 mL, 104 mmol) and butyllithium
(41.6 mL, 104 mmol) in tetrahydrofuran (300 mL) at -78.degree. C.
The resulting mixture was stirred for 20 minutes. Methyl acrylate
(21.51 mL, 236 mmol) was added over 15 minutes. The reaction was
stirred at -72.degree. C. for 5 hours. Aqueous 10% acetic acid (199
g, 331 mmol) was added (pH 4-5) and the reaction was allowed to
warm to ambient temperature. Ethyl acetate was added (600 mL). The
organic layer was washed with saturated aqueous NaHCO.sub.3 and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
crude mixture was purified by flash column chromatography (0 to 40%
ethyl acetate in heptanes) to afford the title compound. MS (DCI+)
m/z 236.0 (M+H).sup.+.
Example I-113C
1-methoxy-6,7-dihydroisoquinolin-8(5H)-one
[1257] Methyl
1-methoxy-8-oxo-5,6,7,8-tetrahydroisoquinoline-7-carboxylate (1.04
g, 4.42 mmol) was dissolved in 6 N aqueous HCl solution and the
mixture was stirred at ambient temperature over the weekend. Ethyl
acetate (100 mL) was added. The pH was adjusted to .about.10 by
addition of 6 M potassium hydroxide. The aqueous layer was
extracted twice with ethyl acetate (2.times.50 mL). The combined
organic layers were concentrated to provide the title compound. MS
(ESI+) m/z 178.0 (M+H).sup.+.
Example I-113D
4-bromo-1-methoxy-6,7-dihydroisoquinolin-8(5H)-one
[1258] Dibromine (0.243 mL, 4.74 mmol) in dichloromethane (1 mL)
was added to 1-methoxy-6,7-dihydroisoquinolin-8(5H)-one (Example
I-113C, 0.700 g, 3.95 mmol) in a mixture of H.sub.2O (5 mL) and
methanol (5.00 mL) slowly at room temperature. After the addition,
the mixture was stirred for another 30 minutes.
Na.sub.2S.sub.3O.sub.7 was added followed by dichloromethane (30
mL). The organic layer was washed with saturated aqueous
NaHCO.sub.3 and brine, dried over MgSO.sub.4, and filtered. The
filtrate was concentrated and the residue was purified via
chromatography on a 24 g silica gel cartridge, eluting with
methanol/ethyl acetate 0-20% gradient to provide the title
compound. .sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 8.35 (s,
1H), 4.03 (s, 3H), 2.96 (t, J=6.2 Hz, 2H), 2.67-2.61 (m, 2H),
2.18-2.07 (m, 2H). MS (ESI+) m/z 256.1 (M+H).sup.+.
Example I-113E
4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline-8-carbonitrile
[1259] To 4-bromo-1-methoxy-6,7-dihydroisoquinolin-8(5H)-one (560
mg, 2.187 mmol) in dimethoxyethane (20 mL) was added
1-((isocyanomethyl)sulfonyl)-4-methylbenzene (555 mg, 2.84 mmol).
The mixture was cooled to -15.degree. C. with ice/acetone under a
nitrogen atmosphere. Potassium 2-methylpropan-2-olate (613 mg, 5.47
mmol) was added in portions keeping the internal temperature
<-10.degree. C. The reaction was stirred at room temperature
overnight. The mixture was dissolved in dichloromethane and washed
with brine, dried over MgSO.sub.4, filtered and concentrated to
provide the crude product which used in next step without further
purification.
Example I-113F
4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline-8-carboxylic
acid
[1260] To
4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline-8-carbonitrile
from Example I-113E (600 mg, 2.246 mmol) in ethanol (10 mL) was
added sodium hydroxide (1348 mg, 33.7 mmol). The mixture was heated
at 140.degree. C. overnight. The solvent was removed and the
residue was purified via chromatography on a 40 g silica gel
cartridge, eluting with ethyl acetate/methanol (9:1) in heptane at
0-70% gradient to provide the title compound. MS(APCI+) m/z 288
(M+H).sup.+.
Example I-113G
4-bromo-1-methoxy-N-(naphthalen-1-ylsulfonyl)-5,6,7,8-tetrahydroisoquinoli-
ne-8-carboxamide
[1261] A mixture of Example I-113F (250 mg, 0.874 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne, hydrochloric acid (335 mg, 1.748 mmol) and
N,N-dimethylpyridin-4-amine (117 mg, 0.961 mmol) in dichloromethane
(4 mL) was stirred at room temperature for 30 minutes.
Naphthalene-1-sulfonamide (181 mg, 0.874 mmol) was added. The
mixture was stirred for another two hours. The solvent was removed
and the residue was purified by reverse-phase HPLC [Waters
XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm, flow rate 40
mL/minute, 20 to 90% gradient of acetonitrile in 0.1% aqueous TFA]
to provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.63 (s, 1H), 8.67 (dd, J=8.6, 1.0
Hz, 1H), 8.30 (dt, J=8.3, 1.1 Hz, 1H), 8.25 (dd, J=7.4, 1.2 Hz,
1H), 8.14 (dt, J=8.2, 0.9 Hz, 1H), 8.05 (s, 1H), 7.82 (ddd, J=8.5,
6.9, 1.4 Hz, 1H), 7.75-7.65 (m, 2H), 3.68-3.60 (m, 1H), 3.04 (s,
3H), 2.58-2.37 (m, 2H), 1.84 (dddd, J=13.6, 9.8, 6.6, 2.9 Hz, 1H),
1.79-1.67 (m, 1H), 1.57-1.44 (m, 1H), 1.32 (tdd, J=10.7, 8.4, 5.1
Hz, 1H). MS (ESI+) m/z 477.0 (M+H).sup.+.
Example I-114
2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3,5-tr-
iene-7-carboxamide
[1262] A solution of Example I-102H
(2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid) (37 mg, 0.159 mmol) in CH.sub.2Cl.sub.2 (1 mL) at 0.degree.
C. was treated with oxalyl chloride (69.7 .mu.l, 0.796 mmol),
treated with 1 drop of N,N-dimethylformamide, stirred at room
temperature for 30 minutes and concentrated to dryness with a
stream of nitrogen. The residue was dissolved in CH.sub.2Cl.sub.2
(.about.0.5 mL), treated with quinoline-5-sulfonamide (43.1 mg,
0.207 mmol), treated with triethylamine (44.4 .mu.l, 0.319 mmol),
treated with a catalytic amount of 4-dimethylaminopyridine (2 mg),
and stirred at room temperature overnight. The mixture was
partitioned between ethyl acetate (75 mL) and 1 M aqueous HCl (10
mL). The ethyl acetate layer was washed with brine, dried
(MgSO.sub.4), filtered, concentrated, and purified by reverse-phase
HPLC [Waters XBridge.TM. RP18 column, 5 .mu.m, 30.times.100 mm,
flow rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1%
TFA]. The material was chromatographed again on silica gel, eluting
with a gradient of 25% to 100% [200:1:1 ethyl
acetate:HCOOH:H.sub.2O] in heptanes to provide the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 12.84
(s, 1H), 9.08 (dd, J=1.6, 4.2 Hz, 1H), 9.04-9.00 (m, 1H), 8.39-8.35
(m, 2H), 7.95 (t, J=8.0 Hz, 1H), 7.81 (dd, J=4.2, 8.8 Hz, 1H), 6.88
(d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 4.33 (dd, J=2.4, 5.7 Hz,
1H), 3.34 (s, 3H), 3.35-3.23 (m, 2H), 2.84 (dd, J=2.5, 13.8 Hz,
1H), 2.12 (tdtd, J=1.7, 3.1, 6.3, 7.5 Hz, 2H), 2.01-1.81 (m, 3H),
1.76-1.68 (m, 1H). LC/MS (APCI+) m/z 423 (M+H).sup.+.
Example I-115
(8S)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoqui-
noline-8-carboxamide
[1263]
4-Bromo-1-methoxy-N-(naphthalen-1-ylsulfonyl)-5,6,7,8-tetrahydroiso-
quinoline-8-carboxamide from Example I-113G (190 mg) was separated
via chiral SFC, using Regis Whelk-O/Column (size: 21.times.250 mm,
5 micron; concentration: 20 mg/mL) at a flow rate of 56 mL/minute
CO.sub.2, and 14 mL/minute methanol. The first fraction at 9.5
minute was the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.63 (s, 1H), 8.74-8.63 (m, 1H),
8.34-8.21 (m, 2H), 8.14 (dd, J=8.3, 1.3 Hz, 1H), 8.05 (s, 1H), 7.81
(ddd, J=8.5, 6.8, 1.4 Hz, 1H), 7.75-7.63 (m, 2H), 3.64 (dd, J=6.4,
4.8 Hz, 1H), 3.05 (s, 3H), 2.56-2.37 (m, 2H), 1.84 (dddd, J=13.6,
9.8, 6.6, 2.9 Hz, 1H), 1.75 (dq, J=10.5, 3.8 Hz, 1H), 1.59-1.44 (m,
1H), 1.39-1.22 (m, 1H). MS(ESI+) m/z 475.0 (M+H).sup.+.
Example I-116
(8R)-4-bromo-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroisoqui-
noline-8-carboxamide
[1264] During the chiral separation described in Example I-115, the
second fraction at 9.99 minute was the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.63 (s, 1H),
8.71-8.64 (m, 1H), 8.29 (d, J=8.2 Hz, 1H), 8.24 (dd, J=7.5, 1.2 Hz,
1H), 8.14 (dd, J=8.3, 1.3 Hz, 1H), 8.05 (s, 1H), 7.81 (ddd, J=8.5,
6.9, 1.4 Hz, 1H), 7.75-7.62 (m, 2H), 3.70-3.57 (m, 1H), 3.05 (s,
3H), 2.57-2.37 (m, 2H), 1.83 (dtt, J=9.6, 6.3, 2.7 Hz, 1H),
1.79-1.70 (m, 1H), 1.58-1.45 (m, 1H), 1.38-1.24 (m, 1H). MS (ESI+)
m/z 475.0 (M+H).sup.+.
Example I-117
(1S)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-di-
hydro-1H-indene-1-carboxamide
Example I-117A
7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one
[1265] A mixture of 7-methoxy-2,3-dihydro-1H-inden-1-one
(CAS#34985-41-6, 1 g, 6.17 mmol), trimethyl(trifluoromethyl)silane
(1.753 g, 12.33 mmol), silver(I) fluoride (0.196 g, 1.541 mmol) and
PhI(OAc).sub.2 ((diacetoxyiodo)benzene, 3.97 g, 12.33 mmol) in
dimethyl sulfoxide (10 mL) was stirred at 45.degree. C. overnight.
The reaction mixture was dissolved in dichloromethane (50 mL) and
washed with brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by reverse-phase HPLC
[Waters XBridge.TM. RP18 column, 5 .mu.m, 30.times.100 mm, flow
rate 40 mL/minute, 5-95% gradient of acetonitrile in 0.1% TFA]. The
second fraction was the title compound. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm 7.79 (dd, J=8.6, 0.8 Hz, 1H), 6.88 (d,
J=8.6 Hz, 1H), 4.01 (s, 3H), 3.28-3.22 (m, 2H), 2.76-2.68 (m, 2H).
MS (ESI+) m/z 231 (M+H).sup.+. The first fraction was
7-methoxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one. .sup.1H
NMR (500 MHz, Chloroform-d) .delta. ppm 7.29 (dq, J=1.6, 0.8 Hz,
1H), 6.99 (d, J=1.2 Hz, 1H), 4.00 (s, 3H), 3.19-3.11 (m, 2H),
2.77-2.71 (m, 2H). MS (ESI+) m/z 231 (M+H).sup.+.
Example I-117B
7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carbonitrile
[1266] In a 50 mL round bottom flask
7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-one (0.290 g,
1.260 mmol) from Example I-117A and TOSMIC (toluenesulfonylmethyl
isocyanide, 0.320 g, 1.638 mmol) were dissolved in dimethoxyethane
(12.60 mL). The reaction mixture was cooled to -8.degree. C.
(internal temperature) with ice/acetone/dry ice under nitrogen.
Solid potassium tert-butoxide (0.325 g, 2.90 mmol) was added in
portions keeping the internal temperature below -5.degree. C. about
30 minutes. The reaction was allowed to slowly warm to room
temperature and was stirred overnight. The solvent was removed in
vacuo and quenched with water (20 mL). The aqueous layer was
extracted with ether (3.times.60 mL). The solvent was removed in
vacuo and the crude material was chromatographed using a 25 g
silica gel cartridge with 5-50% ethyl acetate/hexanes over 40
minutes to provide the title compound. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm 7.57 (d, J=8.5 Hz, 1H), 6.82 (d, J=8.5
Hz, 1H), 4.14 (dd, J=8.4, 5.3 Hz, 1H), 3.96 (s, 3H), 3.32 (dt,
J=16.5, 8.1 Hz, 1H), 3.17 (dtd, J=14.4, 6.5, 3.2 Hz, 1H), 2.66-2.46
(m, 2H). MS (APCI+) m/z 258 (M+H).sup.+.
Example I-117C
7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxylic
acid
[1267] A mixture of Example I-117B (170 mg, 0.705 mmol) and sodium
hydroxide (282 mg, 7.05 mmol) in ethanol (6 mL) was stirred at
90.degree. C. overnight. The reaction mixture was purified via
chromatography on 12 g cartridge, eluting with ethyl
acetate/methanol (9:1) in heptane at 0-70% gradient to provide the
title compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6)
.delta. ppm 12.28 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 6.98 (d, J=8.5
Hz, 1H), 3.92 (dd, J=9.4, 4.6 Hz, 1H), 3.83 (s, 3H), 3.14-2.96 (m,
2H), 2.46-2.35 (m, 1H), 2.19 (ddt, J=13.2, 8.6, 4.8 Hz, 1H). MS
(APCI+) m/z 258 (M+H).sup.+.
Example I-117D
(1S)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-di-
hydro-1H-indene-1-carboxamide
[1268] A mixture of
7-methoxy-4-(trifluoromethyl)-2,3-dihydro-1H-indene-1-carboxylic
acid (36 mg, 0.138 mmol) from Example I-117C and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne, hydrochloric acid (53.0 mg, 0.277 mmol) and
N,N-dimethylpyridin-4-amine (18.59 mg, 0.152 mmol) in
dichloromethane (1.5 mL) was stirred at room temperature for 30
minutes. 2-Methylquinoline-5-sulfonamide (33.8 mg, 0.152 mmol) was
added. The mixture was stirred at room temperature for 2 hours.
[1269] The crude product, without work up, was purified by
reverse-phase HPLC [Waters XBridge.TM. RP18 column, 5 .mu.m,
30.times.100 mm, flow rate 40 mL/minute, 5-95% gradient of
acetonitrile in 0.1% TFA] to provide
7-methoxy-N-((2-methylquinolin-5-yl)sulfonyl)-4-(trifluoromethyl)-2,3-dih-
ydro-1H-indene-1-carboxamide. The resulting compound was subjected
to chiral SFC separation, using Whelk-O (S,S) column (size:
21.times.250 mm, 5 micron; concentration: 30 mg/mL) at a flow rate
of 49 mL/minute CO.sub.2, and 21 mL/minute methanol. The first
fraction was the title compound. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 8.94 (d, J=8.8 Hz, 1H), 8.02 (dd,
J=7.7, 4.9 Hz, 2H), 7.75-7.68 (m, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.41
(d, J=8.6 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 3.73 (dd, J=9.4, 3.9 Hz,
1H), 3.39 (s, 3H), 2.97-2.79 (m, 2H), 2.67 (s, 3H), 2.21 (dq,
J=12.7, 8.8 Hz, 1H), 1.96 (ddt, J=12.8, 8.5, 4.2 Hz, 1H). MS (ESI+)
m/z 465.0 (M+H).sup.+.
Example I-118
(1R)-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-4-(trifluoromethyl)-2,3-di-
hydro-1H-indene-1-carboxamide
[1270] The title compound was the second fraction acquired during
the chiral separation of Example I-117D. .sup.1H NMR (501 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 8.95 (d, J=8.8 Hz, 1H),
8.04 (dd, J=7.7, 4.1 Hz, 2H), 7.73 (dd, J=8.4, 7.3 Hz, 1H), 7.51
(d, J=8.9 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H),
3.76 (dd, J=9.5, 4.1 Hz, 1H), 3.37 (s, 3H), 2.95-2.81 (m, 2H), 2.68
(s, 3H), 2.30-2.17 (m, 1H), 1.94 (ddq, J=13.3, 9.0, 4.5 Hz, 1H). MS
(ESI+) m/z 465.0 (M+H).sup.+.
Example I-119
4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-dihy-
dro-1H-indene-1-carboxamide
[1271] N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne (46.7 mg, 0.244 mmol) were combined in dichloromethane (0.6 mL).
To this suspension was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30
mg, 0.122 mmol) from Example I-127C. After 30 minutes,
1,2,3,4-tetrahydroquinoline-8-sulfonamide (25.9 mg, 0.122 mmol) was
added. The reaction was stirred at room temperature for 18 hours.
The reaction mixture was quenched with 1 N aqueous citric acid (1
mL) to pH .about.4, and was extracted with 2 mL dichloromethane.
The solvent was evaporated in vacuo, and the residue was purified
by reverse-phase preparative HPLC on a Phenomenex.RTM. Luna.RTM.
C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column (30 mm.times.150 mm). A
gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water
(B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A,
0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A,
10.0-12.0 minutes linear gradient 95-10% A) to provide the title
compound as a trifluoroacetic acid salt. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 11.82 (s, 1H), 7.41 (dd,
J=8.2, 1.6 Hz, 1H), 7.11 (dd, J=7.2, 1.5 Hz, 1H), 7.05 (d, J=8.3
Hz, 1H), 6.70 (d, J=8.3 Hz, 1H), 6.54-6.47 (m, 1H), 6.16 (bs, 1H),
3.90 (dd, J=9.1, 5.6 Hz, 1H), 3.56 (s, 3H), 3.41 (m, 1H), 3.34 (t,
J=5.6 Hz, 2H), 2.86-2.64 (m, 4H), 2.31-2.16 (m, 3H), 2.05-1.86 (m,
4H), 1.85-1.70 (m, 3H). MS (APCI.sup.+) m/z 441 (M+H).sup.+.
Example I-120
(8R)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroi-
soquinoline-8-carboxamide
[1272] Example I-120 was prepared and isolated as described in
Example I-111, substituting Example 1-116 for Example I-110F.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.66 (d, J=8.5 Hz, 1H), 8.26 (dd, J=19.0, 7.7
Hz, 2H), 8.13 (d, J=8.2 Hz, 1H), 7.84-7.78 (m, 1H), 7.76-7.61 (m,
3H), 3.64-3.57 (m, 1H), 3.48-3.27 (m, 1H), 2.99 (s, 3H), 2.39-2.30
(m, 2H), 2.27-2.13 (m, 2H), 2.04-1.62 (m, 6H), 1.55-1.12 (m, 2H).
MS (APCI+) m/z 451.0 (M+H).sup.+.
Example I-121
(8S)-4-cyclobutyl-1-methoxy-N-(naphthalene-1-sulfonyl)-5,6,7,8-tetrahydroi-
soquinoline-8-carboxamide
[1273] Example I-121 was prepared and isolated as described in
Example I-111, substituting Example 1-115 for Example I-110F.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.67 (d, J=8.4 Hz, 1H), 8.25 (dd, J=18.6, 7.6
Hz, 2H), 8.13 (d, J=8.2 Hz, 1H), 7.81 (t, J=7.9 Hz, 1H), 7.75-7.61
(m, 3H), 3.59 (t, J=5.8 Hz, 1H), 3.41-3.32 (m, 1H), 2.99 (s, 3H),
2.43-2.27 (m, 2H), 2.23-2.14 (m, 2H), 1.97-1.60 (m, 6H), 1.47-1.42
(m, 1H), 1.33-1.28 (m, 1H). MS (APCI+) m/z 451.0 (M+H).sup.+.
Example I-122
(1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide
[1274] N,N-Dimethylpyridin-4-amine (27.3 mg, 0.223 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (78 mg, 0.406 mmol) were combined in
dichloromethane (1 mL). To the suspension was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (50
mg, 0.203 mmol) from Example I-127C. After 30 minutes,
1,2,3,4-tetrahydroquinoline-5-sulfonamide (43.1 mg, 0.203 mmol) was
added. The reaction was stirred at room temperature for 18 hours.
The reaction mixture was quenched with 1 N aqueous citric acid (1
mL) to pH .about.4. The mixture was extracted with 2 mL
dichloromethane, and the organic layer was concentrated in vacuo.
The residue was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide
4-cyclobutyl-7-methoxy-N-((1,2,3,4-tetrahydroquinolin-5-yl)sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide, trifluoroacetic acid. The material
was separated by chiral preparative SFC chromatography using an YMC
Amylose-C, column size 21.times.250 mm, 5 micron, using a
concentration of 12 mg/mL in methanol at a flow rate of 49
mL/minute CO.sub.2 and UV monitoring at 220 nm to provide the title
compound as the trifluoroacetic acid salt. .sup.1H NMR (501 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.69 (s, 1H), 9.10 (dd,
J=4.2, 1.6 Hz, 1H), 9.07-8.99 (m, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.34
(dd, J=7.4, 1.2 Hz, 1H), 8.00-7.91 (m, 1H), 7.83 (dd, J=8.8, 4.2
Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.17 (s,
1H), 4.03 (dd, J=9.2, 5.7 Hz, 1H), 3.10 (s, 3H), 2.77 (t, J=7.5 Hz,
2H), 2.30 (ddt, J=13.0, 9.2, 7.4 Hz, 1H), 1.83 (dtd, J=13.2, 7.4,
5.6 Hz, 1H). MS (APCI+) m/z 441 (M+H).sup.+. R.sub.T (chiral
SFC)=4.34 minutes.
Example I-123
(1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-d-
ihydro-1H-indene-1-carboxamide
[1275] N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (46.7 mg, 0.244 mmol) were combined in
dichloromethane (0.6 mL). To the suspension was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30
mg, 0.122 mmol) from Example I-127C. After 30 minutes,
1-methyl-1H-benzo[d]imidazole-7-sulfonamide (Example I-133D, 25.7
mg, 0.122 mmol) was added. The reaction mixture was stirred at room
temperature for 18 hours. The reaction mixture was quenched with 1
N aqueous citric acid (1 mL) to pH .about.4, and extracted with 2
mL dichloromethane. The solvent was evaporated in vacuo, and the
residue was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100A AXIA.TM. column (30
mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide
4-cyclobutyl-7-methoxy-N-((l-methyl-1H-benzo[d]imidazol-7-yl)sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide, trifluoroacetic acid. The
material was separated by chiral preparative SFC chromatography
using an YMC Amylose-C, column size 21.times.250 mm, 5 micron,
using a concentration of 6 mg/mL in methanol at a flow rate of 49
mL/minute CO.sub.2 and UV monitoring at 220 nm to provide the title
compound as the trifluoroacetic acid salt. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.49 (s, 1H), 8.46 (s,
1H), 8.02 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.40 (t, J=8.0
Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 4.21 (s,
3H), 4.00 (dd, J=9.1, 5.8 Hz, 1H), 3.40 (p, J=8.7 Hz, 1H), 3.31 (s,
3H), 2.90-2.65 (m, 2H), 2.32 (dtd, J=12.9, 8.9, 5.8 Hz, 1H), 2.21
(tdd, J=8.0, 5.2, 2.8 Hz, 2H), 2.07-1.85 (m, 4H), 1.80-1.70 (m,
1H). MS (APCI+) m/z 440 (M+H.sup.+). R.sub.T (chiral SFC)=3.17
minutes.
Example I-124
7-methoxy-N-(naphthalene-1-sulfonyl)-4-(prop-1-en-2-yl)-2,3-dihydro-1H-ind-
ene-1-carboxamide
Example I-124A
methyl
7-methoxy-1-((naphthalen-1-ylsulfonyl)carbamoyl)-2,3-dihydro-1H-ind-
ene-4-carboxylate
[1276] To Example I-19C
(4-bromo-7-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide) (1 g, 2.172 mmol), and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
(Heraeus, 0.032 g, 0.043 mmol) in a 50 mL Hast C reactor was added
methanol and triethylamine (0.606 mL, 4.34 mmol). The reactor was
degassed with argon several times followed by carbon monoxide and
the reaction mixture was heated at 100.degree. C. for 16 hours at
60 psi. The reaction mixture was filtered and the solvent was
evaporated in vacuo. The residue was purified using a 24 g silica
gel cartridge with a gradient of 0-10% methanol/dichloromethane to
provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 12.59 (s, 1H), 8.66 (dd, J=8.7, 1.1
Hz, 1H), 8.30 (d, J=8.2 Hz, 1H), 8.26 (dd, J=7.4, 1.3 Hz, 1H),
8.17-8.10 (m, 1H), 7.84-7.78 (m, 1H), 7.76 (d, J=8.6 Hz, 1H),
7.74-7.71 (m, 1H), 7.68 (dd, J=8.2, 7.4 Hz, 1H), 6.73 (d, J=8.7 Hz,
1H), 3.95 (dd, J=9.4, 5.6 Hz, 1H), 3.74 (s, 3H), 3.16 (s, 3H), 3.06
(t, J=7.6 Hz, 2H), 2.35-2.21 (m, 1H), 1.80 (td, J=13.1, 7.2 Hz,
1H). MS (APCI+) m/z 440 (M+H.sup.+).
Example I-124B
7-methoxy-N-(naphthalene-1-sulfonyl)-4-(prop-1-en-2-yl)-2,3-dihydro-1H-ind-
ene-1-carboxamide
[1277] To a solution of methyl
7-methoxy-1-((naphthalen-1-ylsulfonyl)carbamoyl)-2,3-dihydro-1H-indene-4--
carboxylate (100 mg, 0.228 mmol) from Example I-124A in
tetrahydrofuran (1.5 mL) at 25.degree. C. was added dropwise methyl
magnesium bromide in diethyl ether (1.517 mL, 4.55 mmol). The
reaction mixture was stirred for 60 minutes, quenched with 1 N
aqueous HCl (3 mL), and extracted with 10 mL dichloromethane. The
solvent was evaporated in vacuo and the resulting residue was
purified on a 12 g silica gel cartridge with a gradient of 0-100%
ethyl acetate/hexane over a period of 17 minutes to provide the
title compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6)
.delta. ppm 12.48 (s, 1H), 8.63 (d, J=1.0 Hz, 1H), 8.26 (d, J=8.1
Hz, 1H), 8.23 (dd, J=7.4, 1.2 Hz, 1H), 8.12-8.08 (m, 1H), 7.77
(ddd, J=8.5, 6.9, 1.4 Hz, 1H), 7.70-7.67 (m, 1H), 7.65 (dd, J=8.2,
7.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 5.04
(t, J=1.7 Hz, 1H), 4.82 (d, J=1.2 Hz, 1H), 3.91 (dd, J=9.0, 5.7 Hz,
1H), 3.07 (s, 3H), 2.77 (t, J=7.4 Hz, 2H), 2.24-2.10 (m, 1H), 1.93
(d, J=0.6 Hz, 3H), 1.74 (ddt, J=13.0, 7.7, 6.3 Hz, 1H). MS (ESI+)
m/z 422 (M+H).sup.+.
Example I-125
4-(2-hydroxypropan-2-yl)-7-methoxy-N-(naphthalene-1-sulfonyl)-2,3-dihydro--
1H-indene-1-carboxamide
[1278] To a solution of methyl
7-methoxy-1-((naphthalen-1-ylsulfonyl)carbamoyl)-2,3-dihydro-1H-indene-4--
carboxylate (60 mg, 0.137 mmol) from Example I-124A in 2-methyl
tetrahydrofuran (1.5 mL) at 25.degree. C. was added dropwise
methylmagnesium bromide in diethyl ether (0.910 mL, 2.73 mmol). The
reaction mixture was stirred for 30 minutes, quenched with 2 mL
saturated aqueous ammonium chloride, and extracted with ethyl
acetate. The solvent was evaporated in vacuo and the resulting
residue was purified on 2.times.0.25 mm silica gel plate eluting
with 70% ethyl acetate/heptanes. The material was repurified on a
2.times.0.25 mm silica gel plate eluting with 3%
methanol/dichloromethane to provide the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.48 (s, 1H),
8.68 (dd, J=8.6, 1.0 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.26 (dd,
J=7.5, 1.2 Hz, 1H), 8.16-8.11 (m, 1H), 7.84-7.77 (m, 1H), 7.74-7.70
(m, 1H), 7.67 (dd, J=8.1, 7.4 Hz, 1H), 7.14 (d, J=8.5 Hz, 1H), 6.50
(d, J=8.5 Hz, 1H), 4.70 (s, 1H), 3.88 (dd, J=9.0, 5.9 Hz, 1H), 3.07
(s, 3H), 3.04-2.87 (m, 2H), 2.17 (dtd, J=12.7, 8.6, 6.2 Hz, 1H),
1.74 (ddt, J=12.5, 8.5, 6.2 Hz, 1H), 1.34 (d, J=1.5 Hz, 6H). MS
(ESI+) m/z 440 (M+H).sup.+.
Example I-126
(1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-d-
ihydro-1H-indene-1-carboxamide
[1279] N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol), and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (46.7 mg, 0.244 mmol) were combined in
dichloromethane (0.6 mL). To the mixture was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30
mg, 0.122 mmol) from Example I-127C. After 30 minutes,
1-methyl-1H-benzo[d]imidazole-7-sulfonamide (Example I-133D, 25.7
mg, 0.122 mmol) was added. The reaction was stirred at room
temperature for 18 hours. The reaction mixture was quenched with 1
N aqueous citric acid (1 mL) to pH .about.4, and was extracted with
2 mL dichloromethane. The solvent was evaporated in vacuo. The
residue was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide
4-cyclobutyl-7-methoxy-N-((1-methyl-1H-benzo[d]imidazol-7-yl)sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide, trifluoroacetic acid salt. The
material was separated by chiral preparative SFC chromatography
using an YMC Amylose-C, column size 21.times.250 mm, 5 micron, and
using a concentration of 6 mg/mL in methanol at a flow rate of 49
mL/minute CO.sub.2 and UV monitoring at 220 nm to provide the title
compound as the trifluoroacetic acid salt. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.49 (s, 1H), 8.46 (s,
1H), 8.02 (d, J=7.9 Hz, 1H), 7.89 (d, J=7.7 Hz, 1H), 7.40 (t, J=8.0
Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.3 Hz, 1H), 4.21 (s,
3H), 4.00 (dd, J=9.1, 5.8 Hz, 1H), 3.40 (p, J=8.7 Hz, 1H), 3.31 (s,
3H), 2.90-2.65 (m, 2H), 2.32 (dtd, J=12.9, 8.9, 5.8 Hz, 1H), 2.21
(tdd, J=8.0, 5.2, 2.8 Hz, 2H), 2.07-1.85 (m, 4H), 1.80-1.70 (m,
1H). MS (APCI+) m/z 440 (M+H.sup.+). R.sub.T (chiral SFC)=5.16
minutes.
Example I-127
(1S)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1-
H-indene-1-carboxamide
Example I-127A
4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonitrile
[1280] In a 50 mL round bottom flask,
4-bromo-7-methoxy-2,3-dihydro-1H-inden-1-one (0.977 g, 4.05 mmol)
(CAS#5411-61-0) and TOSMIC (toluenesulfonylmethyl isocyanide, 1.029
g, 5.27 mmol) were dissolved in dimethoxyethane (20 mL). The
reaction was cooled to -8.degree. C. (internal temperature) with
ice/acetone/dry ice under nitrogen. Solid potassium tert-butoxide
(1.046 g, 9.32 mmol) was added in portions, keeping the internal
temperature <-5.degree. C. over about an hour. The reaction
mixture was allowed to slowly warm to room temperature overnight.
The solvent was removed in vacuo and the crude material was
quenched with water (30 mL). The aqueous layer was extracted with
diethyl ether (4.times.50 mL) and the organics were washed with
brine and dried (Na.sub.2SO.sub.4). After filtration, the solvent
was removed in vacuo and the crude material was chromatographed
using a 40 g silica gel cartridge with 1-50% ethyl acetate/hexanes
to provide the title compound. .sup.1H NMR (400 MHz, chloroform-d)
.delta. ppm 7.40 (dd, J=8.7, 0.7 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H),
4.23-4.17 (m, 1H), 3.89 (s, 3H), 3.24-3.11 (m, 1H), 3.06-2.95 (m,
1H), 2.61-2.42 (m, 2H).
Example I-127B
4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid
[1281] 4-Bromo-7-methoxy-2,3-dihydro-1H-indene-1-carbonitrile (1.3
g, 5.16 mmol) from Example I-127A was dissolved in ethanol (17.2
mL). A solution of sodium hydroxide (2.062 g, 51.6 mmol) in 17.2 mL
of water was added, and the resulting mixture was heated at
80.degree. C. After 16 hours, the reaction was cooled in an ice
bath and acidified with 6 M aqueous HCl (11 mL) to pH .about.2. The
resulting precipitate was filtered and washed with water to provide
the title compound. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 7.38 (d, J=8.6 Hz, 1H), 6.79 (d,
J=8.7 Hz, 1H), 3.97 (dd, J=9.4, 4.5 Hz, 1H), 3.74 (s, 3H), 2.95
(ddd, J=16.1, 8.7, 7.2 Hz, 1H), 2.85 (ddd, J=16.3, 9.0, 4.8 Hz,
1H), 2.39 (dtd, J=13.1, 9.2, 7.2 Hz, 1H), 2.15 (tt, J=8.6, 4.5 Hz,
1H). MS (ESI+) m/z 271 (M+H+).sup.+-Br doublet.
Example I-127C
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid
[1282] A solution of
4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (100 mg,
0.369 mmol) from Example I-127B and
(dichloro[4,5-dichloro-1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](-
3-chloropyridyl)palladium(II) (Peppsi-IPent-Cl, 27.0 mg, 0.037
mmol) in tetrahydrofuran (1 mL) was treated with 0.5 M
cyclobutylzinc bromide in tetrahydrofuran (3 mL, 1.500 mmol) and
the reaction was stirred at room temperature under nitrogen
overnight. The solvent was reduced in volume to about half and the
reaction was quenched with 1 mL of saturated aqueous ammonium
chloride. The aqueous layer was removed by pipette (pH neutral) and
the organics were directly applied to a 12 g silica gel cartridge
and chromatographed with an ethyl acetate/ethanol/heptanes solvent
system to provide the title compound. .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm 9.73 (s, 1H), 7.14 (d, J=8.3 Hz, 1H),
6.76 (d, J=8.3 Hz, 1H), 4.13 (dd, J=9.2, 3.4 Hz, 1H), 3.91 (s, 3H),
3.52 (p, J=8.9, 8.4 Hz, 1H), 3.01 (dt, J=16.5, 8.5 Hz, 1H), 2.84
(ddd, J=16.1, 9.1, 3.6 Hz, 1H), 2.60 (ddt, J=13.2, 8.6, 3.5 Hz,
1H), 2.40-2.27 (m, 3H), 2.17-1.94 (m, 3H), 1.90-1.79 (m, 1H). MS
(APCI+) m/z 247 (M+H.sup.+).
Example I-127D
2-methylquinoline-5-sulfonamide
[1283] Thionyl chloride (2.1 mL, 28.8 mmol) was added dropwise to
water at 5.degree. C. and was allowed to warm to room temperature
and stir overnight. To the mixture was added copper(I) chloride
(0.01 g, 0.101 mmol) and the reaction was cooled to 0.degree. C.
2-Methylquinolin-5-amine (0.978 g, 6.18 mmol) was added portionwise
to a cooled (ice bath) solution of concentrated aqueous HCl (6.75
mL). To the cooled (-5.degree. C.) solution was added a solution of
sodium nitrite (0.5 g, 7.25 mmol) in water (2 mL) dropwise. After
the addition, the resulting mixture was added slowly to the cooled
thionyl chloride/CuCl mixture at -5.degree. C. The mixture was
stirred at 0.degree. C. for 2 hours and was filtered. The solvent
was reduced in vacuo and filtered into a cooled (ice bath) solution
of 100 mL ammonium hydroxide with rapid stirring. The ammonium
hydroxide solution was then filtered again and the solvent was
removed in vacuo. The material was taken up in water (25 mL) and
filtered, and the material was washed with water (2.times.15 mL) to
provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 8.86 (dd, J=8.9, 0.9 Hz, 1H), 8.11
(dt, J=8.5, 1.0 Hz, 1H), 8.07 (dd, J=7.5, 1.2 Hz, 1H), 7.79 (dd,
J=8.4, 7.4 Hz, 1H), 7.70 (s, 2H), 7.57 (d, J=8.8 Hz, 1H), 2.66 (s,
3H). MS (ESI+) m/z 223 (M+H.sup.+).
Example I-127E
(1S)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1-
H-indene-1-carboxamide
[1284] A suspension of
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (46
mg, 0.187 mmol) form Example I-127C, N,N-dimethylpyridin-4-amine
(25.10 mg, 0.205 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (71.6 mg, 0.374 mmol) in dichloromethane (2 mL)
was stirred for 30 minutes at room temperature, and treated with
2-methylquinoline-5-sulfonamide (45.7 mg, 0.205 mmol) from Example
I-127D. The reaction was stirred at room temperature overnight. The
solvent was reduced in volume and the organics were directly
applied to a 12 g silica gel cartridge and chromatographed with an
ethyl acetate/methanol solvent system to provide
4-cyclobutyl-7-methoxy-N-((2-methylquinolin-5-yl)sulfonyl)-2,3-dihydro-1H-
-indene-1-carboxamide, which was separated by chiral preparative
SFC chromatography using a ChiralCel.RTM. OJ-H, column size
21.times.250 mm, 5 micron, serial Number: OJH0SA0D002-011121, using
a concentration of 12 mg/mL in methanol at a flow rate of 50
g/minute CO.sub.2 and UV monitoring at 220 nm to provide the title
compound. .sup.1H NMR (501 MHz, Chloroform-d) .delta. ppm 9.86 (s,
1H), 8.69 (dd, J=8.9, 0.9 Hz, 1H), 8.41 (dd, J=7.5, 1.2 Hz, 1H),
8.26 (dt, J=8.6, 1.0 Hz, 1H), 7.77 (dd, J=8.5, 7.5 Hz, 1H), 7.32
(d, J=8.8 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H),
4.03 (s, 3H), 3.97 (dd, J=8.9, 1.5 Hz, 1H), 3.47-3.36 (m, 1H), 2.77
(s, 3H), 2.72-2.65 (m, 2H), 2.63-2.53 (m, 1H), 2.36-2.27 (m, 1H),
2.27-2.19 (m, 1H), 2.15-1.91 (m, 4H), 1.90-1.78 (m, 1H). MS (APCI+)
m/z 451 (M+H.sup.+). R.sub.T (chiral SFC)=2.87 minutes.
Example I-128
(1R)-4-cyclobutyl-7-methoxy-N-(2-methylquinoline-5-sulfonyl)-2,3-dihydro-1-
H-indene-1-carboxamide
[1285] A suspension of
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (46
mg, 0.187 mmol) from Example I-127C, N,N-dimethylpyridin-4-amine
(25.10 mg, 0.205 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (71.6 mg, 0.374 mmol) in dichloromethane (2 mL)
was stirred for 30 minutes at room temperature, and treated with
2-methylquinoline-5-sulfonamide (45.7 mg, 0.205 mmol) from Example
I-127D. The reaction was stirred at room temperature overnight. The
solvent was reduced in volume and the organics were directly
applied to a 12 g silica gel cartridge and chromatographed with an
ethyl acetate/methanol solvent system to provide
4-cyclobutyl-7-methoxy-N-((2-methylquinolin-5-yl)sulfonyl)-2,3-dihydro-1H-
-indene-1-carboxamide which was separated by chiral preparative SFC
chromatography using a ChiralCel.RTM. OJ-H, column size
21.times.250 mm, 5 micron, serial Number: OJH0SA0D002-011121, using
a concentration of 12 mg/mL in methanol at a flow rate of 50
g/minute CO.sub.2 and UV monitoring at 220 nm to provide the title
compound. .sup.1H NMR (501 MHz, Chloroform-d) .delta. ppm 9.86 (s,
1H), 8.69 (dd, J=8.9, 0.9 Hz, 1H), 8.41 (dd, J=7.5, 1.2 Hz, 1H),
8.26 (dt, J=8.6, 1.0 Hz, 1H), 7.77 (dd, J=8.5, 7.5 Hz, 1H), 7.32
(d, J=8.8 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H),
4.03 (s, 3H), 3.97 (dd, J=8.9, 1.5 Hz, 1H), 3.47-3.36 (m, 1H), 2.77
(s, 3H), 2.72-2.65 (m, 2H), 2.63-2.53 (m, 1H), 2.36-2.27 (m, 1H),
2.27-2.19 (m, 1H), 2.15-1.91 (m, 4H), 1.90-1.78 (m, 1H). MS (APCI+)
m/z 451 (M+H.sup.+). R.sub.T (chiral SFC)=3.37 minutes.
Example I-129
(1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide
[1286] N,N-Dimethylpyridin-4-amine (27.3 mg, 0.223 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (78 mg, 0.406 mmol) were combined in
dichloromethane (1 mL). To the suspension was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (50
mg, 0.203 mmol) from Example I-127C. After 30 minutes,
1,2,3,4-tetrahydroquinoline-5-sulfonamide (43.1 mg, 0.203 mmol)
(CAS#1155515-51-7) was added. The reaction mixture was stirred at
room temperature for 18 hours. The reaction mixture was quenched
with 1 N aqueous citric acid (1 mL) to pH .about.4 and was
extracted with 2 mL dichloromethane. The solvent was evaporated in
vacuo, and the residue was purified by reverse-phase preparative
HPLC on a Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG.
AXIA.TM. column (30 mm.times.150 mm). A gradient of acetonitrile
(A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow
rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear
gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear
gradient 95-10% A) to provide
4-cyclobutyl-7-methoxy-N-((1,2,3,4-tetrahydroquinolin-5-yl)sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide, trifluoroacetic acid salt. The
material was separated by chiral preparative SFC chromatography
using an YMC Amylose-C, column size 21.times.250 mm, 5 micron,
using a concentration of 12 mg/mL in methanol at a flow rate of 49
mL/minute CO.sub.2 and UV monitoring at 220 nm to provide the title
compound as a trifluoroacetic acid salt. .sup.1H NM R (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.69 (s, 1H), 9.10 (dd,
J=4.2, 1.6 Hz, 1H), 9.07-8.99 (m, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.34
(dd, J=7.4, 1.2 Hz, 1H), 8.00-7.91 (m, 1H), 7.83 (dd, J=8.8, 4.2
Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.7 Hz, 1H), 6.17 (s,
1H), 4.03 (dd, J=9.2, 5.7 Hz, 1H), 3.10 (s, 3H), 2.77 (t, J=7.5 Hz,
2H), 2.30 (ddt, J=13.0, 9.2, 7.4 Hz, 1H), 1.83 (dtd, J=13.2, 7.4,
5.6 Hz, 1H). MS (APCI+) m/z 441 (M+H).sup.+. R.sub.T (chiral
SFC)=6.66 minutes.
Example I-130
(1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide
Example I-130A
1,2,3,4-tetrahydroquinoline-8-sulfonamide
[1287] Quinoline-8-sulfonamide (101.1 mg, 0.486 mmol) and ethanol
(2 mL) were added to 20% Pd(OH).sub.2/C, wet (22 mg, 0.080 mmol) in
a 20 mL Barnstead Hast C. The mixture was stirred at 50 psi
hydrogen and 65.degree. C. overnight. The reaction was filtered and
the solvent was removed in vacuo to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 7.36
(dd, J=8.0, 1.6 Hz, 1H), 7.14 (s, 2H), 7.01 (dd, J=7.3, 1.5 Hz,
1H), 6.46 (dd, J=7.9, 7.3 Hz, 1H), 5.89 (s, 1H), 3.33-3.30 (m, 2H),
2.70 (t, J=6.3 Hz, 2H), 1.93-1.60 (m, 2H). MS (APCI+) m/z 213
(M+H.sup.+).
Example I-130B
(1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide
[1288] N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (46.7 mg, 0.244 mmol) were combined in
dichloromethane (0.6 mL). To the suspension was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30
mg, 0.122 mmol) from Example I-127C. After 30 minutes,
1,2,3,4-tetrahydroquinoline-8-sulfonamide (25.9 mg, 0.122 mmol)
from Example I-130A was added. The reaction was stirred at room
temperature for 18 hours. The reaction mixture was quenched with 1
N aqueous citric acid (1 mL) to pH .about.4 and extracted with 2 mL
dichloromethane. The solvent was evaporated in vacuo, and the
residue was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide
4-cyclobutyl-7-methoxy-N-((1,2,3,4-tetrahydroquinolin-8-yl)sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide, trifluoroacetic acid. The material
was separated by chiral preparative SFC chromatography using a YMC
Amylose-C, column size 21.times.250 mm, 5 micron, and a
concentration of 6 mg/mL in methanol at a flow rate of 1 mL/minute
CO.sub.2 and UV monitoring at 220 nm to provide
(1S)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide as a trifluoroacetic acid salt.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.70
(s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27
(dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd,
J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H),
6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H),
2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80
(dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396
(M+H).sup.+. R.sub.T (chiral SFC)=9.36 minutes.
Example I-131
(1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,3-
-dihydro-1H-indene-1-carboxamide
[1289] N,N-Dimethylpyridin-4-amine (16.37 mg, 0.134 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (46.7 mg, 0.244 mmol) were combined in
dichloromethane (0.6 mL). To the suspension was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid (30
mg, 0.122 mmol) from Example I-127C. After 30 minutes,
1,2,3,4-tetrahydroquinoline-8-sulfonamide (25.9 mg, 0.122 mmol)
from Example I-130A was added. The reaction was stirred at room
temperature for 18 hours. The reaction mixture was quenched with 1
N aqueous citric acid (1 mL) to pH .about.4, and was extracted with
2 mL dichloromethane. The solvent was evaporated in vacuo, and the
residue was purified by reverse-phase preparative HPLC on a
Phenomenex.RTM. Luna.RTM. C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column
(30 mm.times.150 mm). A gradient of acetonitrile (A) and 0.1%
trifluoroacetic acid in water (B) was used, at a flow rate of 50
mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient
10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient
95-10% A) to provide
4-cyclobutyl-7-methoxy-N-((1,2,3,4-tetrahydroquinolin-8-yl)sulfonyl)-2,3--
dihydro-1H-indene-1-carboxamide, trifluoroacetic acid salt. The
material was separated by chiral preparative SFC chromatography
using a YMC Amylose-C, column size 21.times.250 mm, 5 micron, using
a concentration of 6 mg/mL in methanol at a flow rate of 50
mL/minute CO.sub.2 and UV monitoring at 220 nm to provide
(1R)-4-cyclobutyl-7-methoxy-N-(1,2,3,4-tetrahydroquinoline-8-sulfonyl)-2,-
3-dihydro-1H-indene-1-carboxamide as a trifluoroacetic acid salt.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.70
(s, 1H), 8.65 (dd, J=8.6, 1.0 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.27
(dd, J=7.4, 1.3 Hz, 1H), 8.14 (dd, J=8.1, 1.3 Hz, 1H), 7.78 (ddd,
J=8.5, 6.9, 1.4 Hz, 1H), 7.74-7.63 (m, 2H), 6.72 (d, J=8.2 Hz, 1H),
6.61 (d, J=8.2 Hz, 1H), 3.95 (dd, J=9.3, 4.7 Hz, 1H), 3.66 (s, 3H),
2.65 (t, J=7.4 Hz, 2H), 2.24 (ddt, J=13.0, 9.3, 7.9 Hz, 1H), 1.80
(dtd, J=13.3, 6.8, 4.6 Hz, 1H), 1.44 (s, 3H). MS (APCI+) m/z 396
(M+H).sup.+. R.sub.T (chiral SFC)=10.40 minutes.
Example I-132
2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2.0]oc-
ta-1,3,5-triene-7-carboxamide
[1290] Into a 4 mL vial was added
2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid (Example 102H, 60.0 mg, 0.258 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (99 mg, 0.516 mmol), and
N,N-dimethylpyridin-4-amine (34.7 mg, 0.284 mmol) in
dichloromethane (1 mL). 1-Methyl-1H-indazole-7-sulfonamide (Example
I-97A, 60 mg, 0.284 mmol) was added. The reaction was stirred for 2
hours at room temperature. The solvent removed under a stream of
nitrogen. The residue was reconstituted in methanol and purified
using preparative reverse phase HPLC/MS method TFA8 to provide the
title compound. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.32 (s, 1H),
8.17 (dd, J=7.9, 1.2 Hz, 1H), 8.10 (dd, J=7.5, 1.1 Hz, 1H), 7.32
(t, J=7.7 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H),
4.43 (s, 3H), 4.36 (dd, J=5.4, 2.4 Hz, 1H), 3.49 (s, 3H), 3.42-3.27
(m, 2H), 3.01 (dd, J=13.8, 2.4 Hz, 1H), 2.22-2.11 (m, 2H),
2.06-1.94 (m, 2H), 1.94-1.84 (m, 1H), 1.81-1.71 (m, 1H). MS (APCI+)
m/z 426.1 (M+H).sup.+.
Example I-133
4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide
Example I-133A
2-bromo-N-methyl-6-nitroaniline
[1291] 1-Bromo-2-fluoro-3-nitrobenzene (10.00 g, 45.5 mmol) was
dissolved in a solution of methanamine (68.2 mL, 136 mmol) in
tetrahydrofuran (2 M). The mixture was heated to 60.degree. C. in a
sealed flask and was allowed to stir for 18 hours. The reaction
mixture was concentrated in vacuo. The resulting residue was
dissolved in ethyl acetate (200 mL) and washed sequentially with
water (30 mL) and brine (30 mL), then dried over Na.sub.2SO.sub.4,
filtered and concentrated to provide the title compound. MS (ESI+)
m/z 231.1 (M+H).sup.+.
Example I-133B
7-bromo-1-methyl-1H-benzo[d]imidazole
[1292] A suspension of iron (10.15 g, 182 mmol) in a solution of
2-bromo-N-methyl-6-nitroaniline (7.00 g, 30.3 mmol) and ammonium
chloride (9.72 g, 182 mmol) in isopropyl alcohol (60 mL) and formic
acid (60 mL, 1564 mmol) was stirred at 90.degree. C. under N.sub.2
for 16 hours. The mixture was diluted with CH.sub.2Cl.sub.2 (200
mL) and filtered. The filtrate was concentrated to dryness and the
resulting residue was partitioned between CH.sub.2Cl.sub.2 (100 mL)
and saturated aqueous NaHCO.sub.3 (100 mL). The aqueous layer was
extracted with CH.sub.2Cl.sub.2 (3.times.100 mL). The combined
organic layers were dried over Na.sub.2SO.sub.4, filtered, and
concentrated. The residue was purified by silica gel chromatography
(10% methanol in CH.sub.2Cl.sub.2) to provide the title compound.
MS (ESI+) m/z 211.1 (M+H).sup.+.
Example I-133C
1-methyl-1H-benzo[d]imidazole-7-sulfonyl fluoride
[1293] A 20 mL microwave vial was charged with DABSO
(1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) adduct, 569 mg,
2.369 mmol), PdCl.sub.2(AmPhos).sub.2
(bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),
84 mg, 0.118 mmol) and 7-bromo-1-methyl-1H-benzo[d]imidazole (500
mg, 2.369 mmol). A mixture of N-cyclohexyl-N-methylcyclohexanamine
(1.531 mL, 7.11 mmol) in anhydrous isopropyl alcohol (11 mL) was
added. The vial was sealed with a Teflon cap, sparged for 5 minutes
with N.sub.2 and subjected to microwave conditions at 110.degree.
C. for 2.5 hours. After cooling to room temperature,
N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (1121 mg, 3.55 mmol)
was added and the reaction mixture was stirred for 2 hours until
completion. The reaction mixture was diluted with H.sub.2O (30 mL)
and extracted with ethyl acetate (2.times.100 mL). The organics
were dried over anhydrous Na.sub.2SO.sub.4, filtered and
concentrated in vacuo. The crude material was purified by silica
gel chromatography (50%-80% ethyl acetate in petroleum) to provide
the title compound. MS (ESI+) m/z 215.1 (M+H).sup.+.
Example I-133D
1-methyl-1H-benzo[d]imidazole-7-sulfonamide
[1294] Ammonium hydroxide (65 mL, 1669 mmol) in a round bottomed
flask was cooled to 0.degree. C.
1-Methyl-1H-benzo[d]imidazole-7-sulfonyl fluoride (1.250 g, 5.84
mmol) was added, and the mixture was stirred at 0.degree. C. for 5
hours, and stirred at room temperature for 16 hours After
completion, the mixture was added dropwise into an aqueous 1 N HCl
solution at 0.degree. C., adjusting the pH to within 4-5. The
acidic solution was purified by combi-flash chromatography (mobile
phase: 5% methanol (B) in H.sub.2O (0.04% TFA) (A), time: 15-20
minutes) to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 8.75 (s, 1H), 7.98 (s, 2H),
7.98 (d, J=7.6 Hz, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.48 (t, J=7.8 Hz,
1H), 4.19 (s, 3H). MS (ESI+) m/z 212.1 (M+H).sup.+.
Example I-133E
4-cyclobutyl-7-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide
[1295] Example I-133E was prepared and isolated as described in
Example I-132, substituting
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid
(Example I-127C) for Example I-102H, and
1-methyl-1H-benzo[d]imidazole-7-sulfonamide for Example I-97A.
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1
(v/v)) .delta. ppm 8.48 (s, 1H), 8.04 (dd, J=8.1, 1.1 Hz, 1H), 7.93
(dd, J=7.9, 1.0 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.03 (d, J=8.3 Hz,
1H), 6.64 (d, J=8.3 Hz, 1H), 4.22 (s, 3H), 4.00 (dd, J=9.0, 5.8 Hz,
1H), 3.46-3.36 (m, 1H), 3.31 (s, 3H), 2.86-2.68 (m, 2H), 2.39-2.28
(m, 1H), 2.26-2.14 (m, 2H), 2.03-1.86 (m, 4H), 1.81-1.69 (m, 1H).
MS (APCI+) m/z 440.1 (M+H).sup.+.
Example I-134
2-cyclobutyl-5-methoxy-N-(1-methyl-1H-benzimidazole-7-sulfonyl)bicyclo[4.2-
.0]octa-1,3,5-triene-7-carboxamide
[1296] Example I-134 was isolated as described in Example I-132,
substituting 1-methyl-1H-benzo[d]imidazole-7-sulfonamide for
1-methyl-1H-indazole-7-sulfonamide. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.43 (s, 1H),
8.04 (dd, J=8.1, 1.1 Hz, 1H), 7.94 (dd, J=7.9, 1.1 Hz, 1H), 7.43
(t, J=7.9 Hz, 1H), 6.95 (d, J=8.6 Hz, 1H), 6.61 (d, J=8.6 Hz, 1H),
4.37 (dd, J=5.4, 2.4 Hz, 1H), 4.21 (s, 3H), 3.53 (s, 3H), 3.42-3.27
(m, 2H), 3.05 (dd, J=13.9, 2.4 Hz, 1H), 2.22-2.12 (m, 2H),
2.04-1.84 (m, 3H), 1.81-1.71 (m, 1H). MS (APCI+) m/z 442.0
(M+H).sup.+.
Example I-135
4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro--
1H-indene-1-carboxamide
Example I-135A
methyl 4-sulfamoylpyrazolo[1,5-a]pyridine-3-carboxylate
[1297] n-Butyllithium (0.251 g, 3.92 mmol) (2.5 M in
tetrahydrofuran) and dibutylmagnesium (1.629 g, 11.76 mmol) (1.0 M
in heptane) were charged into a nitrogen filled three-necked flask
at room temperature. A mixture of methyl
4-bromopyrazolo[1,5-a]pyridine-3-carboxylate (2.000 g, 7.84 mmol)
in tetrahydrofuran (25 mL) was added dropwise to the n-Bu.sub.3MgLi
solution at -25.degree. C. and the mixture was stirred at
-10.degree. C. for 1 hour. The resulting mixture was added to a
solution of sulfuryl dichloride (1.587 mL, 19.60 mmol) in toluene
(20 mL) at -10.degree. C. and the mixture was stirred for 20
minutes at -10.degree. C. The reaction mixture was concentrated.
Ammonium hydroxide (15 mL, 7.84 mmol) was added to the crude
material at room temperature, and the mixture was stirred for 15
minutes. After completion, the mixture was concentrated. The crude
material was purified by silica gel chromatography (25%-40% ethyl
acetate in petroleum). The resultant material was purified again by
Prep-HPLC on a Gilson 281(PHG013) with Boston pHlex ODS column
(21.2.times.250 mm, 10 .mu.m), using a gradient of acetonitrile (B)
and 0.05% trifluoroacetic acid in water (A) at 35-55% B in 10
minutes with stop at 15 minutes, at a flow rate of 25 mL/minute to
provide the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.70 (dd, J=6.8, 1.0 Hz, 1H), 8.50 (s, 1H), 8.25 (dd,
J=7.4, 1.0 Hz, 1H), 7.08 (t, J=7.1 Hz, 1H), 6.60 (s, 2H), 3.96 (s,
3H). MS (ESI+) m/z 256.1 (M+H).sup.+.
Example I-135B
pyrazolo[1,5-a]pyridine-4-sulfonamide
[1298] Methyl 4-sulfamoylpyrazolo[1,5-a]pyridine-3-carboxylate
(0.535 g, 1.258 mmol) was heated in H.sub.2SO.sub.4 (12.33 g, 62.9
mmol) at 90.degree. C. for 10 hours. After cooling, the reaction
mixture was neutralized with 4 N aqueous NaOH to pH 5. The mixture
was extracted with ethyl acetate (2.times.100 mL) and washed with
brine (30 mL). The organics were dried over Na.sub.2SO.sub.4 (5 g),
filtered, and concentrated. The residue was purified by Combi-Flash
chromatography (H.sub.2O (0.01% TFA) (A)/methanol (B), gradient
from 5-25% of B at 10 minutes-25 minutes to provide the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 8.92 (d, J=7.2, 1H), 8.18 (s, 1H), 7.74 (s, 2H), 7.70 (d,
J=6.8, 1H), 7.03 (t, J=7.0, 1H), 6.99 (s, 1H). MS (ESI+) m/z 198.7
(M+H).sup.+.
Example 135C
4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dihydro--
1H-indene-1-carboxamide
[1299] Example I-135C was prepared and isolated as described in
Example I-132, substituting Example I-127C for Example I-102H, and
pyrazolo[1,5-a]pyridine-4-sulfonamide (Example I-135B) for Example
I-97A. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.98 (d, J=7.0
Hz, 1H), 8.26 (d, J=2.3 Hz, 1H), 7.87 (d, J=7.2 Hz, 1H), 7.09 (t,
J=7.1 Hz, 1H), 7.05-6.98 (m, 2H), 6.61 (d, J=8.4 Hz, 1H), 3.92 (dd,
J=9.1, 5.7 Hz, 1H), 3.40 (p, J=8.6 Hz, 1H), 3.24 (s, 3H), 2.79-2.63
(m, 2H), 2.31-2.16 (m, 3H), 2.03-1.78 (m, 4H), 1.79-1.70 (m, 1H).
MS (APCI+) m/z 426.1 (M+H).sup.+.
Example I-136
2-cyclobutyl-5-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)bicyclo[4.2.0-
]octa-1,3,5-triene-7-carboxamide
[1300] Example I-136 was prepared and isolated as described in
Example I-132, substituting pyrazolo[1,5-a]pyridine-4-sulfonamide
(Example I-135B) for Example I-97A. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.99 (dt, J=6.9,
1.0 Hz, 1H), 8.29-8.24 (m, 1H), 7.92 (dd, J=7.2, 1.1 Hz, 1H), 7.11
(t, J=7.1 Hz, 1H), 7.00-6.95 (m, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.58
(d, J=8.5 Hz, 1H), 4.34 (dd, J=5.8, 2.4 Hz, 1H), 3.43 (s, 3H), 3.39
(dd, J=13.9, 5.7 Hz, 1H), 3.31 (p, J=8.8, 8.3 Hz, 1H), 2.90 (dd,
J=13.9, 2.5 Hz, 1H), 2.20-2.10 (m, 2H), 2.04-1.83 (m, 3H),
1.80-1.70 (m, 1H). MS (APCI+) m/z 412.1 (M+H).sup.+.
Example I-137
2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicyclo[4-
.2.0]octa-1,3,5-triene-7-carboxamide
[1301] Example I-137 was prepared as described in Example I-132,
substituting 1,2,3,4-tetrahydroquinoline-5-sulfonamide for Example
I-97A. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 7.09 (dd, J=7.8,
1.4 Hz, 1H), 7.03 (t, J=7.9 Hz, 1H), 6.97 (d, J=8.6 Hz, 1H), 6.73
(dd, J=7.9, 1.4 Hz, 1H), 6.65 (d, J=8.6 Hz, 1H), 4.37 (dd, J=5.7,
2.3 Hz, 1H), 3.64 (s, 3H), 3.47-3.29 (m, 2H), 3.25-3.13 (m, 2H),
3.11-2.91 (m, 3H), 2.26-2.12 (m, 2H), 2.12-1.71 (m, 6H). MS (APCI+)
m/z 427.1 (M+H).sup.+.
Example I-138
7-methoxy-N-(naphthalene-1-sulfonyl)-4-(oxolan-2-yl)-2,3-dihydro-1H-indene-
-1-carboxamide
Example I-138A
ethyl 4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylate
[1302] A solution of Example I-19B
(4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid) (1 g,
3.69 mmol) in ethanol (13 mL) was treated with 9 drops of
concentrated H.sub.2SO.sub.4 and heated at 84.degree. C. for 2
hours. The reaction mixture was cooled to room temperature, treated
with 2 g of NaHCO.sub.3, and stirred at room temperature for 15
minutes. The mixture was concentrated in vacuo. The residue was
treated with ethyl acetate and the resulting mixture was filtered,
concentrated, and chromatographed on silica gel, eluting with
CH.sub.2Cl.sub.2 to provide the title compound. .sup.1H NMR (500
MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 7.40 (dd, J=8.6, 0.8
Hz, 1H), 6.84-6.77 (m, 1H), 4.16-4.01 (m, 3H), 3.73 (s, 3H),
3.03-2.93 (m, 1H), 2.87 (ddd, J=16.1, 8.9, 5.9 Hz, 1H), 2.41 (dtd,
J=12.9, 9.0, 6.1 Hz, 1H), 2.12 (ddt, J=12.8, 8.9, 5.8 Hz, 1H),
1.24-1.16 (m, 3H). MS (ESI+) m/z 299, 301 (M+H).sup.+.
Example I-138B
ethyl
7-methoxy-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-indene-1-carboxyla-
te
[1303] A mixture of Example I-138A (ethyl
4-bromo-7-methoxy-2,3-dihydro-1H-indene-1-carboxylate) (25 mg,
0.084 mmol),
[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N.sup.1,N.sup.1']bis[-
3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]Iridium(III)
hexafluorophosphate ([Ir{dF(CF.sub.3)ppy}2(dtbpy)]PF.sub.6) (2.8
mg, 2.5 .mu.M), quinuclidine (0.93 mg, 8.4 .mu.M), and potassium
carbonate (23 mg, 0.17 mmol) under nitrogen was treated with a
mixture of 4,4'-di-tert-butyl-2,2'-bipyridine (1.1 mg, 4.2 .mu.M)
and nickel(II) chloride ethylene glycol dimethyl ether complex
(0.93 mg, 4.2 micromol) in tetrahydrofuran (0.5 mL). The resulting
mixture was irradiated with 450 nM light (140 Watt) for 15 hours.
The mixture was concentrated to dryness and the residue was
chromatographed on silica gel eluting with a gradient of 15% to
100% tert-butyl methyl ether in heptanes to provide the title
compound. LC/MS (APCI+) m/z 291.5 (M+H).sup.+.
Example I-138C
7-methoxy-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-indene-1-carboxylic
acid
[1304] A solution of Example I-138B (ethyl
7-methoxy-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-indene-1-carboxylate)
(61 mg, 0.210 mmol) in tetrahydrofuran (1.5 mL) was diluted with
methanol (1.5 mL), treated with 1 M aqueous NaOH (1 mL), stirred at
room temperature for 20 minutes, heated to 60.degree. C. for 2
hours, and cooled. The mixture was partitioned between tert-butyl
methyl ether (25 mL) and 1 M aqueous HCl (10 mL). The layers were
separated and the aqueous layer was extracted with tert-butyl
methyl ether (25 mL). The combined tert-butyl methyl ether layers
were washed with brine, dried (MgSO.sub.4), filtered, and
concentrated to provide the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 7.32-7.25 (m, 1H), 6.75 (d, J=8.5 Hz,
0.6H), 6.73 (d, J=8.3 Hz, 0.4H), 4.92-4.82 (m, 1H), 4.14-4.05 (m,
2H), 3.94-3.82 (m, 1H), 3.89 (s, 1.8H), 3.87 (s, 1.2H), 3.14-2.99
(m, 1H), 2.96-2.88 (m, 1H), 2.61-2.49 (m, 1H), 2.43-2.20 (m, 2H),
2.06-1.95 (m, 2H), 1.79-1.65 (m, 1H). LC/MS (APCI+) m/z 263
(M+H).sup.+.
Example I-138D
7-methoxy-N-(naphthalene-1-sulfonyl)-4-(oxolan-2-yl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1305] A mixture of Example I-138C
(7-methoxy-4-(tetrahydrofuran-2-yl)-2,3-dihydro-1H-indene-1-carboxylic
acid) (14.8 mg, 0.056 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (21.63
mg, 0.113 mmol) and naphthalene-1-sulfonamide (15.20 mg, 0.073
mmol) in N,N-dimethylformamide (0.3 mL) was treated with
4-dimethylaminopyridine (7.58 mg, 0.062 mmol) and stirred
overnight. The mixture was partitioned between tert-butyl methyl
ether (75 mL) and 1 M aqueous HCl (25 mL). The layers were
separated and the aqueous layer was extracted with tert-butyl
methyl ether (25 mL). The combined tert-butyl methyl ether layers
were washed with 0.1 M aqueous HCl (15 mL), washed with brine,
dried (MgSO.sub.4), filtered, and concentrated. The residue was
chromatographed on silica gel, eluting with a gradient of 25% to
50% [200:1:1 ethyl acetate:HCOOH:H.sub.2O] in heptanes to provide
the title compound. .sup.1H NMR (500 MHz,
dimethylsulfoxide-d.sub.6) .delta. ppm 12.48 (s, 1H), 8.67 (d,
J=8.7 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 8.27-8.24 (m, 1H), 8.13 (d,
J=8.2 Hz, 1H), 7.81-7.77 (m, 1H), 7.73-7.65 (m, 2H), 7.07 (d, J=8.3
Hz, 1H), 6.56-6.53 (m, 1H), 4.69-4.63 (m, 1H), 3.92 (ddd, J=6.3,
8.5, 14.9 Hz, 2H), 3.71 (qd, J=3.0, 7.3 Hz, 1H), 3.12 (s, 1.6H),
3.09 (s, 1.3H), 2.74 (td, J=7.2, 15.2, 16.0 Hz, 2H), 2.27-2.18 (m,
1H), 2.18-2.08 (m, 1H), 1.93-1.84 (m, 2H), 1.83-1.73 (m, 1H),
1.55-1.46 (m, 1H). LC/MS (APCI+) m/z 452 (M+H).sup.+.
Example I-139
7-methoxy-4-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide
Example I-139A
4-(hydroxymethyl)-7-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide
[1306] To a solution of methyl
7-methoxy-1-((naphthalen-1-ylsulfonyl)carbamoyl)-2,3-dihydro-1H-indene-4--
carboxylate (217 mg, 0.494 mmol) from Example I-124A in
dichloromethane (7 mL) at 0.degree. C. was added a 1 M solution of
diisobutylaluminum hydride in dichloromethane (1 mL, 1.000 mmol).
The reaction was stirred for 30 minutes and warmed to room
temperature over 3 hours. The reaction was cooled in an ice bath
and was quenched with 10 mL 1 N aqueous citric acid. The solvent
was evaporated in vacuo and the resulting residue was
chromatographed using a 12 g silica gel cartridge with 0-100% ethyl
acetate/heptanes over a period of 6 minutes to provide the title
compound. .sup.1H NMR (500 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.50 (s, 1H), 8.68 (d, J=8.7 Hz, 1H), 8.30 (d, J=8.2 Hz, 1H),
8.27 (d, J=7.5 Hz, 1H), 8.15 (d, J=8.2 Hz, 1H), 7.83-7.78 (m, 1H),
7.75-7.65 (m, 2H), 7.07 (d, J=8.2 Hz, 1H), 6.55 (d, J=8.3 Hz, 1H),
4.86 (s, 1H), 4.41-4.17 (m, 2H), 3.95 (dd, J=9.1, 5.8 Hz, 1H), 3.10
(d, J=1.1 Hz, 3H), 2.73 (q, J=6.6 Hz, 2H), 2.23 (dq, J=14.9, 8.0
Hz, 1H), 1.79 (dq, J=14.0, 6.8 Hz, 1H). MS (APCI+) m/z 394
(M+H).sup.+.
Example I-139B
7-methoxy-4-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inde-
ne-1-carboxamide
[1307] To a solution of
4-(hydroxymethyl)-7-methoxy-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-in-
dene-1-carboxamide (40 mg, 0.097 mmol) from Example I-139A in
N,N-dimethylformamide (0.8 mL) at 0.degree. C. was added sodium
hydride (7.78 mg, 0.194 mmol), as a 60% dispersion in mineral oil.
After 15 minutes, iodomethane (0.012 mL, 0.194 mmol) was added and
the reaction was stirred at 0.degree. C. for 2 hours. The mixture
was quenched via addition of 1 N aqueous citric acid (1 mL) and was
extracted with ethyl acetate. The crude material was purified with
a 12 g silica gel cartridge using a gradient of 0-100% ethyl
acetate/heptanes over 15 minutes to provide the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.52
(s, 1H), 8.73-8.66 (m, 1H), 8.31-8.21 (m, 2H), 8.12 (d, J=8.0 Hz,
1H), 7.83-7.75 (m, 1H), 7.74-7.62 (m, 2H), 7.03 (d, J=8.2 Hz, 1H),
6.55 (d, J=8.2 Hz, 1H), 4.22 (s, 2H), 3.93 (dd, J=9.1, 5.6 Hz, 1H),
3.18 (s, 3H), 3.12 (s, 3H), 2.73 (m, 2H), 2.31-2.15 (m, 1H),
1.87-1.69 (m, 1H). MS (ESI+) m/z 426 (M+H).sup.+.
Example I-140
7-methoxy-4-(2-methylpropyl)-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide
[1308] A suspension of Example I-44
(4-bromo-7-methoxy-N-(quinolin-5-ylsulfonyl)-2,3-dihydro-1H-indene-1-carb-
oxamide) (35.4 mg, 0.077 mmol) and
1,1'-bis(diphenylphosphino)ferrocenedichloro palladium(II)
dichloromethane complex (5.61 mg, 7.67 .mu.mol) in tetrahydrofuran
(0.5 mL) was treated with 1 M tert-butylzinc bromide in
tetrahydrofuran (460 .mu.l, 0.230 mmol). The mixture was stirred
over the weekend at room temperature, heated to 60.degree. C. for
2.5 hours and then heated to 80.degree. C. for 2.5 hours. The
mixture was cooled and partitioned between tert-butyl methyl ether
(30 mL) and 1 M aqueous HCl (10 mL). The tert-butyl methyl ether
layer was washed with brine, dried (MgSO.sub.4), filtered, and
concentrated. The residue was chromatographed on silica gel,
eluting with a gradient of 25% to 100% [200:1:1 ethyl
acetate:HCOOH:H.sub.2O] in heptanes to provide the title compound.
.sup.1H NMR (400 MHz, dimethylsulfoxide-d.sub.6) .delta. ppm 12.59
(s, 1H), 9.09 (dd, J=1.6, 4.2 Hz, 1H), 9.07-9.04 (m, 1H), 8.38-8.35
(m, 1H), 8.34 (dd, J=1.3, 7.5 Hz, 1H), 7.94 (dd, J=7.5, 8.4 Hz,
1H), 7.83 (dd, J=4.2, 8.8 Hz, 1H), 6.85 (d, J=8.2 Hz, 1H), 6.51 (d,
J=8.3 Hz, 1H), 3.93 (dd, J=5.9, 8.9 Hz, 1H), 3.07 (s, 3H),
2.80-2.65 (m, 2H), 2.30-2.19 (m, 3H), 1.84-1.74 (m, 1H), 1.73-1.65
(m, 1H), 0.81 (d, J=3.7 Hz, 3H), 0.79 (d, J=3.7 Hz, 3H). LC/MS
(APCI+) m/z 439 (M+H).sup.+.
Example I-141
(1S)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide
[1309] Into a 4 mL vial was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid
(Example I-127C, 79 mg, 0.323 mmol),
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (124 mg, 0.646 mmol), and
N,N-dimethylpyridin-4-amine (43.4 mg, 0.355 mmol) in
dichloromethane. 1-Methyl-1H-indazole-7-sulfonamide (Example I-97A,
75 mg, 0.355 mmol) was added. The reaction was stirred overnight at
room temperature. The solvent was removed under a stream of
nitrogen and the residue was reconstituted in methanol and was
purified using preparative reverse phase HPLC/MS method TFA8 to
provide the racemate of the title compound. The racemate was
separated by chiral preparative SFC chromatography using a WHELK-O
(S,S), column size 21.times.250 mm, serial number 43170, 5 micron,
using a concentration of 25 mg/mL in 3:1 methanol/dichloromethane
at a flow rate of 49 g/minute CO.sub.2 and UV monitoring at 220 nm
to provide the title compound as the first eluting isomer. .sup.1H
NMR (400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. ppm 8.31 (s, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.05 (d, J=7.5
Hz, 1H), 7.30 (t, J=7.8 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.60 (d,
J=8.4 Hz, 1H), 4.42 (s, 3H), 4.00-3.92 (m, 1H), 3.46-3.34 (m, 1H),
3.22 (s, 3H), 2.84-2.69 (m, 2H), 2.34-2.29 (m, 1H), 2.24-2.17 (m,
2H), 2.00-1.88 (m, 4H), 1.78-1.71 (m, 1H). MS (APCI+) m/z 440.1
(M+H).sup.+.
Example I-142
(1R)-4-cyclobutyl-7-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)-2,3-dihydr-
o-1H-indene-1-carboxamide
[1310] Example I-142 was isolated as the second eluting isomer from
the preparative SFC separation described in Example I-141. .sup.1H
NMR (500 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v))
.delta. ppm 8.32 (s, 1H), 8.16 (d, J=8.0 Hz, 1H), 8.07 (d, J=7.5
Hz, 1H), 7.31 (t, J=7.7 Hz, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.61 (d,
J=8.4 Hz, 1H), 4.43 (s, 3H), 3.98 (d, J=7.8 Hz, 1H), 3.40 (q, J=8.7
Hz, 1H), 3.22 (s, 3H), 2.85 2.67 (m, 2H), 2.39-2.27 (m, 1H),
2.26-2.17 (m, 2H), 2.03-1.87 (m, 4H), 1.79-1.72 (m, 1H). MS (APCI+)
m/z 440.1 (M+H).sup.+.
Example I-143
(7S)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2-
.0]octa-1,3,5-triene-7-carboxamide
[1311] Example I-132 (164.4 mg) was separated by chiral preparative
SFC chromatography using a WHELK-O (S,S), column size 21.times.250
mm, serial number 43170, 5 micron, using a concentration of 15
mg/mL in methanol at a flow rate of 56 g/minute CO.sub.2 and UV
monitoring at 220 nm to provide the title compound as the first
eluting isomer. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.32 (s, 1H),
8.17 (dd, J=8.0, 1.1 Hz, 1H), 8.10 (dd, J=7.6, 1.1 Hz, 1H), 7.32
(t, J=7.8 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.59 (d, J=8.6 Hz, 1H),
4.43 (s, 3H), 4.36 (dd, J=5.6, 2.4 Hz, 1H), 3.48 (s, 3H), 3.43-3.25
(m, 2H), 3.01 (dd, J=13.7, 2.5 Hz, 1H), 2.23-2.10 (m, 2H),
2.07-1.82 (m, 3H), 1.82-1.69 (m, 1H). MS (APCI+) m/z 426.1
(M+H).sup.+.
Example I-144
(7R)-2-cyclobutyl-5-methoxy-N-(1-methyl-1H-indazole-7-sulfonyl)bicyclo[4.2-
.0]octa-1,3,5-triene-7-carboxamide
[1312] Example I-144 was isolated as the second enantiomer from the
preparative SFC separation described in Example I-143. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
ppm 8.31 (s, 1H), 8.15 (dd, J=8.0, 1.1 Hz, 1H), 8.08 (dd, J=7.5,
1.1 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 6.93 (d, J=8.6 Hz, 1H), 6.58
(d, J=8.6 Hz, 1H), 4.42 (s, 3H), 4.34 (dd, J=5.6, 2.4 Hz, 1H), 3.48
(s, 3H), 3.42-3.25 (m, 2H), 3.01 (dd, J=13.7, 2.5 Hz, 1H),
2.23-2.10 (m, 2H), 2.08-1.84 (m, 3H), 1.82-1.69 (m, 1H). MS (APCI+)
m/z 426.1 (M+H).sup.+.
Example I-145
(7S)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicy-
clo[4.2.0]octa-1,3,5-triene-7-carboxamide
[1313] Example I-137 (46 mg) was separated by chiral preparative
SFC chromatography using a WHELK-O (S,S), column size 21.times.250
mm, serial number 43170, 5 micron, using a concentration of 15
mg/mL in methanol at a flow rate of 45 g/minute CO.sub.2 and UV
monitoring at 220 nm to provide the title compound as the first
eluting isomer. .sup.1H NMR (501 MHz, dimethyl
sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 7.09 (dd, J=7.8,
1.3 Hz, 1H), 7.05-6.99 (m, 1H), 6.96 (d, J=8.6 Hz, 1H), 6.72 (dd,
J=8.0, 1.3 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.36 (dd, J=5.6, 2.5
Hz, 1H), 3.64 (s, 3H), 3.45-3.30 (m, 2H), 3.24-3.12 (m, 2H),
3.08-2.93 (m, 3H), 2.24-2.14 (m, 2H), 2.09-1.97 (m, 2H), 1.97-1.86
(m, 1H), 1.86-1.72 (m, 3H). MS (APCI+) m/z 427.1 (M+H).sup.+.
Example I-146
(7R)-2-cyclobutyl-5-methoxy-N-(1,2,3,4-tetrahydroquinoline-5-sulfonyl)bicy-
clo[4.2.0]octa-1,3,5-triene-7-carboxamide
[1314] Example I-146 was isolated as the second enantiomer from the
preparative SFC separation described in Example I-145. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
ppm 7.09 (dd, J=7.8, 1.4 Hz, 1H), 7.07-6.99 (m, 1H), 6.96 (d, J=8.6
Hz, 1H), 6.72 (dd, J=8.0, 1.4 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 4.36
(dd, J=5.6, 2.4 Hz, 1H), 3.64 (s, 3H), 3.46-3.29 (m, 2H), 3.18 (td,
J=9.0, 7.8, 4.4 Hz, 2H), 3.01 (ddt, J=9.5, 6.5, 2.8 Hz, 3H),
2.25-2.12 (m, 2H), 2.10-1.87 (m, 3H), 1.87-1.71 (m, 3H). MS (APCI+)
m/z 427.1 (M+H).sup.+.
Example I-147
(7S)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3-
,5-triene-7-carboxamide
[1315] A solution of Example I-102H
(2-cyclobutyl-5-methoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic
acid) (234 mg, 1.007 mmol),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (386
mg, 2.015 mmol) and quinoline-5-sulfonamide (231 mg, 1.108 mmol) in
N,N-dimethylformamide (4 mL) was treated with
4-dimethylaminopyridine (135 mg, 1.108 mmol). The mixture was
stirred overnight and was partitioned between tert-butyl methyl
ether (100 mL) and 0.5 M aqueous HCl (25 mL). The tert-butyl methyl
ether layer was washed with 0.2 M aqueous HCl (15 mL), washed with
brine, dried (MgSO.sub.4), filtered, and concentrated. The residue
was chromatographed on silica gel, eluting with a gradient of 25%
to 50% [200:1:1 ethyl acetate:HCOOH:H.sub.2O] in heptanes to
provide the racemate of the title compound. The enantiomers of this
racemate were separated by Supercritical Fluid Chromatography (SFC)
using a 21.times.250 mm ChiralPak AD-H chiral column eluting with
20% methanol in liquid CO.sub.2 using a flow rate of 80 mL/minute
to provide the title compound as the first peak to elute from the
column. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 12.83 (s, 1H), 9.08 (dd, J=1.7, 4.2 Hz, 1H), 9.02 (d, J=8.5 Hz,
1H), 8.39-8.35 (m, 2H), 7.94 (t, J=8.0 Hz, 1H), 7.81 (dd, J=4.2,
8.7 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 4.33
(dd, J=2.5, 5.7 Hz, 1H), 3.39-3.23 (m, 5H), 2.84 (dd, J=2.5, 13.8
Hz, 1H), 2.11 (ddt, J=3.4, 6.3, 8.8 Hz, 2H), 2.00-1.82 (m, 3H),
1.76-1.68 (m, 1H). LC/MS (APCI+) m/z 423 (M+H).sup.+.
Example I-148
(7R)-2-cyclobutyl-5-methoxy-N-(quinoline-5-sulfonyl)bicyclo[4.2.0]octa-1,3-
,5-triene-7-carboxamide
[1316] The enantiomers of the racemate from Example I-147 were
separated by Supercritical Fluid Chromatography (SFC) using a
21.times.250 mm ChiralPak AD-H chiral column eluting with 20%
methanol in liquid CO.sub.2 using a flow rate of 80 mL/minute to
provide the title compound as the second peak to elute from the
column. .sup.1H NMR (500 MHz, dimethylsulfoxide-d.sub.6) .delta.
ppm 12.83 (s, 1H), 9.08 (dd, J=1.7, 4.2 Hz, 1H), 9.02 (d, J=8.5 Hz,
1H), 8.39-8.35 (m, 2H), 7.94 (t, J=8.0 Hz, 1H), 7.81 (dd, J=4.2,
8.7 Hz, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.53 (d, J=8.6 Hz, 1H), 4.33
(dd, J=2.5, 5.7 Hz, 1H), 3.39-3.23 (m, 5H), 2.84 (dd, J=2.5, 13.8
Hz, 1H), 2.11 (ddt, J=3.4, 6.3, 8.8 Hz, 2H), 2.00-1.82 (m, 3H),
1.76-1.68 (m, 1H). LC/MS (APCI+) m/z 423 (M+H).sup.+.
Example I-149
7-methoxy-3,3-dimethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
Example I-149A
1-(2-methoxyphenyl)-3-methylbut-2-en-1-one
[1317] N-methoxy-N,3-dimethylbut-2-enamide (2.500 g, 17.46 mmol)
was dissolved in tetrahydrofuran (30 mL) and cooled to -40.degree.
C. using a dry ice/acetone bath. A 1 M solution of
(2-methoxyphenyl)magnesium bromide (20.95 mL, 20.95 mmol) in
tetrahydrofuran was added dropwise over about 10 minutes. The
reaction was allowed to warm to room temperature overnight. The
reaction was diluted with 200 mL of methyl tert-butyl ether, washed
with saturated aqueous ammonium chloride (50 mL) and brine (50 mL)
then dried over sodium sulfate, filtered, and concentrated. The
crude material was chromatographed using an 80 g silica gel
cartridge with a gradient of 5-100% ethyl acetate/hexanes over 40
minutes to provide the title compound. .sup.1H NMR (501 MHz,
Chloroform-d) .delta. ppm 7.57 (dd, J=7.6, 1.8 Hz, 1H), 7.43 (ddd,
J=8.2, 7.3, 1.8 Hz, 1H), 7.02 (td, J=7.5, 1.0 Hz, 1H), 6.97 (dd,
J=8.4, 0.9 Hz, 1H), 6.64 (hept, J=1.2 Hz, 1H), 3.90 (s, 3H), 2.25
(d, J=1.3 Hz, 3H), 1.99 (d, J=1.3 Hz, 3H). MS (APCI+) m/z 191
(M+H.sup.+).
Example I-149B
7-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-one
[1318] A 30 mL vial, open to air via a vent needle, was charged
with aluminum chloride (4.00 g, 30.0 mmol) and sodium chloride
(0.800 g, 13.69 mmol) and heated at 200.degree. C. The melt was
removed from the heat and neat
1-(2-methoxyphenyl)-3-methylbut-2-en-1-one (0.800 g, 4.21 mmol)
from Example I-149A was added dropwise while stirring. The reaction
was returned to the heating block for 1 minute. The reaction was
cooled, quenched with ice, and extracted with ethyl acetate
(4.times.50 mL). The crude extracts were dried over sodium sulfate,
filtered and the solvent removed in vacuo. The crude material was
taken up in acetone (14 mL) and treated with potassium carbonate
(0.872 g, 6.31 mmol) and dimethyl sulfate (0.597 mL, 6.31 mmol).
The mixture was stirred at ambient temperature overnight. The
reaction was quenched with triethylamine (0.5 mL), filtered, and
the solvent was removed in vacuo. The crude material was
chromatographed using a 40 g silica gel cartridge with a gradient
of 0-50% ethyl acetate/heptane over 20 minutes to provide the title
compound. .sup.1H NMR (501 MHz, Chloroform-d) .delta. ppm 7.58 (dd,
J=8.2, 7.6 Hz, 1H), 7.07 (dd, J=7.7, 0.7 Hz, 1H), 6.81 (d, J=8.1
Hz, 1H), 3.98 (s, 3H), 2.60 (s, 2H), 1.42 (s, 6H). MS (APCI+) m/z
191 (M+H).sup.+.
Example I-149C
7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonitrile
[1319] To a solution of
7-methoxy-3,3-dimethyl-2,3-dihydro-1H-inden-1-one (0.205 g, 1.078
mmol) from Example I-149B and zinc(II) iodide (0.014 g, 0.043 mmol)
in dichloromethane (3 mL) cooled to 0.degree. C. was added slowly
trimethylsilanecarbonitrile (0.404 mL, 3.23 mmol). The mixture was
allowed to warm to room temperature over an hour. The solvent was
removed in vacuo and the residue was dissolved in acetic acid (3
mL) and concentrated aqueous HCl (0.3 mL). Tin(II) chloride (0.895
g, 4.72 mmol) was added. The mixture was heated at 90.degree. C.
for 2 hours. The reaction was cooled down to ambient temperature,
filtered and washed with dichloromethane. The solvent was removed
under a stream of nitrogen. The residue was dissolved in
dichloromethane and purified via chromatography on 10 g silica gel
cartridge, eluting with ethyl acetate/methanol (9:1) in heptane at
0-80% gradient to provide the title compound. .sup.1H NMR (501 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 7.27-7.12 (m, 2H),
6.77-6.68 (m, 2H), 3.82 (dd, J=8.8, 6.1 Hz, 1H), 3.70 (s, 3H), 2.08
(dd, J=12.6, 8.8 Hz, 1H), 1.98 (dd, J=12.6, 6.1 Hz, 1H), 1.89 (s,
1H), 1.25 (s, 3H), 1.13 (s, 3H). MS (APCI+) m/z 220
(M+H.sup.+).
Example I-149D
7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid
[1320] A solution of
7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carbonitrile (71 mg,
0.353 mmol) from Example I-149C and sodium hydroxide (137 mg, 3.43
mmol) in water (1 mL) and ethanol (1 mL) was warmed at 100.degree.
C. for 72 hours. The solvent was removed and the crude material was
acidified with 1.5 mL of 3 N aqueous HCl. The precipitate was
triturated, and the mixture was filtered and washed with 1.times.2
mL water to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 12.05 (s, 1H), 7.18 (t,
J=7.8 Hz, 1H), 6.75 (dd, J=7.8, 6.1 Hz, 2H), 3.82 (dd, J=9.1, 6.3
Hz, 1H), 3.69 (s, 3H), 2.22 (dd, J=12.7, 9.1 Hz, 1H), 1.95 (dd,
J=12.7, 6.3 Hz, 1H), 1.23 (s, 3H), 1.13 (s, 3H). MS (APCI+) m/z 221
(M+H.sup.+).
Example I-149E
7-methoxy-3,3-dimethyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-1--
carboxamide
[1321] A mixture of
7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid (70
mg, 0.318 mmol) from Example I-149D, N,N-dimethylpyridin-4-amine
(51 mg, 0.417 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (160 mg, 0.835 mmol) in DMA (dimethylacetamide, 1
mL) was stirred at room temperature for 20 minutes. To the mixture
was added naphthalene-1-sulfonamide (65.9 mg, 0.318 mmol). The
reaction mixture was stirred at room temperature overnight. The
reaction mixture was acidified with 1.0 mL of 1 N aqueous HCl. The
reaction was diluted with dichloromethane and put through an
aqueous/organic extractor tube. The volatiles were removed in vacuo
and the resulting solution was diluted with methanol and purified
by reverse-phase preparative HPLC on a Phenomenex.RTM. Luna.RTM.
C8(2) 5 .mu.m 100 .ANG. AXIA.TM. column (30 mm.times.150 mm). A
gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water
(B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A,
0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A,
10.0-12.0 minutes linear gradient 95-10% A) to provide the title
compound. .sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 10.02 (s,
1H), 8.50 (dd, J=7.4, 1.2 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.07 (d,
J=8.2 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H),
7.55-7.42 (m, 2H), 7.29 (t, J=7.9 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H),
6.74 (d, J=7.6 Hz, 1H), 3.99 (s, 3H), 3.90 (dd, J=9.2, 2.4 Hz, 1H),
2.41 (dd, J=13.2, 2.3 Hz, 1H), 1.90 (dd, J=13.2, 9.2 Hz, 1H), 1.18
(s, 3H), 0.82 (s, 3H). MS (APCI+) m/z 410 (M+H.sup.+).
Example I-151
(1R)-4-cyclobutyl-7-methoxy-N-(pyrazolo[1,5-a]pyridine-4-sulfonyl)-2,3-dih-
ydro-1H-indene-1-carboxamide
[1322] Into a 4 mL vial was added
4-cyclobutyl-7-methoxy-2,3-dihydro-1H-indene-1-carboxylic acid
(56.8 mg, 0.230 mmol),
N.sup.1-(ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diamin-
e hydrochloride (88 mg, 0.461 mmol), and
N,N-dimethylpyridin-4-amine (31.0 mg, 0.254 mmol) in
dichloromethane (1 mL). Pyrazolo[1,5-a]pyridine-4-sulfonamide
(Example I-135B, 50 mg, 0.254 mmol) was added. The reaction was
stirred for 2 hours at room temperature. The solvent was removed
under a stream of nitrogen and the residue was reconstituted in
methanol and purified using preparative reverse phase HPLC/MS
method TFA7 to provide the racemate of title compound. The racemate
was separated by chiral preparative SFC chromatography using a
WHELK-O (S,S), column size 21.times.250 mm, serial number 43170, 5
micron, using a concentration of 14.25 mg/mL in methanol at a flow
rate of 80 g/minutes at isocratic 30% methanol in CO.sub.2 and UV
monitoring at 220 nm to provide the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta.
ppm 8.99 (dt, J=7.2, 1.0 Hz, 1H), 8.27 (d, J=2.3 Hz, 1H), 7.89 (dd,
J=7.2, 1.0 Hz, 1H), 7.10 (t, J=7.1 Hz, 1H), 7.06-6.98 (m, 2H), 6.61
(d, J=8.4 Hz, 1H), 3.93 (dd, J=9.1, 5.7 Hz, 1H), 3.39 (p, J=9.0,
8.5 Hz, 1H), 3.22 (s, 3H), 2.80-2.62 (m, 2H), 2.32 2.11 (m, 3H),
2.04-1.68 (m, 5H). MS (APCI+) m/z 426.1 (M+H).sup.+.
Example I-152
7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-1-ca-
rboxamide
[1323] A mixture of
7-methoxy-3,3-dimethyl-2,3-dihydro-1H-indene-1-carboxylic acid from
Example I-149D (118 mg, 0.536 mmol), N,N-dimethylpyridin-4-amine
(82 mg, 0.671 mmol) and
N.sup.1-((ethylimino)methylene)-N.sup.3,N.sup.3-dimethylpropane-1,3-diami-
ne hydrochloride (209 mg, 1.090 mmol) in dichloromethane (2 mL) was
stirred at room temperature for 20 minutes. To the mixture was
added quinoline-5-sulfonamide (112 mg, 0.536 mmol). The reaction
was stirred at room temperature overnight. The crude reaction was
acidified with 1.0 mL of 1 N aqueous HCl. The reaction was diluted
with water and dichloromethane and put through an aqueous/organic
extractor tube. The volatiles were removed in vacuo and the
resulting solution was diluted with methanol and was purified by
reverse-phase preparative HPLC on a Phenomenex.RTM. Luna.RTM. C8(2)
5 .mu.m 100 .ANG. AXIA.TM. column (30 mm.times.150 mm). A gradient
of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was
used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0
minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0
minutes linear gradient 95-10% A) to provide crude title compound.
The material was triturated with methanol to provide the title
compound. .sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm 10.11 (s,
1H), 8.97 (dd, J=4.3, 1.6 Hz, 1H), 8.85 (ddd, J=8.8, 1.7, 0.9 Hz,
1H), 8.54 (dd, J=7.5, 1.2 Hz, 1H), 8.39 (dt, J=8.5, 1.1 Hz, 1H),
7.85 (dd, J=8.5, 7.4 Hz, 1H), 7.41 (dd, J=8.7, 4.3 Hz, 1H),
7.35-7.29 (m, 1H), 6.84 (dd, J=8.2, 0.8 Hz, 1H), 6.76 (dd, J=7.6,
0.8 Hz, 1H), 4.02 (s, 3H), 3.93 (dd, J=9.2, 2.3 Hz, 1H), 2.43 (dd,
J=13.2, 2.3 Hz, 1H), 1.92 (dd, J=13.2, 9.2 Hz, 1H), 1.20 (s, 3H),
0.81 (s, 3H). MS (APCI+) m/z 411 (M+H.sup.+).
Example I-153
(1S)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1324]
7-Methoxy-3,3-dimethyl-N-(quinolin-5-ylsulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide from Example I-152 (98 mg) was separated by
chiral preparative SFC chromatography using a ChiralCel.RTM. AD-H
column size 21.times.250 mm, 5 micron, serial Number:
ADHOSAQB001-210041, using a concentration 24.5 mg in methanol at a
flow rate of 59 g/minute CO.sub.2 and UV monitoring at 220 nm to
provide the title compound. .sup.1H NMR (500 MHz, Chloroform-d)
.delta. ppm 10.13 (s, 1H), 8.96 (dd, J=4.4, 1.6 Hz, 1H), 8.79 (ddd,
J=8.7, 1.5, 0.8 Hz, 1H), 8.54 (dd, J=7.4, 1.2 Hz, 1H), 8.37 (dt,
J=8.4, 1.1 Hz, 1H), 7.84 (dd, J=8.5, 7.4 Hz, 1H), 7.39 (dd, J=8.8,
4.2 Hz, 1H), 7.35-7.30 (m, 1H), 6.84 (dd, J=8.1, 0.8 Hz, 1H), 6.77
(dd, J=7.6, 0.8 Hz, 1H), 4.02 (s, 3H), 3.94 (dd, J=9.2, 2.3 Hz,
1H), 2.44 (dd, J=13.2, 2.4 Hz, 1H), 1.93 (dd, J=13.2, 9.2 Hz, 1H),
1.20 (s, 3H), 0.82 (s, 3H). MS (APCI+) m/z 411 (M+H.sup.+). R.sub.T
(chiral SFC)=3.4 minutes.
Example I-154
(1R)-7-methoxy-3,3-dimethyl-N-(quinoline-5-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1325]
7-Methoxy-3,3-dimethyl-N-(quinolin-5-ylsulfonyl)-2,3-dihydro-1H-ind-
ene-1-carboxamide from Example I-152 (98 mg) was separated by
chiral preparative SFC chromatography using a ChiralCel.RTM. AD-H
column size 21.times.250 mm, 5 micron, serial Number:
ADHOSAQB001-210041, using a concentration 24.5 mg in methanol at a
flow rate of 59 g/minute CO.sub.2 and UV monitoring at 220 nm to
provide the title compound. .sup.1H NMR (500 MHz, Chloroform-d)
.delta. .mu.m 10.10 (s, 1H), 8.95 (dd, J=4.2, 1.6 Hz, 1H), 8.77
(ddd, J=8.7, 1.6, 0.9 Hz, 1H), 8.54 (dd, J=7.4, 1.2 Hz, 1H), 8.36
(dt, J=8.5, 1.1 Hz, 1H), 7.83 (dd, J=8.5, 7.4 Hz, 1H), 7.38 (dd,
J=8.8, 4.2 Hz, 1H), 7.32 (ddd, J=8.2, 7.5, 0.6 Hz, 1H), 6.85 (dd,
J=8.2, 0.8 Hz, 1H), 6.77 (dd, J=7.6, 0.7 Hz, 1H), 4.03 (s, 3H),
3.94 (dd, J=9.2, 2.2 Hz, 1H), 2.44 (dd, J=13.2, 2.3 Hz, 1H), 1.93
(dd, J=13.2, 9.3 Hz, 1H), 1.21 (s, 3H), 0.82 (s, 3H). MS (APCI+)
m/z 411 (M+H.sup.+). R.sub.T (chiral SFC)=4.2 minutes.
Example I-155
(7R)-2-cyclobutyl-5-methoxy-N-(3-methylimidazo[1,2-a]pyridine-5-sulfonyl)b-
icyclo[4.2.0]octa-1,3,5-triene-7-carboxamide
[1326] The racemate of the title compound was prepared and isolated
using the same procedure as described in Example I-132,
substituting Example I-100A for 1-methyl-1H-indazole-7-sulfonamide.
The material was separated by chiral preparative SFC chromatography
using a ChiralPak AD-H, column size 21.times.250 mm, serial number
ADHOSAQB001-210041, 5 micron, using a concentration of 20 mg/mL in
methanol at a flow rate of 49 g/minute CO.sub.2 and UV monitoring
at 220 nm to provide the title compound. .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6:D.sub.2O=9:1 (v/v)) .delta. ppm 8.03
(dd, J=7.3, 1.3 Hz, 1H), 7.99 7.91 (m, 2H), 7.84 (dd, J=8.9, 7.3
Hz, 1H), 6.89 (d, J=8.6 Hz, 1H), 6.54 (d, J=8.5 Hz, 1H), 4.06 (dd,
J=5.7, 2.5 Hz, 1H), 3.56 (s, 3H), 3.41-3.25 (m, 2H), 2.98 (dd,
J=13.6, 2.5 Hz, 1H), 2.89 (s, 3H), 2.25-2.12 (m, 2H), 2.11-1.86 (m,
3H), 1.83-1.72 (m, 1H). MS (APCI+) m/z 426.1 (M+H).sup.+.
Example 11-3
4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carboxamid-
e
[1327] 4-Chloroindane-1-carboxylic acid (CAS#66041-25-6, 50 mg,
0.26 mmol) and 1,1'-carbonyldiimidazole (CAS#530-62-1, 68 mg, 0.42
mmol) were combined in anhydrous tetrahydrofuran (1 mL), heated at
50.degree. C. and stirred for 30 minutes. The mixture was cooled to
room temperature, 2-methylbenzenesulfonamide (CAS#88-19-7, 46 mg,
0.27 mmol) and DBU
(2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine, CAS#6674-22-2,
42 .mu.L, 0.29 mmol) were added, and the resultant mixture was
stirred at room temperature for 4 hours. The reaction mixture was
concentrated under reduced pressure and the resultant residue was
taken up in acetonitrile and filtered. The crude material was
purified by reverse-phase HPLC (method 1) to provide the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.59 (s, 1H), 7.95-7.92 (m, 1H), 7.59-7.54 (m, 1H), 7.43-7.39
(m, 2H), 7.29-7.23 (m, 1H), 7.23-7.20 (m, 2H), 4.13 (dd, J=5.5, 8.5
Hz, 1H), 2.97-2.80 (m, 2H), 2.63 (s, 3H), 2.32-2.08 (m, 2H). MS
(ESI+) m/z 350 (M+H).sup.+.
Example 11-29
(1S)-4-chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-carbo-
xamide
[1328]
4-Chloro-N-(2-methylbenzene-1-sulfonyl)-2,3-dihydro-1H-indene-1-car-
boxamide (Example II-3, 52 mg 0.15 mmol) was dissolved in methanol
(1.5 mL). The isomers were separated by chiral SFC (injected 250
.mu.L (8.7 mg per injection), and eluted isocratically with
methanol (0.1% diethylamine), 15% and 85% carbon dioxide, at 100 mL
per minute (120 bar, 40.degree. C.) over YMC amylose-C stationary
phase). The faster eluting isomer eluted at 3.4 minutes and the
slower eluting isomer, the title compound, eluted at 4.4 minutes.
The process was repeated seven times to complete the purification.
The fractions that contained the title compound were combined,
concentrated and assessed for enantiomeric excess. The title
compound was isolated as the diethylamine salt, ee=96.2%, 100%.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 8.15
(1H, s), 7.78-7.75 (1H, m), 7.29-7.22 (2H, m), 7.19-7.09 (4H, m),
3.80-3.72 (1H, m), 2.96-2.89 (5H, m), 2.34-2.20 (1H, m), 2.12-2.02
(1H, m), 1.16 (dd, J=7.3, 7.3 Hz, 6H). MS (ESI+) m/z 350
(M+H).sup.+.
Example II-36
N-(2-methylbenzene-1-sulfonyl)-4-phenyl-2,3-dihydro-1H-indene-1-carboxamid-
e
Example II-36A
4-bromoindane-1-carbonitrile
[1329] To a stirred suspension of
1-((isocyanomethyl)sulfonyl)-4-methylbenzene (CAS#36635-61-7, 7.56
g, 38.7 mmol) in dry 1,2-dimethoxyethane (115 mL) cooled to
0.degree. C. under a stream of nitrogen with an ice bath was added
potassium tert-butoxide (CAS#865-47-4, 7.56 g, 70.0 mmol) in small
portions over 15 minutes. tert-Butanol (45 mL) was added. The
stirring was continued with cooling for another 15 minutes and
4-bromoindan-1-one was added (CAS#15115-60-3, 7.28 g, 34.7 mmol).
After 20 minutes, the ice bath was removed. After 6 hours, water
was added, and the mixture was extracted with ethyl acetate (three
times). The combined organic layers were dried (MgSO.sub.4),
filtered, concentrated under reduced pressure onto silica, and
purified by flash chromatography using Biotage.RTM. SNAP 100 g
silica column, eluting with 0-100% ethyl acetate in iso-hexane to
provide the title compound. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 7.45 (d, J=8.0 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.15
(dd, J=7.7, 7.7 Hz, 1H), 4.21 (t, J=8.4 Hz, 1H), 3.14 (ddd, J=4.1,
8.9, 16.6 Hz, 1H), 3.02-2.92 (m, 1H), 2.65-2.56 (m, 1H), 2.40 (ddd,
J=8.3, 13.0, 17.0 Hz, 1H).
Example II-36B
4-bromoindane-1-carboxamide
[1330] To a stirred solution of 4-bromoindane-1-carbonitrile (4.7
g, 21.2 mmol) in methanol (50 mL) was added water (50 mL) and
concentrated aqueous sodium hydroxide (50 mL). The resultant
suspension was stirred and heated to 80.degree. C. for 24 hours.
The reaction mixture was concentrated under reduced pressure and
extracted with dichloromethane (twice). The combined organic phases
were concentrated under reduced pressure to provide the crude title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 7.38 (d, J=7.5 Hz, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.06 (dd,
J=7.7, 7.7 Hz, 1H), 3.89-3.83 (m, 1H), 2.98-2.71 (m, 2H), 2.35-2.06
(m, 2H).
Example II-36C
4-bromoindane-1-carboxylic acid
[1331] Concentrated sulfuric acid (70 mL) was diluted with water
(30 mL) and at room temperature sodium nitrite (CAS#7632-00-0, 2.2
g, 32 mmol) was added followed by 4-bromoindane-1-carboxamide (5.1
g, 21.2 mmol). After 3 hours, the mixture was diluted with water
and extracted with ethyl acetate (three times). The combined
organic layers were dried (MgSO.sub.4), filtered and concentrated
under reduced pressure to provide the title compound. .sup.1H NMR
(400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 7.43 (d, J=7.9
Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.15 (dd, J=7.7, 7.7 Hz, 1H), 4.12
(dd, J=7.5, 7.5 Hz, 1H), 3.02-2.81 (m, 2H), 2.29 (q, J=7.5 Hz,
2H).
Example II-36D
4-phenylindane-1-carboxylic acid
[1332] A mixture of phenylboronic acid (CAS#98-80-6, 62 mg 0.51
mmol) and 4-bromoindane-1-carboxylic acid (100 mg, 0.41 mmol) in
1,2-dimethoxyethane (3 mL) and an aqueous solution of 1 M sodium
bicarbonate solution (1 mL) was deoxygenated under N.sub.2 flow for
5 minutes. Palladium(II)bis(triphenylphosphine) dichloride
(CAS#13965-03-2, 20 mg, 0.028 mmol) was added and deoxygenation was
continued for another 2 minutes. The reaction vessel was sealed and
was stirred at 100.degree. C. for 18 hours. The reaction mixture
was concentrated under reduced pressure, partitioned between ethyl
acetate and water, acidified to pH 2 with dilute aqueous HCl, and
extracted with ethyl acetate (three times). The combined organic
layers were dried (MgSO.sub.4), filtered and concentrated under
reduced pressure to provide the crude title compound. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. ppm 8.26-8.23 (m, 1H), 7.70-7.24 (m,
7H), 4.17-4.09 (m, 1H), 3.22-3.13 (m, 1H), 3.01-2.91 (m, 1H),
2.48-2.28 (m, 2H).
Example II-36E
N-(2-methylbenzene-1-sulfonyl)-4-phenyl-2,3-dihydro-1H-indene-1-carboxamid-
e
[1333] A solution of 4-phenylindane-1-carboxylic acid (110 mg, 0.46
mmol), DMAP (4-dimethylaminopyridine) (CAS#1122-58-3, 57 mg, 0.46
mmol) and 2-methylbenzenesulfonamide (CAS#88-19-7, 79 mg, 0.46
mmol) was prepared in dichloromethane (1 mL).
N-Ethyl-N-(3-dimethylaminopropyl)carbodiimide hydrochloride/EDC
(CAS#25952-53-8, 88 mg, 0.46 mmol) was added. The reaction was
stirred at room temperature for 18 hours, poured over a 10 g SCX
cartridge and eluted with dichloromethane and dichloromethane with
10% methanol (v/v). Fractions containing the title compound were
combined and concentrated. The crude material was purified by
reversed-phase HPLC (method 2) to provide the title compound.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.31-8.27 (m, 1H),
8.18 (dd, J=1.2, 8.0 Hz, 1H), 7.55-7.50 (m, 1H), 7.43-7.29 (m, 9H),
7.18 (dd, J=4.3, 4.3 Hz, 1H), 4.02 (dd, J=6.2, 8.6 Hz, 1H),
3.13-3.04 (m, 1H), 2.99-2.90 (m, 1H), 2.59 (s, 3H), 2.45-2.35 (m,
1H), 2.29-2.19 (m, 1H). MS (ESI+) m/z 392 (M+H).sup.+.
Example II-47
4-chloro-N-(naphthalene-1-sulfonyl)-1-[(pyrrolidin-1-yl)methyl]-2,3-dihydr-
o-1H-indene-1-carboxamide
[1334] A solution of pyrrolidine (19 .mu.L, 0.23 mmol), 37%
formalin (34 .mu.L, 0.46 mmol) and acetic acid (30 .mu.L) in
methanol (300 .mu.L) was added to crude Example I-8 (58 mg,
<0.15 mmol) with a methanol (150 .mu.L) rinse. After Example I-8
dissolved, the reaction mixture was heated at 60.degree. C. for 11
hours, additional 37% formalin (34 .mu.L, 0.46 mmol) was added and
heating at 60.degree. C. was continued another 20 hours before the
reaction mixture was brought to room temperature, concentrated and
chromatographed on silica (0 to 15% methanol/ethyl acetate) to
provide the title compound. .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm 8.60 (d, J=8.4 Hz, 1H), 8.03 (dd,
J=7.3, 1.3 Hz, 1H), 7.97 (d, J=8.2 Hz, 1H), 7.93-7.90 (m, 1H),
7.53-7.42 (m, 3H), 7.22 (dd, J=6.2, 2.7 Hz, 1H), 7.08-7.03 (m, 2H),
3.77 (d, J=12.9 Hz, 1H), 3.19 (d, J=12.9 Hz, 1H), 3.13-2.85 (m,
6H), 2.65 (ddd, J=13.2, 8.5, 5.0 Hz, 1H), 2.01 (ddd, J=12.8, 8.5,
6.7 Hz, 1H), 1.78-1.64 (m, 4H). MS (ESI+) m/z 469 (M+H).sup.+.
Example II-80
4-chloro-N-(3,4-dihydroquinoline-1(2H)-sulfonyl)-1-ethyl-2,3-dihydro-1H-in-
dene-1-carboxamide
[1335] To a solution of Example I-17A (27 mg, 0.12 mmol), EDAC
(1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 46
mg, 0.24 mmol) and DMAP (4-dimethylaminopyridine) (16 mg, 0.13
mmol) in anhydrous dichloromethane (300 .mu.L) was added
3,4-dihydroquinoline-1(2H)-sulfonamide (30 mg, 0.14 mmol). The
solution was stirred overnight at room temperature and was placed
directly onto silica with a drop of acetic acid in CHCl.sub.3 for
chromatography (100% CHCl.sub.3) to provide the title compound.
.sup.1H NMR (501 MHz, CD.sub.2Cl.sub.2) .delta. ppm 7.71 (bs, 1H),
7.43-7.40 (m, 1H), 7.25 (dd, J=8.0, 0.9 Hz, 1H), 7.16-7.13 (m, 1H),
7.12-7.03 (m, 3H), 6.78-6.75 (m, 1H), 4.02-3.92 (m, 2H), 2.85 (ddd,
J=16.9, 8.8, 5.6 Hz, 1H), 2.75-2.68 (m, 3H), 2.24 (ddd, J=13.3,
8.7, 5.5 Hz, 1H), 2.05-1.95 (m, 3H), 1.80 (dq, J=13.9, 7.4 Hz, 1H),
1.73 (dq, J=13.9, 7.4 Hz, 1H), 0.65 (t, J=7.4 Hz, 3H). MS (ESI+)
m/z=419 (M+H).sup.+.
Example II-81
4-chloro-1-(hydroxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide
[1336] A solution of the Example I-8 (58 mg, 0.15 mmol) in
anhydrous DMI (1,3-dimethyl-2-imidazolidinone) (50 .mu.L) and
anhydrous tetrahydrofuran (250 .mu.L) was added slowly dropwise to
1 M LiHMDS (lithium hexamethyldisilazide) in tetrahydrofuran (330
.mu.L) under nitrogen. The mixture was cooled to 0.degree. C. After
stirring cold for 20 minutes, it was removed from the bath, and
added dropwise to paraformaldehyde (14 mg, .about.0.47 mmol) under
nitrogen that had been cooled with a -20.degree. C. bath, followed
by a tetrahydrofuran (100 .mu.L) rinse. The resulting suspension
was stirred below -15.degree. C. for 20 minutes, removed from the
bath, and stirred at room temperature two weeks. The reaction
mixture was applied directly to silica for chromatography (40 to
100% methyl tert-butyl ether/heptane then 5 to 20%
CH.sub.3CN/methyl tert-butyl ether) to give the impure product,
which was repurified by reverse-phase HPLC [Waters XBridge.TM. C18
5 .mu.m OBD column, 30.times.100 mm, flow rate 40 mL/minute, 20 to
80% gradient of acetonitrile in 0.1% aqueous TFA] to give the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 12.08 (bs, 1H), 8.59-8.55 (m, 1H), 8.30-8.26 (m, 2H), 8.11-8.08
(m, 1H), 7.73-7.64 (m, 3H), 7.24-7.19 (m, 1H), 7.06-7.04 (m, 2H),
3.70 (d, J=10.8 Hz, 1H), 3.62 (d, J=10.8 Hz, 1H), 2.80 (ddd,
J=16.4, 8.7, 6.9 Hz, 1H), 2.70 (ddd, J=16.4, 9.1, 4.7 Hz, 1H), 2.23
(ddd, J=13.4, 9.1, 6.9 Hz, 1H), 2.07 (ddd, J=13.4, 8.7, 4.7 Hz,
1H), 2.07 (s, 1H). MS (ESI+) m/z=416 (M+H).sup.+.
Example II-115
8-methoxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene-1-carbo-
xamide
[1337] To a solution of Example I-70D (25 mg, 0.12 mmol), EDAC
(1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride, 46
mg, 0.24 mmol) and DMAP (4-dimethylaminopyridine) (16 mg, 0.13
mmol) in anhydrous dichloromethane (400 .mu.L) was added
naphthalene-1-sulfonamide (30 mg, 0.14 mmol). The solution was
stirred at room temperature overnight and was purified by
reverse-phase HPLC [Waters XBridge.TM. C18 5 .mu.m OBD column,
30.times.100 mm, flow rate 40 mL/minute, using a 20 to 80% gradient
of acetonitrile in 0.1% aqueous TFA] to give the title compound.
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm 12.44
(s, 1H), 8.70 (d, J=8.6 Hz, 1H), 8.28 (d, J=8.2 Hz, 1H), 8.24 (dd,
J=7.4, 1.2 Hz, 1H), 8.15-8.12 (m, 1H), 7.81 (ddd, J=8.6, 6.8, 1.4
Hz, 1H), 7.71 (ddd, J=8.2, 6.8, 1.1 Hz, 1H), 7.66 (dd, J=8.2, 7.4
Hz, 1H), 7.00 (dd, J=8.0, 7.6 Hz, 1H), 6.59 (d, J=7.6 Hz, 1H), 6.50
(d, J=8.0 Hz, 1H), 3.69-3.65 (m, 1H), 2.91 (s, 3H), 2.56-2.51 (m,
2H), 1.88-1.79 (m, 1H), 1.71-1.62 (m, 1H), 1.47-1.33 (m, 2H). MS
(ESI+) m/z=396 (M+H).sup.+.
Example II-128
5-chloro-8-hydroxy-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalen-
e-1-carboxamide
[1338] To a solution of Example I-70 (192 mg, 0.44 mmol) in
anhydrous dichloromethane (4 mL) at -15.degree. C. under nitrogen
was added dropwise 1 M BBr.sub.3 in CHCl.sub.2 (1.3 mL, 1.3 mmol).
After two hours, the cold bath was removed and the reaction mixture
was stirred at room temperature overnight. The reaction mixture was
cooled with an ice bath and quenched first with methanol (200
.mu.L) and then with 1 M aqueous KH.sub.2PO.sub.4 (1 mL). Ethyl
acetate and heptane were added and the aqueous phase was separated
and extracted with ethyl acetate. The combined organic phases were
dried (Na.sub.2SO.sub.4), filtered and concentrated to give the
title compound. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 9.04
(bs, 1H), 8.51 (dd, J=7.4, 1.2 Hz, 1H), 8.40-8.36 (m, 1H), 8.12 (d,
J=8.2 Hz, 1H), 7.98-7.94 (m, 1H), 7.64-7.56 (m, 3H), 7.16-7.11 (m,
1H), 6.52 (d, J=8.5 Hz, 1H), 3.75-3.71 (m, 1H), 2.72-2.62 (m, 1H),
2.57-2.46 (m, 1H), 2.03? (m, 1H), 1.69-1.55 (m, 3H). MS (ESI+) m/z
416 (M+H).sup.+.
Example III-111
4-chloro-N-(naphthalene-1-sulfonyl)-1-[2-(pyrrolidin-1-yl)ethyl]-2,3-dihyd-
ro-1H-indene-1-carboxamide
[1339] Example I-16A (29 mg, .ltoreq.60 .mu.mol) was dissolved into
tetrahydrofuran (300 .mu.L), treated with two drops of 2 M aqueous
HCl, stirred at room temperature for 30 minutes and concentrated.
The residue was dissolved into buffer (300 .mu.L) (prepared from
3.6 g sodium acetate trihydrate, 4.6 mL acetic acid and sufficient
methanol to bring the total volume to 100 mL) with pyrrolidine (7
.mu.L, 84 .mu.mol), then treated with sodium cyanoborohydride (6
mg, 95 .mu.mol) and stirred at room temperature overnight. The
reaction mixture was diluted with additional methanol and purified
by reverse-phase HPLC [Waters XBridge.TM. C18 5 .mu.m OBD column,
30.times.100 mm, flow rate 40 mL/minute, 5-70% gradient of
acetonitrile in buffer (0.025 M aqueous ammonium bicarbonate,
adjusted to pH 10 with ammonium hydroxide)] to give the title
compound. .sup.1H NMR (501 MHz, CD.sub.2Cl.sub.2) .delta. ppm 8.81
(dd, J=8.7, 1.1 Hz, 1H), 8.26-8.24 (m, 1H), 7.96-7.93 (m, 1H),
7.92-7.89 (m, 1H), 7.63 (ddd, J=8.5, 6.8, 1.4 Hz, 1H), 7.56 (ddd,
J=8.0, 6.8, 1.2 Hz, 1H), 7.48 (dd, J=8.2, 7.3 Hz, 1H), 7.07 (dd,
J=7.4, 1.4 Hz, 1H), 6.89-6.86 (m, 1H), 6.86-6.82 (m, 1H), 3.5-3.1
(m, 4H), 3.00-2.96 (m, 2H), 2.91-2.84 (m, 1H), 2.80-2.70 (m, 2H),
2.24-2.16 (m, 4H), 2.11-1.96 (m, 2H), 1.84-1.77 (m, 1H). MS (ESI+)
m/z 483 (M+H).sup.+.
Example III-112
4-chloro-1-{2-[(2-methoxyethyl)(methyl)amino]ethyl}-N-(naphthalene-1-sulfo-
nyl)-2,3-dihydro-1H-indene-1-carboxamide
[1340] Example I-16A (29 mg, .ltoreq.60 .mu.mol) was dissolved into
tetrahydrofuran (300 .mu.L), treated with two drops of 2 M aqueous
HCl, stirred at room temperature for 20 minutes and concentrated.
The residue was dissolved into buffer (300 .mu.L) (prepared from
3.6 g sodium acetate trihydrate, 4.6 mL acetic acid and sufficient
methanol to bring the total volume to 100 mL) with
(2-methoxyethyl)methylamine (9 .mu.L, 83 .mu.mol), then treated
with sodium cyanoborohydride (6 mg, 95 .mu.mol) and stirred at room
temperature overnight. The reaction mixture was diluted with
additional methanol and purified by reverse-phase HPLC [Waters
XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm, flow rate 40
mL/minute, 5-70% gradient of acetonitrile in buffer (0.025 M
aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium
hydroxide)] to give the title compound. .sup.1H NMR (400 MHz,
CD.sub.2Cl.sub.2) .delta. ppm 8.79-8.75 (m, 1H), 8.27-8.23 (m, 1H),
7.97-7.93 (m, 1H), 7.91-7.88 (m, 1H), 7.62-7.52 (m, 2H), 7.49-7.44
(m, 1H), 7.07 (dd, J=6.7, 2.2 Hz, 1H), 6.88-6.81 (m, 2H), 3.76-3.69
(m, 2H), 3.31 (s, 3H), 3.24-3.19 (m, 2H), 3.13-3.05 (m, 1H),
2.97-2.63 (m, 7H?), 2.22-2.12 (m, 1H), 1.93 (ddd, J=15.5, 8.3, 3.4
Hz, 1H), 1.84 (ddd, J=12.7, 7.9, 4.4 Hz, 1H). MS (ESI+) m/z 501
(M+H).sup.+.
Example III-150
4-chloro-1-ethyl-N-methyl-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1341] To a solution of the acid Example I-17A (27 mg, 0.12 mmol),
EDAC (1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide
hydrochloride, 46 mg, 0.24 mmol) and DMAP (4-dimethylaminopyridine)
(16 mg, 0.13 mmol) in anhydrous dichloromethane (300 .mu.L) was
added N-methylnaphthalene-1-sulfonamide (31 mg, 0.14 mmol). The
solution was stirred overnight at room temperature, concentrated
and purified by reverse-phase HPLC [Waters XBridge.TM. C18 5 .mu.m
OBD column, 30.times.100 mm, flow rate 40 mL/minute, 20 to 90%
gradient of acetonitrile in 0.1% aqueous TFA] to give the title
compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta.
ppm 8.36-8.31 (m, 2H), 8.17-8.13 (m, 1H), 8.13-8.09 (m, 1H),
7.79-7.68 (m, 3H), 7.34-7.31 (m, 1H), 7.20-7.14 (m, 1H), 6.60 (d,
J=7.5 Hz, 1H), 3.12 (s, 3H), 3.08-2.93 (m, 2H), 2.44 (ddd, J=13.9,
10.1, 8.1 Hz, 1H), 2.05 (ddd, J=13.9, 8.5, 4.0 Hz, 1H), 1.66-1.51
(m, 2H), 0.29 (dd, J=7.3, 7.3 Hz, 3H). MS (ESI+) m/z 428
(M+H).sup.+.
Example III-151
4-chloro-1-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide
Example III-151A
1-(bromomethyl)-4-chloro-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-
-1-carboxamide
[1342] To a solution of 1 M LiHMDS (lithium hexamethyldisilazide)
in tetrahydrofuran (2.0 mL, 2.0 mmol) under nitrogen and cooled to
0.degree. C. was added dropwise a solution of
4-chloro-N-(naphthalen-1-ylsulfonyl)-2,3-dihydro-1H-indene-1-carboxamide
(Example I-8, 308 mg, 0.80 mmol) in tetrahydrofuran (2 mL) over 12
minutes. After the reaction mixture had been stirred cold another
15 minutes, dibromomethane (85 .mu.L, 1.2 mmol) was added dropwise,
the bath was removed and the reaction mixture was stirred at room
temperature overnight. The mixture was added to 1 M aqueous citric
acid (1.5 mL) with a methyl tert-butyl ether rinse. The aqueous
phase was separated and extracted with methyl tert-butyl ether and
the combined organic phases were dried (Na.sub.2SO.sub.4),
concentrated and filtered through silica (100% methyl tert-butyl
ether) to give the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.55-8.51 (m, 1H), 8.30-8.22 (m, 2H), 8.16
(d, J=8.2 Hz, 1H), 7.98 (dd, J=6.3, 3.2 Hz, 1H), 7.67-7.59 (m, 3H),
7.28-7.24 (m, 1H), 7.09-7.04 (m, 1H), 7.00 (d, J=7.6 Hz, 1H), 3.58
(d, J=10.6 Hz, 1H), 3.54 (d, J=10.6 Hz, 1H), 3.04-2.82 (m, 2H),
2.34 (ddd, J=14.0, 8.8, 6.0 Hz, 1H), 2.23 (ddd, J=14.0, 8.9, 6.1
Hz, 1H). MS (ESI+) m/z 478/480 (M+H).sup.+.
Example III-151B
4-chloro-1-(methoxymethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-inden-
e-1-carboxamide
[1343] Water (4 .mu.L, 0.22 mmol) was added to 1 M KHMDS (potassium
bis(trimethylsilyl)amide) in tetrahydrofuran (200 .mu.L, 0.2 mmol)
under nitrogen. To the resulting suspension was added a solution of
Example III-151A (29 mg, 61 .mu.mol) in dimethyl sulfoxide (150
.mu.L) and the mixture was stirred more than 70 minutes before
additional 1 M KHMDS in tetrahydrofuran (80 .mu.L, 0.08 mmol) was
added, followed by iodomethane (37.5 .mu.L, 0.60 mmol). The
reaction mixture was stirred vigorously overnight, quenched with
four drops of 1 M aqueous citric acid, and stirred 90 minutes. The
tetrahydrofuran was removed by evaporation and the remaining
suspension was diluted with acetonitrile, filtered through a PTFE
syringe filter and purified by reverse-phase HPLC [Waters
XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm, flow rate 40
mL/minute, 20 to 90% gradient of acetonitrile in buffer (0.025 M
aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium
hydroxide)] to give the title compound. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm 8.58 (d, J=8.5 Hz, 1H), 8.21-8.18 (m, 1H),
8.06 (d, J=8.2 Hz, 1H), 7.98-7.94 (m, 1H), 7.71-7.65 (m, 1H),
7.65-7.59 (m, 1H), 7.54-7.49 (m, 1H), 7.17 (d, J=8.0 Hz, 1H),
7.01-6.95 (m, 1H), 6.86 (d, J=7.5 Hz, 1H), 3.57 (s, 3H), 3.33 (d,
J=12.9 Hz, 1H), 3.08 (d, J=12.9 Hz, 1H), 3.06-2.97 (m, 1H), 2.90
(ddd, J=16.9, 8.7, 6.2 Hz, 1H), 2.50 (ddd, J=13.5, 9.1, 6.2 Hz,
1H), 2.21 (ddd, J=13.5, 8.8, 5.5 Hz, 1H). MS (ESI+) m/z 430
(M+H).sup.+.
Example III-155
4-chloro-1-(cyanomethyl)-N-(naphthalene-1-sulfonyl)-2,3-dihydro-1H-indene--
1-carboxamide
[1344] To a solution of 1 M LiHMDS (lithium
bis(trimethylsilyl)amide) in tetrahydrofuran (280 .mu.L, 0.28 mmol)
under nitrogen and cooled to 0.degree. C. was added dropwise a
solution of Example I-8 (44 mg, 0.11 mmol) in tetrahydrofuran (280
.mu.L) over 13 minutes. After the reaction mixture had been stirred
cold another 15 minutes, iodoacetonitrile (12.4 .mu.L, 0.17 mmol)
was added dropwise, the bath was removed and the reaction mixture
was stirred at room temperature for one day. The mixture was
quenched with 1 M aqueous citric acid (200 .mu.L) and extracted
several times with methyl tert-butyl ether. The combined organic
phases were dried (Na.sub.2SO.sub.4), filtered, concentrated and
purified by reverse-phase HPLC [Waters XBridge.TM. C18 5 .mu.m OBD
column, 30.times.100 mm, flow rate 40 mL/minute, 10 to 70% gradient
of acetonitrile in 0.1% aqueous TFA] to give the impure product
which was repurified by chromatography on silica (20 to 25%
(200:1:1 ethyl acetate/water/formic acid)/heptane) to give the
title compound. .sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6)
.delta. ppm 8.47-8.43 (m, 1H), 8.34-8.29 (m, 2H), 8.14-8.11 (m,
1H), 7.75-7.62 (m, 3H), 7.39-7.36 (m, 1H), 7.16-7.11 (m, 1H), 6.77
(d, J=7.3 Hz, 1H), 3.05-2.93 (m, 2H), 2.93-2.91 (m, 2H), 2.5-2.41
(m, 1H), 2.08-2.00 (m, 1H). MS (ESI+) m/z 442
(M+NH.sub.4).sup.+.
Example III-157
8-chloro-1-cyano-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide
Example III-157A
phenyl
8-chloro-1-cyano-1,2,3,4-tetrahydronaphthalene-1-carboxylate
[1345] To 1 M LiHMDS (lithium bis(trimethylsilyl)amide) in
tetrahydrofuran (1.3 mL, 1.3 mmol) under nitrogen and cooled to
0.degree. C. was added dropwise over seven minutes a solution of
Example I-2A (192 mg, 1.0 mmol) in anhydrous tetrahydrofuran (2
mL). The reaction mixture was stirred cold for 15 minutes and then
cannulated dropwise into a solution of phenyl chloroformate (190
.mu.L, 1.5 mmol) in tetrahydrofuran (3.0 mL) cooled to -78.degree.
C. After 15 minutes near -78.degree. C., the temperature was
permitted to rise to 0.degree. C. over 50 minutes. The bath was
removed. The reaction mixture was stirred 30 minutes, quenched with
trifluoroacetic acid (100 .mu.L) and concentrated. The residue was
partitioned between chloroform and water and the separated aqueous
phase was extracted with chloroform. The combined organic phases
were washed with dilute brine, dried (Na.sub.2SO.sub.4), filtered,
concentrated and chromatographed on silica (20 to 60%
CH.sub.2Cl.sub.2/heptane) to give the title compound. .sup.1H NMR
(500 MHz, CD.sub.2Cl.sub.2) .delta. ppm 7.45-7.40 (m, 2H), 7.37
(ddt, J=7.9, 1.4, 0.7 Hz, 1H), 7.33-7.28 (m, 2H), 7.21-7.18 (m,
1H), 7.17-7.14 (m, 2H), 2.97-2.94 (m, 2H), 2.84-2.79 (m, 1H), 2.43
(ddd, J=13.4, 11.9, 2.8 Hz, 1H), 2.17-2.10 (m, 1H), 2.07-1.98 (m,
1H). MS (ESI+) m/z 329 (M+NH.sub.4).sup.+.
Example III-157B
8-chloro-1-cyano-N-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydronaphthalene--
1-carboxamide
[1346] A solution of naphthalene-1-sulfonamide (63 mg, 0.30 mmol)
and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 45 .mu.L, 0.30 mmol)
in anhydrous N-methylmorpholine (1.0 mL) was added to the phenyl
ester (Example III-157A, 63 mg, 0.20 mmol) under nitrogen with an
N-methylmorpholine (300 .mu.L) rinse. The reaction mixture was
stirred at room temperature overnight, and heated at 60.degree. C.
for 30 minutes and at 100.degree. C. for two hours. Sodium
1,2,4-triazolide (18 mg, 0.2 mmol) was added and the reaction
mixture was heated again at 100.degree. C. for two hours, brought
to room temperature, concentrated and purified by reverse-phase
HPLC [Waters XBridge.TM. C18 5 .mu.m OBD column, 30.times.100 mm,
flow rate 40 mL/minute, 10 to 70% gradient of acetonitrile in 0.1%
aqueous TFA] to give the title compound. .sup.1H NMR (500 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm 8.61-8.55 (m, 1H),
8.29-8.24 (m, 2H), 8.12-8.08 (m, 1H), 7.71-7.63 (m, 3H), 7.39-7.29
(m, 1H), 7.23-7.18 (m, 2H), 2.92-2.73 (m, 2H), 2.27-2.19 (m, 1H),
2.03-1.77 (m, 2H), 1.61-1.51 (m, 1H). MS (ESI+) m/z 442
(M+NH.sub.4).sup.+.
TABLE-US-00002 Example N-(benzenesulfonyl)-4-chloro-1- II-1
methyl-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-1-methyl-N-(2- .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm II-2 methylbenzene-1-sulfonyl)-2,3- 8.20-8.17 (m, 1H),
7.73-7.67 (m, 1H), 7.59-7.54 (m, 1H),
dihydro-1H-indene-1-carboxamide 7.46-7.41 (m, 1H), 7.36-7.24 (m,
2H), 7.08-7.05 (m, 1H), 3.07-3.02 (m, 2H), 2.59-2.48 (m, 1H), 2.48
(s, 3H), 2.14-2.07 (m, 1H), 1.47 (s, 3H). MS (ESI+) m/z 434 (M +
H).sup.+. Example 4-chloro-N-(2-methylbenzene-1- .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.59 (s, II-3
sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 7.95-7.92 (m, 1H),
7.59-7.54 (m, 1H), carboxamide 7.43-7.39 (m, 2H), 7.29-7.23 (m,
1H), 7.23-7.20 (m, 2H), 4.13 (dd, J = 5.5, 8.5 Hz, 1H), 2.97-2.80
(m, 2H), 2.63 (s, 3H), 2.32-2.08 (m, 2H). MS (ESI+) m/z 350 (M +
H).sup.+. Example (1S)-6-chloro-1-methyl-N-(2- .sup.1H NMR (400
MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-4
methylbenzene-1-sulfonyl)-2,3- ppm 7.93 (dd, J = 7.9, 1.3 Hz, 1H),
7.58 (td, J = 7.5, dihydro-1H-indene-1-carboxamide 1.5 Hz, 1H),
7.46-7.36 (m, 2H), 7.30-7.12 (m, 3H), 2.91-2.70 (m, 2H), 2.52-2.42
(m, 4H), 2.03-1.91 (m, 1H), 1.42 (s, 3H). MS (APCI+) m/z 364.1 (M +
H).sup.+. Example (1R)-6-chloro-1-methyl-N-(2- .sup.1NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.03 (s, II-5
methylbenzene-1-sulfonyl)-2,3- 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.57
(dd, J = 7.2, 7.2 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.40
(dd, J = 7.7, 12.7 Hz, 2H), 7.23 (d, J = 3.5 Hz, 3H), 3.32 (s, 3H),
2.88-2.71 (m, 2H), 2.48-2.40 (m, 1H), 2.01-1.92 (m, 1H), 1.43 (s,
3H). MS (ESI+) m/z 364 (M + H).sup.+. Example
4-chloro-N-(2-chlorobenzene-1- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 12.93 (s, II-6 sulfonyl)-2,3-dihydro-1H-indene-1- 1H),
8.08 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 3.8 Hz, carboxamide 2H),
7.60-7.55 (m, 1H), 7.29-7.19 (m, 3H), 4.18 (dd, J = 5.7, 8.5 Hz,
1H), 2.93-2.85 (m, 2H), 2.35-2.24 (m, 1H), 2.19-2.09 (m, 1H). MS
(ESI+) m/z 370 (M + H).sup.+. Example
N-(2-methylbenzene-1-sulfonyl)- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-7
1,2,3,4-tetrahydronaphthalene-1- ppm 12.44 (s, 1H), 7.93 (dd, J =
7.9, 1.3 Hz, 1H), carboxamide 7.57 (td, J = 7.5, 1.4 Hz, 1H),
7.46-7.36 (m, 2H), 7.15-6.99 (m, 3H), 6.88-6.78 (m, 1H), 3.79 (t, J
= 6.5 Hz, 1H), 2.65-2.60 (m, 5H), 1.91 (ddt, J = 14.5, 6.1, 3.3 Hz,
1H), 1.84-1.69 (m, 2H), 1.59-1.54 (m, 1H). MS (APCI+) m/z 330.1 (M
+ H).sup.+. Example 5-methoxy-N-(2-methylbenzene-1- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-8
sulfonyl)-1,2,3,4- ppm 7.93 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 (td, J
= 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.35 (m, 2H),
7.04 (t, J = 8.0 Hz, carboxamide 1H), 6.78 (dd, J = 8.3, 1.1 Hz,
1H), 6.48-6.40 (m, 1H), 3.77 (d, J = 12.4 Hz, 1H), 3.73 (s, 3H),
2.63 (s, 3H), 2.48 (t, J = 6.4 Hz, 2H), 1.92-1.50 (m, 4H). MS
(APCI+) m/z 360.2 (M + H).sup.+. Example
5,6-dimethoxy-N-(2-methylbenzene- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-9
1-sulfonyl)-1,2,3,4- ppm 7.93 (dd, J = 8.0, 1.4 Hz, 1H), 7.59 (td,
J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.38 (m, 2H),
6.80 (d, J = 8.5 Hz, carboxamide 1H), 6.57 (dd, J = 8.4, 0.8 Hz,
1H), 3.79-3.70 (m, 4H), 3.64 (s, 3H), 2.63 (s, 3H), 2.57 (t, J =
6.5 Hz, 2H), 1.91-1.48 (m, 4H). MS (APCI+) m/z 390.1 (M + H).sup.+.
Example 8-chloro-N-(2-methylbenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-10 sulfonyl)-1,2,3,4-
ppm 7.91 (dd, J = 7.9, 1.4 Hz, 1H), 7.58 (td, J = 7.5,
tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.46-7.33 (m, 2H),
carboxamide 7.19-7.10 (m, 2H), 7.10-7.03 (m, 1H), 3.93 (t, J = 5.1
Hz, 1H), 2.75-2.60 (m, 5H), 2.02-1.89 (m, 2H), 1.72-1.60 (m, 1H),
1.52-1.37 (m, 1H). MS (APCI+) m/z 364.1 (M + H).sup.+. Example
N-(2-methylbenzene-1-sulfonyl)-2,3- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-11
dihydro-1H-indene-1-carboxamide ppm 7.97-7.88 (m, 1H), 7.58 (td, J
= 7.4, 1.4 Hz, 1H), 7.46-7.37 (m, 2H), 7.26-7.09 (m, 4H), 4.03 (dd,
J = 8.4, 5.7 Hz, 1H), 2.98-2.75 (m, 2H), 2.64 (s, 3H), 2.28-2.15
(m, 1H), 2.13-2.02 (m, 1H). MS (APCI+) m/z 316.2 (M + H).sup.+.
Example 6-fluoro-N-(2-methylbenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-12 sulfonyl)-1,2,3,4-
ppm 7.93 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 (td, J = 7.5,
tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.37 (m, 2H),
carboxamide 7.00-6.82 (m, 3H), 3.78 (t, J = 6.3 Hz, 1H), 2.72-2.60
(m, 5H), 1.98-1.74 (m, 2H), 1.74-1.52 (m, 2H). MS (APCI+) m/z 348.1
(M + H).sup.+. Example (1R)-5-methoxy-N-(2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-13
methylbenzene-1-sulfonyl)-1,2,3,4- ppm 7.93 (dd, J = 8.0, 1.4 Hz,
1H), 7.59 (td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H),
7.48-7.37 (m, 2H), 7.04 (t, J = 8.0 Hz, carboxamide 1H), 6.80-6.74
(m, 1H), 6.44 (d, J = 7.7 Hz, 1H), 3.80-3.75 (m, 1H), 3.73 (s, 3H),
2.63 (s, 3H), 2.48 (t, J = 6.5 Hz, 2H), 1.93-1.46 (m, 4H). MS
(APCI+) m/z 360.1 (M + H).sup.+. Example (1S)-N-(2-methylbenzene-1-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-14 sulfonyl)-1,2,3,4- ppm 7.94 (dd, J = 8.0, 1.4 Hz, 1H), 7.59
(td, J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.37 (m,
2H), carboxamide 7.19-6.98 (m, 3H), 6.87-6.75 (m, 1H), 3.79 (t, J =
6.4 Hz, 1H), 2.68-2.61 (m, 5H), 2.00-1.85 (m, 1H), 1.85-1.66 (m,
2H), 1.65-1.51 (m, 1H). MS (APCI+) m/z 330.2 (M + H).sup.+. Example
6,7-dimethoxy-N-(2-methylbenzene- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-15
1-sulfonyl)-1,2,3,4- ppm 7.95 (dd, J = 8.2, 1.3 Hz, 1H), 7.58 (td,
J = 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.42 (d, J = 7.7 Hz,
2H), 6.63 (s, carboxamide 1H), 6.33 (s, 1H), 3.72-3.66 (m, 4H),
3.56 (s, 3H), 2.64 (s, 3H), 2.61-2.54 (m, 2H), 1.95-1.68 (m, 3H),
1.61-1.46 (m, 1H). MS (APCI+) m/z 390.1 (M + H).sup.+. Example
4-methoxy-N-(2-methylbenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-16
sulfonyl)-2,3-dihydro-1H-indene-2- ppm 7.99-7.91 (m, 1H), 7.59 (td,
J = 7.5, 1.4 Hz, carboxamide 1H), 7.43 (t, J = 7.2 Hz, 2H), 7.12
(t, J = 7.8 Hz, 1H), 6.76 (dd, J = 13.2, 7.8 Hz, 2H), 3.75 (s, 3H),
3.40-3.25 (m, 1H), 3.20-2.99 (m, 2H), 2.92 (dd, J = 16.2, 6.8 Hz,
1H), 2.78 (dd, J = 16.3, 6.6 Hz, 1H), 2.62 (s, 3H). MS (APCI+) m/z
346.2 (M + H).sup.+. Example (1R)-N-(2-methylbenzene-1- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-17
sulfonyl)-1,2,3,4- ppm 7.94 (dd, J = 8.0, 1.3 Hz, 1H), 7.59 (td, J
= 7.5, tetrahydronaphthalene-1- 1.4 Hz, 1H), 7.48-7.37 (m, 2H),
carboxamide 7.19-6.98 (m, 3H), 6.87-6.75 (m, 1H), 3.79 (t, J = 6.4
Hz, 1H), 2.76-2.58 (m, 5H), 2.00-1.66 (m, 3H), 1.65-1.53 (m, 1H).
MS (APCI+) m/z 330.2 (M + H).sup.+. Example
(1S)-6-methoxy-1-methyl-N-(2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-18
methylbenzene-1-sulfonyl)-2,3- ppm 7.93 (dd, J = 8.0, 1.3 Hz, 1H),
7.57 (td, J = 7.5, dihydro-1H-indene-1-carboxamide 1.4 Hz, 1H),
7.45-7.35 (m, 2H), 7.19-7.07 (m, 1H), 6.82-6.73 (m, 2H), 3.71 (d, J
= 5.2 Hz, 3H), 2.79-2.71 (m, 2H), 2.52-2.47 (m, 4H), 1.98-1.84 (m,
1H), 1.41 (s, 3H). MS (APCI+) m/z 360.2 (M + H).sup.+. Example
7-chloro-1-methyl-N-(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O
= 9:1 (v/v)) .delta. II-19 methylbenzene-1-sulfonyl)-2,3- ppm 7.97
(d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.3 Hz,
dihydro-1H-indene-1-carboxamide 1H), 7.63-7.49 (m, 1H), 7.49-7.36
(m, 2H), 7.32-7.12 (m, 2H), 3.12-2.91 (m, 2H), 2.44-2.31 (m, 4H),
1.99-1.87 (m, 1H), 1.27 (s, 3H). MS (APCI+) m/z 364.1 (M +
H).sup.+. Example 4,5-difluoro-1-methyl-N-(2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-20
methylbenzene-1-sulfonyl)-2,3- ppm 7.93 (dd, J = 7.9, 1.3 Hz, 1H),
7.58 (td, J = 7.5, dihydro-1H-indene-1-carboxamide 1.4 Hz, 1H),
7.42 (ddd, J = 10.3, 6.2, 1.9 Hz, 2H), 7.29-7.17 (m, 1H), 6.98-6.89
(m, 1H), 3.02-2.80 (m, 2H), 2.51 (s, 4H), 2.12-1.98 (m, 1H), 1.39
(s, 3H). MS (APCI+) m/z 366.1 (M + H).sup.+. Example
1-methyl-N-(2-methylbenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-21
sulfonyl)-2,3-dihydro-1H-indene-1- ppm 7.92 (dd, J = 8.0, 1.3 Hz,
1H), 7.57 (td, J = 7.5, carboxamide 1.4 Hz, 1H), 7.48-7.35 (m, 2H),
7.28-7.10 (m, 4H), 3.01-2.75 (m, 2H), 2.53-2.43 (m, 4H), 1.98-1.86
(m, 1H), 1.39 (s, 3H). MS (APCI+) m/z 330.2 (M + H).sup.+. Example
1,5-dimethyl-N-(2-methylbenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-22
sulfonyl)-2,3-dihydro-1H-indene-1- ppm 7.91 (dd, J = 7.8, 1.3 Hz,
1H), 7.63-7.46 (m, carboxamide 1H), 7.45-7.35 (m, 2H), 7.09-6.95
(m, 3H), 2.91-2.70 (m, 2H), 2.53-2.34 (m, 4H), 2.26 (s, 3H),
1.95-1.83 (m, 1H), 1.36 (s, 3H). MS (APCI+) m/z 344.2 (M +
H).sup.+. Example 4-methoxy-N-(2-methylbenzene-1- .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.58 (s, II-23
sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 7.98 (d, J = 7.1 Hz, 1H),
7.64-7.59 (m, 1H), carboxamide 7.48-7.42 (m, 2H), 7.20 (dd, J =
7.8, 7.8 Hz, 1H), 6.87 (dd, J = 7.8, 16.4 Hz, 2H), 4.08 (dd, J =
5.7, 8.2 Hz, 1H), 3.80 (s, 3H), 2.90-2.71 (m, 2H), 2.69 (s, 3H),
2.28-2.11 (m, 2H). MS (ESI+) m/z 346 (M + H).sup.+. Example
N-(2-ethylbenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.62 (s, II-24
methoxy-2,3-dihydro-1H-indene-1- 1H), 7.98 (d, J = 8.1 Hz, 1H,),
7.66 (dd, J = 7.6, 7.6 Hz, carboxamide 1H,), 7.52 (d, J = 7.6 Hz,
1H,), 7.45 (dd, J = 7.5, 7.5 Hz, 1H,), 7.20 (dd, J = 7.8, 7.8 Hz,
1H,), 6.87 (dd, J = 8.0, 12.3 Hz, 2H), 4.07 (dd, J = 6.9, 6.9 Hz,
1H,), 3.80 (s, 3H), 3.18-3.03 (m, 2H), 2.90-2.72 (m, 2H), 2.26-2.12
(m, 2H), 1.30 (dd, J = 7.5, 7.5 Hz, 3H). MS (ESI+) m/z 360 (M +
H).sup.+. Example 4-chloro-N-(2-ethylbenzene-1- .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.69 (s, II-25
sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 7.98 (dd, J = 1.1, 8.0 Hz,
1H), 7.70-7.65 (m, carboxamide 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.45
(dd, J = 7.7, 7.7 Hz, 1H), 7.33-7.25 (m, 3H), 4.17 (dd, J = 5.7,
8.5 Hz, 1H), 3.16-3.00 (m, 2H), 2.99-2.87 (m, 2H), 2.36-2.14 (m,
2H), 1.30 (dd, J = 7.5, 7.5 Hz, 3H). MS (ESI+) m/z 364 (M +
H).sup.+. Example 4-chloro-N-(3-chlorobenzene-1- II-26
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-N-(4-chlorobenzene-1- II-27
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-N-(2-fluorobenzene-1- II-28
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
(1S)-4-chloro-N-(2-methylbenzene- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.15 (1H, II-29
1-sulfonyl)-2,3-dihydro-1H-indene- s), 7.78-7.75 (1H, m), 7.29-7.22
(2H, m), 1-carboxamide 7.19-7.09 (4H, m), 3.80-3.72 (1H, m),
2.96-2.89 (5H, m), 2.34-2.20 (1H, m), 2.12-2.02 (1H, m), 1.16 (dd,
J = 7.3, 7.3 Hz, 6H). MS (ESI+) m/z 350 (M + H).sup.+. Example
N-(2-chlorobenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.90 (s, II-30
methoxy-2,3-dihydro-1H-indene-1- 1H), 8.12 (d, J = 7.6 Hz, 1H),
7.73 (d, J = 3.5 Hz, carboxamide 2H), 7.64-7.58 (m, 1H), 7.20 (dd,
J = 8.0, 8.0 Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 8.3
Hz, 1H), 4.14-4.07 (m, 1H), 3.80 (s, 3H), 2.90-2.71 (m, 2H),
2.31-2.13 (m, 2H). MS (ESI-) m/z 364 (M - H).sup.-. Example
4-methoxy-N-(2-nitrobenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-31
sulfonyl)-2,3-dihydro-1H-indene-1- ppm 8.22-8.11 (m, 1H), 8.04-7.97
(m, 1H), carboxamide 7.96-7.81 (m, 2H), 7.14 (t, J = 7.8 Hz, 1H),
6.91 (d, J = 7.5 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H),
4.14-4.04 (m, 1H), 3.75 (s, 3H), 2.88-2.65 (m, 2H), 2.29-2.08 (m,
2H). MS (APCI+) m/z 377 (M + H).sup.+. Example
4-chloro-1-ethyl-N-(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 11.94 (s, II-32 methylbenzene-1-sulfonyl)-2,3- 1H), 7.93 (d, J
= 7.9 Hz, 1H), 7.56 (dd, J = 7.0, 7.0 Hz,
dihydro-1H-indene-1-carboxamide 1H), 7.40 (dd, J = 7.7, 17.4 Hz,
2H), 7.29 (d, J = 6.4 Hz, 2H), 7.27-7.21 (m, 1H), 2.85 (dd, J =
7.2, 7.2 Hz, 2H), 2.49-2.39 (m, 1H), 2.11-2.03 (m, 2H), 1.78-1.69
(m, 1H), 0.67 (dd, J = 7.3, 7.3 Hz, 3H). MS (ESI+) m/z 378 (M +
H).sup.+. Example 4-bromo-N-(2-methylbenzene-1- .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. ppm 8.24-8.24 (m, II-33
sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 8.15 (d, J = 7.9 Hz, 1H),
7.54-7.50 (m, 1H), carboxamide 7.43-7.35 (m, 2H), 7.31 (d, J = 7.7
Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 7.08 (dd, J = 7.7, 7.7 Hz, 1H),
4.05 (dd, J = 6.2, 8.8 Hz, 1H), 3.11-2.89 (m, 2H), 2.58 (s, 3H),
2.48-2.37 (m, 1H), 2.31-2.21 (m, 1H). MS (ESI-) m/z 392 (M -
H).sup.-. Example 4-(3,6-dihydro-2H-pyran-4-yl)-N-(2- .sup.1H NMR
400 MHz (DMSO-d.sub.6) .delta. ppm II-34
methylbenzene-1-sulfonyl)-2,3- 7.89-7.87 (m, 1H), 7.47 (t, j = 6.6
Hz, 1H), 7.35-7.30 (m, dihydro-1H-indene-1-carboxamide 2H),
7.17-7.01 (3H, m), 5.80 (m, 1H), 4.18-4.16 (2H, m), 3.90 (t, J =
7.3 Hz, 1H), 3.77 (t, J = 5.6 Hz, 2H), 2.98-2.76 (m, 2H), 2.58 (s,
3H), 2.36-2.31 (m, 2H), 2.13-2.06 (m, 2H). MS (ESI-) m/z 398.2 (M +
H).sup.-. Example 4-cyclobutyl-N-(2-methylbenzene-1- II-35
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
N-(2-methylbenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.31-8.27 (m, II-36 phenyl-2,3-dihydro-1H-indene-1-
1H), 8.18 (dd, J = 1.2, 8.0 Hz, 1H), 7.55-7.50 (m, carboxamide 1H),
7.43-7.29 (m, 9H), 7.18 (dd, J = 4.3, 4.3 Hz, 1H), 4.02 (dd, J =
6.2, 8.6 Hz, 1H), 3.13-3.04 (m, 1H), 2.99-2.90 (m, 1H), 2.59 (s,
3H), 2.45-2.35 (m, 1H), 2.29-2.19 (m, 1H). MS (ESI+) m/z 392 (M +
H).sup.+. Example 4-methoxy-N-[2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.82 (s, II-37
(trifluoromethyl)benzene-1- 1H), 8.31-8.27 (m, 1H), 8.04-8.00 (m,
1H), sulfonyl]-2,3-dihydro-1H-indene-1- 7.93-7.90 (m, 2H), 7.14
(dd, J = 7.8, 7.8 Hz, 1H), carboxamide 6.82 (dd, J = 7.9, 14.6 Hz,
2H), 4.06 (dd, J = 5.5, 8.3 Hz, 1H), 3.75 (s, 3H), 2.86-2.67 (m,
2H), 2.19-2.08 (m, 2H). MS (ESI+) m/z 400 (M + H).sup.+. Example
N-(2-fluorobenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.88 (s, II-38
methoxy-2,3-dihydro-1H-indene-1- 1H), 7.93-7.87 (m, 1H), 7.80-7.74
(m, 1H), carboxamide 7.51-7.40 (m, 2H), 7.15 (dd, J = 7.8, 7.8 Hz,
1H), 6.85 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 4.05 (dd,
J = 5.9, 8.2 Hz, 1H), 3.75 (s, 3H), 2.85-2.67 (m, 2H), 2.22-2.08
(m, 2H). MS (ESI+) m/z 350 (M + H).sup.+. Example
N-(2-bromobenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm II-39 methoxy-2,3-dihydro-1H-indene-1-
12.89-12.87 (m, 1H), 8.12-8.09 (m, 1H), 7.87 (dd, J = 1.8,
carboxamide 7.3 Hz, 1H), 7.64-7.55 (m, 2H), 7.15 (dd, J = 7.8, 7.8
Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 4.09
(dd, J = 5.8, 8.2 Hz, 1H), 3.75 (s, 3H), 2.85-2.67 (m, 2H),
2.27-2.07 (m, 2H). MS (ESI+) m/z 410 (M + H).sup.+. Example
N-(2-methylbenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.15 (d, J = 8.0 Hz, II-40
[(propan-2-yl)oxy]-2,3-dihydro-1H- 1H), 7.51 (dd, J = 7.5, 7.5 Hz,
1H), 7.37 (dd, J = 7.7, indene-1-carboxamide 7.7 Hz, 1H), 7.29 (d,
J = 7.5 Hz, 1H), 7.17 (dd, J = 7.9, 7.9 Hz, 1H), 6.76 (dd, J = 7.8,
11.7 Hz, 2H), 4.61-4.51 (m, 1H), 3.94 (dd, J = 5.5, 9.2 Hz, 1H),
2.99-2.81 (m, 2H), 2.52 (s, 3H), 2.47-2.37 (m, 1H), 2.28-2.18 (m,
1H), 1.35 (dd, J = 6.0, 10.3 Hz, 6H). MS (ESI-) m/z 372 (M -
H).sup.-. Example 7-bromo-4-methoxy-N-(2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.50 (s, II-41
methylbenzene-1-sulfonyl)-2,3- 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.55
(dd, J = 7.3, 7.3 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.39
(dd, J = 8.3, 8.3 Hz, 2H), 7.24 (d, J = 8.7 Hz, 1H), 6.78 (d, J =
8.7 Hz, 1H), 4.04 (dd, J = 3.6, 9.5 Hz, 1H), 3.75 (s, 3H),
2.87-2.80 (m, 2H), 2.65 (s, 3H), 2.45-2.33 (m, 1H), 1.98 (ddd, J =
4.8, 8.2, 17.1 Hz, 1H). MS (ESI-) m/z 422 (M - H).sup.-. Example
4-(2-methoxypyridin-4-yl)-N-(2- II-42
methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example 5-methoxy-N-(quinoline-8-sulfonyl)- .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm II-43 1,2,3,4-tetrahydronaphthalene-1-
8.79 (dd, J = 4.3, 1.8 Hz, 1H), 8.72 (s, 1H), 8.63 (dd, J = 7.4,
carboxamide 1.5 Hz, 1H), 8.28 (dd, J = 8.4, 1.8 Hz, 1H), 8.12 (dd,
J = 8.3, 1.5 Hz, 1H), 7.71 (dd, J = 8.2, 7.4 Hz, 1H), 7.54 (dd, J =
8.3, 4.2 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.81 (dd, J = 8.2, 1.1
Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 3.90 (s, 3H), 3.65 (t, J = 5.2
Hz, 1H), 2.65-2.42 (m, 2H), 2.09 (d, J = 5.6 Hz, 1H), 1.86-1.71 (m,
1H), 1.37-1.17 (m, 2H). MS (APCI+) m/z 397 (M + H).sup.+. Example
(1R)-5-methoxy-1-methyl-N- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-44
(naphthalene-1-sulfonyl)-2,3- 8.58 (dd, J = 8.3, 1.4 Hz, 1H),
8.31-8.23 (m, 2H), dihydro-1H-indene-1-carboxamide 8.15-8.05 (m,
1H), 7.77-7.64 (m, 3H), 6.96 (d, J = 8.3 Hz, 1H), 6.77-6.68 (m,
1H), 6.63 (dd, J = 8.4, 2.6 Hz, 1H), 3.69 (s, 3H), 2.80-2.55 (m,
2H), 2.40-2.29 (m, 1H), 1.86-1.75 (m, 1H), 1.29 (s, 3H). MS (APCI+)
m/z 396.0 (M + H).sup.+. Example (1S)-5-methoxy-1-methyl-N- .sup.1H
NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-45
(naphthalene-1-sulfonyl)-2,3- ppm 8.62-8.54 (m, 1H), 8.27 (dd, J =
7.5, 5.9 Hz, dihydro-1H-indene-1-carboxamide 2H), 8.19-8.03 (m,
1H), 7.78-7.64 (m, 3H), 6.96 (d, J = 8.4 Hz, 1H), 6.78-6.68 (m,
1H), 6.62 (dd, J = 8.5, 2.5 Hz, 1H), 3.69 (s, 3H), 2.83-2.55 (m,
2H), 2.44-2.29 (m, 1H), 1.92-1.74 (m, 1H), 1.29 (s, 3H). MS (APCI+)
m/z 396.0 (M + H).sup.+. Example (1S)-4-methoxy-1-methyl-N- .sup.1H
NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-46
(naphthalene-1-sulfonyl)-2,3- ppm 8.62-8.54 (m, 1H), 8.31-8.23 (m,
2H), dihydro-1H-indene-1-carboxamide 8.19-8.03 (m, 1H), 7.75-7.65
(m, 3H), 7.07 (t, J = 7.9 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 6.60
(d, J = 7.6 Hz, 1H), 3.73 (s, 3H), 2.76-2.55 (m, 2H), 2.48-2.29 (m,
1H), 1.92-1.74 (m, 1H), 1.28 (s, 3H). MS (APCI+) m/z 396.1 (M +
H).sup.+. Example 4-chloro-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 8.60 (d, J = 8.4 Hz, II-47
sulfonyl)-1-[(pyrrolidin-1- 1H), 8.03 (dd, J = 7.3, 1.3 Hz, 1H),
yl)methyl]-2,3-dihydro-1H-indene- 7.97 (d, J = 8.2 Hz, 1H),
7.93-7.90 (m, 1H), 1-carboxamide 7.53-7.42 (m, 3H), 7.22 (dd, J =
6.2, 2.7 Hz, 1H), 7.08-7.03 (m, 2H), 3.77 (d, J = 12.9 Hz, 1H),
3.19 (d, J = 12.9 Hz, 1H), 3.13-2.85 (m, 6H?), 2.65 (ddd, J = 13.2,
8.5, 5.0 Hz, 1H), 2.01 (ddd, J = 12.8, 8.5, 6.7 Hz, 1H), 1.78-1.64
(m, 4H). MS (ESI+) m/z 469 (M + H).sup.+. Example
4-methoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-48
sulfonyl)-2,3-dihydro-1H-indene-2- ppm 8.73-8.65 (m, 1H), 8.28 (dd,
J = 7.4, 1.3 Hz, carboxamide 1H), 8.22 (dt, J = 8.5, 1.1 Hz, 1H,
8.10-8.03 (m, 1H), 7.78-7.70 (m, 1H), 7.69-7.60 (m, 2H), 7.09-6.99
(m, 1H), 6.67 (d, J = 7.9 Hz, 2H), 3.70 (s, 3H), 3.35-3.18 (m, 1H),
2.99 (dt, J = 16.3, 8.0 Hz, 2H), 2.83 (dd, J = 16.0, 7.1 Hz, 1H),
2.72 (dd, J = 16.3, 6.7 Hz, 1H). MS (APCI+) m/z 382.1 (M +
H).sup.+. Example 1-methyl-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-49
sulfonyl)-6-(trifluoromethoxy)-2,3- ppm 8.62-8.55 (m, 1H),
8.31-8.23 (m, 2H), dihydro-1H-indene-1-carboxamide 8.10 (dd, J =
7.9, 1.6 Hz, 1H), 7.75-7.63 (m, 3H), 7.24 (d, J = 8.3 Hz, 1H),
7.15-7.07 (m, 1H), 7.07-7.02 (m, 1H), 2.84-2.72 (m, 1H), 2.66-2.54
(m, 1H), 2.45-2.33 (m, 1H), 1.98-1.86 (m, 1H), 1.37 (s, 3H). MS
(APCI+) m/z 450.0 (M + H).sup.+. Example
8-bromo-5-hydroxy-N-(naphthalene- .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. ppm 12.67 (s, II-50 1-sulfonyl)-1,2,3,4- 1H),
9.51 (bs, 1H), 8.68 (d, J = 8.7 Hz, 1H), tetrahydronaphthalene-1-
8.28 (d, J = 8.3 Hz, 1H), 8.24 (dd, J = 7.4, 1.2 Hz, 1H),
carboxamide 8.11 (d, J = 7.9 Hz, 1H), 7.75 (ddd, J = 8.5, 6.9, 1.4
Hz, 1H), 7.70-7.63 (m, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.53 (d, J =
8.6 Hz, 1H), 3.75 (dd, J = 6.3, 2.4 Hz, 1H), 2.52-2.44 (m, 1H),
2.22 (ddd, J = 17.5, 11.2, 6.1 Hz, 1H), 1.90 (d, J = 12.7 Hz, 1H),
1.73 (dddd, J = 13.5, 9.0, 6.5, 3.2 Hz, 1H), 1.49-1.40 (m, 1H),
1.10-0.97 (m, 1H). LC/MS (ESI+) m/z 460, 462 (M + H).sup.+. Example
5,6-dimethoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-51 sulfonyl)-1,2,3,4-
ppm 8.65 (dd, J = 8.5, 1.1 Hz, 1H), 8.34-8.24 (m,
tetrahydronaphthalene-1- 2H), 8.15 (d, J = 8.1 Hz, 1H), 7.87-7.78
(m, 1H), carboxamide 7.77-7.72 (m, 1H), 7.72-7.64 (m, 1H), 6.50 (d,
J = 8.6 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 3.70-3.65 (m, 4H), 3.59
(s, 3H), 2.53-2.38 (m, 2H), 1.77-1.54 (m, 2H), 1.52-1.34 (m, 2H).
MS (APCI+) m/z 426.0 (M + H).sup.+. Example
N-(naphthalene-1-sulfonyl)- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-52
2,3,7,8,9,10-hexahydronaphtho[1,2- ppm 8.65 (dd, J = 8.6, 1.0 Hz,
1H), 8.33-8.23 (m, b][1,4]dioxine-7-carboxamide 2H), 8.18-8.10 (m,
1H), 7.86-7.77 (m, 1H), 7.77-7.71 (m, 1H), 7.71-7.64 (m, 1H), 6.26
(d, J = 8.4 Hz, 1H), 6.10-6.03 (m, 1H), 4.19-4.13 (m, 2H),
4.13-4.04 (m, 2H), 3.62 (t, J = 6.2 Hz, 1H), 2.44-2.26 (m, 2H),
1.76-1.56 (m, 2H), 1.52-1.30 (m, 2H). MS (APCI+) m/z 424.0 (M +
H).sup.+. Example 6,7-dimethoxy-N-(naphthalene-1- .sup.1H NMR (400
MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-53
sulfonyl)-1,2,3,4- ppm 8.69-8.61 (m, 1H), 8.33-8.27 (m, 2H),
tetrahydronaphthalene-1- 8.16-8.10 (m, 1H), 7.85-7.77 (m, 1H),
carboxamide 7.73-7.67 (m, 2H), 6.54 (s, 1H), 5.95 (s, 1H), 3.72 (s,
3H), 3.66 (t, J = 6.3 Hz, 1H), 3.10 (s, 3H), 2.48 (t, J = 6.3 Hz,
2H), 1.86-1.73 (m, 1H), 1.73-1.61 (m, 1H), 1.60-1.48 (m, 1H),
1.46-1.34 (m, 1H). MS (APCI+) m/z 426.0 (M + H).sup.+. Example
4-chloro-N-(2-chlorobenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-54
sulfonyl)-1-ethyl-2,3-dihydro-1H- ppm 8.07 (dd, J = 7.9, 1.6 Hz,
1H), 7.73-7.60 (m, indene-1-carboxamide 2H), 7.63-7.53 (m, 1H),
7.34-7.19 (m, 3H), 2.94-2.77 (m, 2H), 2.53-2.41 (m, 1H), 2.15-2.00
(m, 2H), 1.84-1.70 (m, 1H), 0.71 (t, J = 7.4 Hz, 3H). MS (APCI+)
m/z 398.0 (M + H).sup.+. Example 4-chloro-1-ethyl-N-(2- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-55
methoxybenzene-1-sulfonyl)-2,3- ppm 7.81 (dd, J = 7.8, 1.7 Hz, 1H),
7.65 (t, J = 7.9 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.36-7.22
(m, 3H), 7.18 (d, J = 8.5 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 3.82
(s, 3H), 2.93-2.75 (m, 2H), 2.51-2.39 (m, 1H), 2.17-2.03 (m, 1H),
1.78-1.68 (m, 1H), 0.69 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 394.0
(M + H).sup.+. Example 4-chloro-1-ethyl-N-[5-methyl-2- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-56
(propan-2-yl)benzene-1-sulfonyl]- ppm 7.70 (d, J = 1.9 Hz, 1H),
7.47-7.39 (m, 1H), 2,3-dihydro-1H-indene-1- 7.38-7.20 (m, 4H), 2.89
(dt, J = 29.5, 7.0 Hz, carboxamide 3H), 2.51-2.39 (m, 4H),
2.16-1.98 (m, 2H), 1.80-1.66 (m, 1H), 1.18 (d, J = 6.9 Hz, 6H),
0.71 (d, J = 7.4 Hz, 3H). MS (APCI+) m/z 420.0 (M + H).sup.+.
Example 4-chloro-N-[3-chloro-2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-57
(methoxymethyl)benzene-1- ppm 7.98 (dd, J = 8.1, 1.2 Hz, 1H), 7.81
(dd, J = 8.1, sulfonyl]-1-ethyl-2,3-dihydro-1H- 1.2 Hz, 1H), 7.58
(t, J = 8.0 Hz, 1H), indene-1-carboxamide 7.33-7.18 (m, 3H), 4.73
(q, J = 10.5 Hz, 2H), 3.34 (s, 3H), 2.93-2.82 (m, 2H), 2.52-2.40
(m, 1H), 2.12-1.90 (m, 2H), 1.83-1.69 (m, 1H), 0.68 (t, J = 7.4 Hz,
3H). MS (APCI+) m/z 441.9 (M + H).sup.+. Example
4-chloro-1-ethyl-N-(2- .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O
= 9:1 (v/v)) .delta. II-58 fluorobenzene-1-sulfonyl)-2,3- ppm 7.89
(td, J = 7.7, 1.9 Hz, 1H),
7.81-7.71 (m, dihydro-1H-indene-1-carboxamide 1H), 7.48-7.37 (m,
2H), 7.33-7.20 (m, 3H), 2.94-2.77 (m, 2H), 2.50-2.38 (m, 1H),
2.15-2.01 (m, 2H), 1.81-1.67 (m, 1H), 0.69 (t, J = 7.3 Hz, 3H). MS
(APO+) m/z 382.0 (M + H).sup.+. Example 4-chloro-1-ethyl-N-(2-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-59 phenoxybenzene-1-sulfonyl)-2,3- ppm 7.95 (dd, J = 8.0, 1.7
Hz, 1H), 7.67-7.57 (m, dihydro-1H-indene-1-carboxamide 1H),
7.49-7.38 (m, 2H), 7.36-7.17 (m, 5H), 7.00-6.92 (m, 2H), 6.92-6.85
(m, 1H), 2.92-2.74 (m, 2H), 2.49-2.37 (m, 1H), 2.13-1.99 (m, 2H),
1.83-1.69 (m, 1H), 0.73 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 456.0
(M + H).sup.+. Example 4-chloro-1-ethyl-N-[2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-60
(trifluoromethoxy)benzene-1- ppm 8.02 (dd, J = 7.9, 1.7 Hz, 1H),
7.86-7.77 (m, sulfonyl]-2,3-dihydro-1H-indene-1- 1H), 7.63-7.50 (m,
2H), 7.33-7.19 (m, 3H), carboxamide 2.94-2.76 (m, 2H), 2.51-2.39
(m, 1H), 2.15-2.01 (m, 2H), 1.81-1.67 (m, 1H), 0.70 (t, J = 7.3 Hz,
3H). MS (APCI+) m/z 447.9 (M + H).sup.+. Example 4-chloro-N-[2-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-61 (difluoromethoxy)benzene-1- ppm 7.96 (dd, J = 8.0, 1.7 Hz,
1H), 7.74 (td, J = 7.8, sulfonyl]-1-ethyl-2,3-dihydro-1H- 1.8 Hz,
1H), 7.51-7.10 (m, 6H), indene-1-carboxamide 2.94-2.76 (m, 2H),
2.51-2.39 (m, 1H), 2.14-1.98 (m, 2H), 1.84-1.70 (m, 1H), 0.70 (t, J
= 7.3 Hz, 3H). MS (APCI+) m/z 430.0 (M + H).sup.+. Example
4-chloro-N-(2,5-dimethylbenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-62
sulfonyl)-1-ethyl-2,3-dihydro-1H- ppm 7.72-7.67 (m, 1H), 7.41-7.34
(m, 1H) indene-1-carboxamide 7.32-7.20 (m, 4H), 2.85 (t, J = 7.3
Hz, 2H), 2.44 (s, 4H), 2.32 (s, 3H), 2.15-1.99 (m, 2H), 1.80-1.66
(m, 1H), 1.05 (d, J = 6.1 Hz, 0H), 0.69 (t, J = 7.3 Hz, 3H). MS
(APCI+) m/z 392.1 (M + H).sup.+. Example 4-chloro-1-ethyl-N-[2-(2-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-63 methoxyethoxy)benzene-1- ppm 7.82 (dd, J = 7.9, 1.7 Hz, 1H),
7.63 (t, J = 8.1 Hz, sulfonyl]-2,3-dihydro-1H-indene-1- 1H),
7.36-7.15 (m, 4H), 7.11 (t, J = 7.6 Hz, carboxamide 1H), 4.19 (t, J
= 4.9 Hz, 2H), 3.75-3.68 (m, 2H), 3.32 (s, 3H), 2.86 (t, J = 7.3
Hz, 2H), 2.46 (dt, J = 14.2, 7.3 Hz, 1H), 2.14-1.96 (m, 2H),
1.81-1.70 (m, 1H), 0.68 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 438.0
(M + H).sup.+. Example N-([1,1'-biphenyl]-2-sulfonyl)-4- .sup.1H
NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-64
chloro-1-ethyl-2,3-dihydro-1H- ppm 8.02 (dd, J = 8.0, 1.4 Hz, 1H),
7.71-7.62 (m, indene-1-carboxamide 1H), 7.61-7.54 (m, 1H),
7.41-7.15 (m, 10H), 2.81 (t, J = 7.3 Hz, 2H), 2.25-2.20 (m, 1H),
1.99-1.86 (m, 1H), 1.71-1.62 (m, 1H), 0.68 (t, J = 7.3 Hz, 3H). MS
(APCI+) m/z 440.0 (M + H).sup.+. Example
4-chloro-1-ethyl-N-(naphthalene-2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-65
sulfonyl)-2,3-dihydro-1H-indene-1- ppm 8.47 (s, 1H), 8.17-8.00 (m,
3H), 7.80 (dd, J = 8.7, carboxamide 1.9 Hz, 1H), 7.76-7.65 (m, 2H),
7.31-7.18 (m, 3H), 2.82 (t, J = 7.3 Hz, 2H), 2.48-2.38 (m, 1H),
2.11-1.93 (m, 2H), 1.72-1.62 (m, 1H), 0.62 (t, J = 7.3 Hz, 3H). MS
(APCI+) m/z 414.0 (M + H).sup.+. Example
N-(benzenesulfonyl)-4-chloro-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-66
ethyl-2,3-dihydro-1H-indene-1- ppm 7.84 (d, J = 7.7 Hz, 2H),
7.71-7.64 (m, 1H), carboxamide 7.59 (t, J = 7.6 Hz, 2H), 7.32-7.19
(m, 3H), 2.84 (t, J = 7.3 Hz, 2H), 2.47-2.35 (m, 1H), 2.10-1.93 (m,
2H), 1.75-1.61 (m, 1H), 0.63 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z
364.1 (M + H).sup.+. Example N-(2,1,3-benzothiadiazole-4- .sup.1H
NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-67
sulfonyl)-4-chloro-1-ethyl-2,3- ppm 8.48-8.34 (m, 1H), 8.34-8.26
(m, 1H), dihydro-1H-indene-1-carboxamide 7.91 (t, J = 8.0 Hz, 1H),
7.26-7.22 (m, 1H), 7.21-7.12 (m, 2H), 2.79 (t, J = 7.4 Hz, 2H),
2.52-2.44 (m, 1H), 2.1-1 1.97 (m, 2H), 1.75 1.49 (m, 1H), 0.58 (t,
J = 7.3 Hz, 3H). MS (APCI+) m/z 422.0 (M + H).sup.+. Example
N-(naphthalene-1-sulfonyl)-2,3- .sup.1H NMR (501 MHz, DMSO-d.sub.6)
.delta. ppm 12.79 (s, II-68 dihydro-1H-indene-1-carboxamide 1H),
8.70 (dd, J = 8.6, 1.0 Hz, 1H), 8.27 (d, J = 7.5 Hz, 2H), 8.12 (dt,
J = 8.2, 1.0 Hz, 1H), 7.83 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.67
(t, J = 7.8 Hz, 1H), 7.12 (dt, J = 7.5, 1.0 Hz, 1H), 7.06 (tt, J =
7.5, 0.9 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.89 (td, J = 7.4, 1.2
Hz, 1H), 3.98 (dd, J = 8.3, 6.1 Hz, 1H), 2.86-2.68 (m, 2H),
2.16-2.08 (m, 1H), 1.98 (ddt, J = 12.8, 8.8, 6.4 Hz, 1H). MS
(APCI+) m/z 352 (M + H).sup.+. Example 4-chloro-N-(naphthalene-1-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-69 sulfonyl)-1-[(oxolan-3-yl)methyl]- ppm 8.76-8.67 (m, 1H),
8.07-8.00 (m, 1H), 2,3-dihydro-1H-indene-1- 7.92 (d, J = 8.2 Hz,
1H), 7.86 (d, J = 8.2 Hz, 1H), carboxamide 7.50-7.38 (m, 3H),
7.27-7.19 (m, 1H), 7.12-6.99 (m, 2H), 3.60-3.29 (m, 3H), 3.03-2.62
(m, 4H), 2.27-2.08 (m, 1H), 1.96-1.61 (m, 3H), 1.60-1.47 (m, 1H),
1.33-1.19 (m, 1H). MS (APCI+) m/z 469.9 (M + H).sup.+. Example
4-chloro-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-70
sulfonyl)-1-[2-(1H-pyrazol-1- ppm 8.79-8.72 (m, 1H), 8.03 (dd, J =
7.3, 1.3 Hz, yl)ethyl]-2,3-dihydro-1H-indene-1- 1H), 7.89 (d, J =
8.2 Hz, 1H), 7.87-7.81 (m, 1H), carboxamide 7.50-7.29 (m, 5H),
7.25-7.18 (m, 1H), 7.12-7.06 (m, 1H), 7.06-6.98 (m, 1H), 6.13 (t, J
= 2.1 Hz, 1H), 3.99-3.81 (m, 2H), 2.92-2.79 (m, 1H), 2.78-2.68 (m,
1H), 2.67-2.58 (m, 1H), 2.51-2.39 (m, 1H), 2.03-1.94 (m, 1H),
1.79-1.67 (m, 1H). MS (APCI+) m/z 479.9 (M + H).sup.+. Example
4-chloro-1-[(5-methoxypyridin-2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-71
yl)methyl]-N-(naphthalene-1- ppm 8.74 (d, J = 8.6 Hz, 1H), 8.04 (d,
J = 7.3 Hz, sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 7.98-7.93 (m,
1H), 7.90 (d, J = 8.2 Hz, 1H), carboxamide 7.86 (d, J = 8.2 Hz,
1H), 7.45 (t, J = 7.6 Hz, 2H), 7.40-7.31 (m, 1H), 7.26 (d, J = 7.3
Hz, 1H), 7.09-6.99 (m, 2H), 6.74 (d, J = 1.8 Hz, 2H), 3.72 (s, 3H),
3.44 (d, J = 13.3 Hz, 1H), 2.90 (d, J = 13.4 Hz, 1H), 2.78-2.64 (m,
1H), 2.49-2.37 (m, 2H), 1.99-1.94 (m, 1H). MS (APCI+) m/z 506.9 (M
+ H).sup.+. Example 4-chloro-1-[(2-methoxypyridin-4- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-72
yl)methyl]-N-(naphthalene-1- ppm 8.64 (d, J = 8.5 Hz, 1H),
8.16-8.11 (m, 1H), sulfonyl)-2,3-dihydro-1H-indene-1- 8.05 (d, J =
8.2 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), carboxamide 7.67 (d, J = 5.2
Hz, 1H), 7.58-7.50 (m, 2H), 7.46 (t, J = 7.6 Hz, 1H), 7.17-7.07 (m,
2H), 7.07-7.00 (m, 1H), 6.39 (dd, J = 5.2, 1.5 Hz, 1H), 6.28 (s,
1H), 3.73 (s, 3H), 3.28 (d, J = 13.5 Hz, 1H), 2.85 (d, J = 13.6 Hz,
1H), 2.81-2.68 (m, 1H), 2.51-2.38 (m, 2H), 1.95-1.84 (m, 1H). MS
(APCI+) m/z 506.9 (M + H).sup.+. Example 4-chloro-N-(naphthalene-1-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-73 sulfonyl)-1-{[3- ppm 8.61 (d, J = 8.8 Hz, 1H), 8.11-8.06 (m,
1H), (trifluoromethyl)pyridin-2- 8.03-7.84 (m, 4H), 7.51-7.46 (m,
2H), yl]methyl}-2,3-dihydro-1H-indene- 7.38-7.33 (m, 1H). 7.21-7.07
(m, 3H), 7.00 (t, J = 7.7 Hz, 1-carboxamide 1H), 3.90 (d, J = 16.8
Hz, 1H), 3.24-3.19 (m, 1H), 2.96-2.61 (m, 3H), 1.95-1.83 (m, 1H).
MS (APCI+) m/z 544.9 (M + H).sup.+. Example
4-chloro-N-(2,3-dihydro-1,4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-74
benzodioxine-5-sulfonyl)-1-ethyl- ppm 7.42-7.32 (m, 2H), 7.32-7.22
(m, 2H), 2,3-dihydro-1H-indene-1- 7.20-7.13 (m, 1H), 6.98 (t, J =
8.0 Hz, 1H), carboxamide 4.36-4.11 (m, 4H), 2.86 (t, J = 7.2 Hz,
2H), 2.52-2.43 (m, 1H), 2.20-2.01 (m, 2H), 1.81-1.65 (m, 1H), 0.73
(t, J = 7.3 Hz, 3H). MS (APCI+) m/z 422.0 (M + H).sup.+. Example
4-bromo-N-(naphthalene-1- .sup.1H NMR (400 MHz, Chloroform-d)
.delta. ppm II-75 sulfonyl)-2,3-dihydro-1H-indene-1- 8.60-8.43 (m,
3H), 8.16 (d, J = 8.2 Hz, 1H), 8.00 (dd, J = 7.5, carboxamide 1.6
Hz, 1H), 7.74-7.57 (m, 3H), 7.36 (dd, J = 6.4, 2.5 Hz, 1H), 6.91
(q, J = 5.2, 4.6 Hz, 2H), 3.97 (dd, J = 9.0, 6.3 Hz, 1H), 2.99-2.77
(m, 2H), 2.32 (dtd, J = 14.6, 8.8, 6.0 Hz, 1H), 2.12 (ddd, J =
13.3, 8.7, 6.4 Hz, 1H). MS (APCI+) m/z 430 (M + H).sup.+. Example
N-(4-bromonaphthalene-1-sulfonyl)- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-76
4-chloro-1-ethyl-2,3-dihydro-1H- ppm 8.68-8.60 (m, 1H), 8.33 (dd, J
= 7.8, 1.7 Hz, indene-1-carboxamide 1H), 8.16 (d, J = 8.0 Hz, 1H),
8.11 (d, J = 8.0 Hz, 1H), 7.89-7.76 (m, 2H), 7.27-7.10 (m, 3H),
2.86-2.71 (m, 2H), 2.37-2.26 (m, 1H), 2.08-1.88 (m, 2H), 1.70-1.56
(m, 1H), 0.47 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 491.8 (M +
H).sup.+. Example 4-chloro-1-ethyl-N-(4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-77
fluoronaphthalene-1-sulfonyl)-2,3- ppm 8.62 (d, J = 8.2 Hz, 1H),
8.33-8.24 (m, 1H), dihydro-1H-indene-1-carboxamide 8.24-8.16 (m,
1H), 7.81-7.73 (m, 2H), 7.52 (t, J = 9.2 Hz, 1H), 7.26-7.10 (m,
3H), 2.86-2.71 (m, 2H), 2.36-2.28 (m, 1H), 2.08-1.89 (m, 2H),
1.67-1.56 (m, 1H), 0.47 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 432.0
(M + H).sup.+. Example N-(5-bromonaphthalene-1-sulfonyl)- .sup.1H
NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-78
4-chloro-1-ethyl-2,3-dihydro-1H- ppm 8.64 (d, J = 8.7 Hz, 1H), 8.46
(d, J = 8.6 Hz, indene-1-carboxamide 1H), 8.31 (d, J = 7.7 Hz, 1H),
8.00 (d, J = 7.4 Hz, 1H), 7.81 (t, J = 7.9 Hz, 1H), 7.55 (t, J =
8.0 Hz, 1H), 7.23-7.08 (m, 3H), 2.75 (s, 2H), 2.41-2.26 (m, 1H),
2.04-1.93 (m, 1H), 1.92-1.87 (m, 1H), 1.63-1.54 (m, 1H), 0.48 (t, J
= 7.3 Hz, 3H). MS (APCI+) m/z 491.8 (M + H).sup.+. Example
4-chloro-1-ethyl-N-(5,6,7,8- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-79
tetrahydronaphthalene-1-sulfonyl)- ppm 7.86-7.75 (m, 1H), 7.48-7.21
(m, 5H), 2,3-dihydro-1H-indene-1- 3.05-2.73 (m, 6H), 2.53-2.38 (m,
1H), 2.23-1.94 (m, carboxamide 2H), 1.83-1.58 (m, 5H), 0.73 (t, J =
7.4 Hz, 3H). MS (APCI+) m/z 418.0 (M + H).sup.+. Example
4-chloro-N-(3,4-dihydroquinoline- .sup.1H NMR (501 MHz,
CD.sub.2Cl.sub.2) .delta. ppm 7.71 (bs, 1H), II-80
1(2H)-sulfonyl)-1-ethyl-2,3-dihydro- 7.43-7.40 (m, 1H), 7.25 (dd, J
= 8.0, 0.9 Hz, 1H), 1H-indene-1-carboxamide 7.16-7.13 (m, 1H),
7.12-7.03 (m, 3H), 6.78-6.75 (m, 1H), 4.02-3.92 (m, 2H), 2.85 (ddd,
J = 16.9, 8.8, 5.6 Hz, 1H), 2.75-2.68 (m, 3H), 2.24 (ddd, J = 13.3,
8.7, 5.5 Hz, 1H), 2.05-1.95 (m, 3H), 1.80 (dq, J = 13.9, 7.4 Hz,
1H), 1.73 (dq, J = 13.9, 7.4 Hz, 1H), 0.65 (t, J = 7.4 Hz, 3H). MS
(ESI+) m/z 419 (M + H).sup.+. Example 4-chloro-1-(hydroxymethyl)-N-
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.08 (bs, II-81
(naphthalene-1-sulfonyl)-2,3- 1H), 8.59-8.55 (m, 1H), 8.30-8.26 (m,
2H), dihydro-1H-indene-1-carboxamide 8.11-8.08 (m, 1H), 7.73-7.64
(m, 3H), 7.24-7.19 (m, 1H), 7.06-7.04 (m, 2H), 3.70 (d, J = 10.8
Hz, 1H), 3.62 (d, J = 10.8 Hz, 1H), 2.80 (ddd, J = 16.4, 8.7, 6.9
Hz, 1H), 2.70 (ddd, J = 16.4, 9.1, 4.7 Hz, 1H), 2.23 (ddd, J =
13.4, 9.1, 6.9 Hz, 1H), 2.07 (ddd, J = 13.4, 8.7, 4.7 Hz, 1H), 2.07
(s, 1H). MS (ESI+) m/z 416 (M + H).sup.+. Example
4-cyclobutyl-N-(4- .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O =
9:1 (v/v)) .delta. II-82 cyclobutylnaphthalene-1-sulfonyl)- ppm
8.65-8.58 (m, 1H), 8.24-8.17 (m, 1H),
1-ethyl-2,3-dihydro-1H-indene-1- 8.14-8.07 (m, 1H), 7.70-7.63 (m,
2H), 7.55 (d, carboxamide J = 7.7 Hz, 1H), 7.20-7.03 (m, 3H),
4.26-4.13 (m, 1H), 3.49-3.38 (m, 1H), 2.70-2.54 (m, 2H), 2.54-2.39
(m, 1H), 2.32-1.69 (m, 12H), 1.61-1.51 (m, 1H), 1.28-1.12 (m, 2H),
0.48 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 488.0 (M + H).sup.+.
Example 4-cyclobutyl-N-(5- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-83
cyclobutylnaphthalene-1-sulfonyl)- ppm 8.45 (d, J = 8.6 Hz,
1H),
8.31 (d, J = 8.5 Hz, 1-ethyl-2,3-dihydro-1H-indene-1- 1H), 8.24 (d,
J = 7.4 Hz, 1H), 7.74-7.59 (m, 2H), carboxamide 7.52 (d, J = 7.2
Hz, 1H), 7.23-7.02 (m, 3H), 4.16 (q, J = 8.5 Hz, 1H), 3.50-3.36 (m,
1H), 2.53 (p, J = 1.9 Hz, 4H), 2.35-1.68 (m, 13H), 1.63-1.47 (m,
1H), 0.48 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 488.0 (M + H).sup.+.
Example 8-bromo-5-(cyclohexylmethoxy)-N- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-84
(naphthalene-1-sulfonyl)-1,2,3,4- ppm 8.71-8.64 (m, 1H), 8.32-8.21
(m, 2H), tetrahydronaphthalene-1- 8.12 (dt, J = 8.0, 1.0 Hz, 1H),
7.82-7.74 (m, 1H), carboxamide 7.73-7.62 (m, 2H), 7.10 (d, J = 8.7
Hz, 1H), 6.67 (d, J = 8.9 Hz, 1H), 3.78 (dd, J = 6.3, 2.6 Hz, 1H),
3.72-3.61 (m, 2H), 2.53-2.48 (m, 1H), 2.34-2.20 (m, 1H), 1.92 (d, J
= 14.0 Hz, 1H), 1.82-1.63 (m, 7H), 1.54-1.45 (m, 1H), 1.28-1.08 (m,
3H), 1.07-0.94 (m, 3H). MS (APCI+) m/z 555.9 (M + H).sup.+. Example
8-bromo-5-[(3- .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1
(v/v)) .delta. II-85 methoxyphenyl)methoxy]-N- ppm 8.72-8.64 (m,
1H), 8.31-8.21 (m, 2H), (naphthalene-1-sulfonyl)-1,2,3,4- 8.15-8.08
(m, 1H), 7.81-7.61 (m, 3H), 7.28 (t, J = 7.9 Hz,
tetrahydronaphthalene-1- 1H), 7.12 (d, J = 8.8 Hz, 1H), carboxamide
6.99-6.92 (m, 2H), 6.87 (dd, J = 8.2, 2.7 Hz, 1H), 6.77 (d, J = 8.9
Hz, 1H), 5.06-4.95 (m, 2H), 3.82-3.75 (m, 1H), 3.73 (s, 3H),
2.65-2.54 (m, 1H), 2.41-2.27 (m, 1H), 1.94 (d, J = 13.9 Hz, 1H),
1.83-1.70 (m, 1H), 1.52-1.47 (m, 1H), 1.10-1.02 (m, 1H). MS (APCI+)
m/z 579.9 (M + H).sup.+. Example 8-bromo-5-[(3- .sup.1H NMR (400
MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-86
methoxyphenyl)methoxy]-N-[(3- ppm 8.40-8.26 (m, 3H), 8.13 (d, J =
8.1 Hz, 1H), methoxyphenyl)methyl]-N- 7.85-7.76 (m, 1H), 7.75-7.64
(m, 2H), (naphthalene-1-sulfonyl)-1,2,3,4- 7.38-7.33 (m, 1H),
7.32-7.16 (m, 3H), 7.12 (d, J = 8.7 Hz, tetrahydronaphthalene-1-
1H), 6.95-6.81 (m, 4H), 6.75 (d, J = 8.7 Hz, carboxamide 1H),
5.71-5.34 (m, 2H), 5.01-4.89 (m, 2H), 4.17-4.12 (m, 1H), 3.77 (s,
3H), 3.70 (s, 3H), 2.46-2.29 (m, 1H), 2.18 (s, 1H), 1.56-1.51 (m,
2H), 1.03 (s, 1H), 0.57-0.09 (m, 1H). MS (APCI+) m/z 699.9 (M +
H).sup.+. Example ethyl ({4-bromo-5-[(naphthalene-1- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-87
sulfonyl)carbamoyl]-5,6,7,8- ppm 8.68 (dd, J = 8.6, 1.1 Hz, 1H),
8.33-8.17 (m, tetrahydronaphthalen-1- 2H), 8.16-8.09 (m, 1H),
7.82-7.75 (m, 1H) yl}oxy)acetate 7.73-7.62 (m, 2H), 7.10 (d, J =
8.7 Hz, 1H), 6.61 (d, J = 8.9 Hz, 1H), 4.71 (s, 2H), 4.12 (q, J =
7.1 Hz, 2H), 3.79 (dd, J = 6.5, 2.6 Hz, 1H), 2.66-2.55 (m, 1H),
2.40-2.26 (m, 1H), 1.98-1.89 (m, 1H), 1.84-1.71 (m, 1H), 1.56-1.48
(m, 1H), 1.17 (t, J = 7.1 Hz, 3H), 1.08-1.03 (m, 1H). MS (APCI+)
m/z 545.7 (M + H).sup.+. Example 8-bromo-5-(cyclopentyloxy)-N-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-88 (naphthalene-1-sulfonyl)-1,2,3,4- ppm 8.71-8.64 (m, 1H),
8.32-8.21 (m, 2H), tetrahydronaphthalene-1- 8.16-8.08 (m, 1H),
7.81-7.74 (m, 1H), carboxamide 7.73-7.62 (m, 2H), 7.09 (d, J = 8.7
Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.71 (t, J = 5.7 Hz, 1H), 3.77
(dd, J = 6.5, 2.6 Hz, 1H), 2.53-2.42 (m, 1H), 2.29-2.15 (m, 1H),
1.92 (d, J = 13.5 Hz, 1H), 1.85-1.69 (m, 3H), 1.69-1.42 (m, 7H),
1.06-0.98 (m, 1H). MS (APCI+) m/z 527.9 (M + H).sup.+. Example
5-(benzyloxy)-8-bromo-N- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-89
(naphthalene-1-sulfonyl)-1,2,3,4- ppm 8.71-8.64 (m, 1H), 8.26 (dd,
J = 14.1, 7.6 Hz, tetrahydronaphthalene-1- 2H), 8.15-8.08 (m, 1H),
7.76 (t, J = 7.6 Hz, carboxamide 1H), 7.73-7.61 (m, 2H), 7.43-7.26
(m, 5H), 7.12 (d, J = 8.7 Hz, 1H), 6.79 (d, J = 8.9 Hz, 1H), 5.03
(d, J = 2.6 Hz, 2H), 3.82-3.75 (m, 1H), 2.64-2.54 (m, 1H),
2.40-2.26 (m, 1H), 1.98-1.90 (m, 1H), 1.80-1.70 (m, 1H), 1.55-1.46
(m, 1H), 1.09-1.04 (m, 1H). MS (APCI+) m/z 549.9 (M + H).sup.+.
Example N-benzyl-5-(benzyloxy)-8-bromo-N- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-90
(naphthalene-1-sulfonyl)-1,2,3,4- ppm 8.44-8.28 (m, 3H), 8.18-8.10
(m, 1H), tetrahydronaphthalene-1- 7.87-7.78 (m, 1H) 7.77-7.65 (m,
2H), carboxamide 7.65-7.60 (m, 2H), 7.48-7.43 (m, 2H), 7.42-7.25
(m, 6H), 7.17-7.06 (m, 1H), 6.78 (d, J = 8.8 Hz, 1H), 5.73-5.46 (m,
2H), 5.05-4.92 (m, 2H), 4.18-4.13 (m, 1H), 2.43-2.38 (m, 1H),
2.21-2.16 (m, 1H), 1.55-1.50 (m, 2H), 1.06-1.01 (m, 1H), 0.39-0.34
(m, 1H). MS (APCI+) m/z 639.9 (M + H).sup.+. Example
8-bromo-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-91
sulfonyl)-5-[(oxetan-3-yl)oxy]- ppm 8.71 (d, J = 8.5 Hz, 1H), 8.37
8.20 (m, 2H), 1,2,3,4-tetrahydronaphthalene-1- 8.14 (d, J = 8.1 Hz,
1H), 7.90-7.75 (m, 1H), carboxamide 7.75-7.61 (m, 2H), 7.12 (d, J =
8.7 Hz, 1H), 6.33 (d, J = 8.7 Hz, 1H), 5.18 (q, J = 5.5 Hz, 1H),
4.97-4.87 (m, 2H), 4.53-4.42 (m, 2H), 2.67-2.59 (m, 2H), 2.44-2.33
(m, 1H), 2.05-1.92 (m, 1H), 1.89-1.74 (m, 1H), 1.64-1.42 (m, 1H),
1.28-0.94 (m, 1H). MS (APCI+) m/z 515.9 (M + H).sup.+. Example
8-bromo-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-92
sulfonyl)-5-[(oxan-4-yl)oxy]-1,2,3,4- ppm 8.70 (d, J = 8.4 Hz, 1H),
8.32 7.87 (m, 3H), tetrahydronaphthalene-1- 7.81-7.42 (m, 3H), 7.09
(d, J = 8.8 Hz, 1H), carboxamide 6.73 (d, J = 8.9 Hz, 1H),
4.61-4.38 (m, 1H), 3.52-3.42 (m, 2H), 2.62-2.54 (m, 1H), 2.34-2.22
(m, 1H), 2.05-1.82 (m, 4H), 1.76-1.39 (m, 4H), 1.13 (d, J = 22.3
Hz, 1H). MS (APCI+) m/z 543.9 (M + H).sup.+. Example
8-bromo-5-(2-hydroxy-2- .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O
= 9:1 (v/v)) .delta. II-93 methylpropoxy)-N-(naphthalene-1- ppm
8.73 8.65 (m, 1H), 8.32-8.22 (m, 2H), sulfonyl)-1,2,3,4- 8.12 (d, J
= 8.2 Hz, 1H), 7.85-7.73 (m, 1H), tetrahydronaphthalene-1-
7.73-7.59 (m, 2H), 7.11 (d, J = 8.7 Hz, 1H), 6.66 (d, J = 8.8 Hz,
carboxamide 1H), 3.80-3.76 (m, 1H), 3.60 (d, J = 8.0 Hz, 2H),
2.65-2.57 (m, 1H), 2.39-2.20 (m, 1H), 1.99-1.88 (m, 1H), 1.85-1.68
(m, 1H), 1.53-1.41 (m, 1H), 1.17 (d, J = 2.0 Hz, 6H), 1.08-0.90 (m,
1H). MS (APCI+) m/z 531.9 (M + H).sup.+. Example
6,8-dimethoxy-N-(naphthalene-1- .sup.1H NMR (501 MHz, DMSO) .delta.
ppm 12.39 (s, 1H), II-94 sulfonyl)-1,2,3,4- 8.69 (dd, J = 1.0, 8.7
Hz, 1H), 8.28 (d, J = 8.3 Hz, tetrahydronaphthalene-1- 1H), 8.24
(dd, J = 1.3, 7.4 Hz, 1H), 8.14-8.12 (m, carboxamide 2H), 7.80
(ddd, J = 1.4, 6.9, 8.5 Hz, 1H), 7.71 (ddd, J = 1.1, 6.9, 8.1 Hz,
1H), 7.66 (dd, J = 7.4, 8.2 Hz, 1H), 6.16 (d, J = 2.4 Hz, 1H), 6.08
(d, J = 2.4 Hz, 1H), 3.63 (s, 3H), 3.58 (dd, J = 5.2, 6.9 Hz, 1H),
2.89 (s, 3H), 2.51-2.47 (m, 2H), 1.84-1.76 (m, 1H), 1.67-1.60 (m,
1H), 1.44-1.32 (m, 2H). LC/MS (APCI+) m/z 426 (M + H).sup.+.
Example 5-methoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-95 sulfonyl)-8-[4-
ppm 8.58-8.42 (m, 1H), 8.32 (d, J = 8.2 Hz, 1H),
(trifluoromethoxy)phenyl]-1,2,3,4- 8.22 (dd, J = 7.5, 1.2 Hz, 1H),
8.20-8.02 (m, 1H), tetrahydronaphthalene-1- 7.82-7.59 (m, 3H),
7.04-6.76 (m, 6H), 3.75 (s, carboxamide 3H), 3.51 (dd, J = 5.6, 3.1
Hz, 1H), 2.50-2.23 (m, 2H), 1.82-1.66 (m, 1H), 1.66-1.50 (m, 1H),
1.44-1.28 (m, 1H), 0.98-0.78 (m, 1H). MS (APCI+) m/z 634.0 (M +
H).sup.+. Example 5-methoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-96
sulfonyl)-8-[(E)-2-phenylethenyl]- ppm 8.66-8.57 (m, 1H), 8.28-8.14
(m, 2H), 1,2,3,4-tetrahydronaphthalene-1- 8.13-8.04 (m, 1H),
7.70-7.60 (m, 2H), 7.55 (dd, carboxamide J = 8.2, 7.4 Hz, 1H),
7.51-7.37 (m, 5H), 7.36-7.27 (m, 1H), 7.00 (d, J = 16.0 Hz, 1H),
6.91-6.81 (m, 2H), 4.10-4.03 (m, 1H), 3.74 (s, 3H), 2.54-2.43 (m,
1H), 2.34-2.21 (m, 1H), 1.83-1.65 (m, 2H), 1.38-1.33 (m, 1H),
1.04-0.96 (m, 1H). MS (APCI+) m/z 497.8 (M + H).sup.+. Example
8-(2,2-difluoro-2H-1,3-benzodioxol- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-97
4-yl)-5-methoxy-N-(naphthalene-1- ppm 8.45-8.37 (m, 1H), 8.29 (d, J
= 8.2 Hz, 1H), sulfonyl)-1,2,3,4- 8.18-8.10 (m, 2H), 7.77-7.68 (m,
2H), 7.64 (t, J = 7.8 Hz, tetrahydronaphthalene-1- 1H), 7.02 (d, J
= 7.9 Hz, 1H), carboxamide 6.95-6.85 (m, 2H), 6.73-6.42 (m, 2H),
3.77 (s, 3H), 3.64 (s, 1H), 2.53-2.44 (m, 1H), 2.43-2.30 (m, 1H),
1.71-1.66 (m, 2H), 1.43-1.34 (m, 1H), 0.98-0.93 (m, 1H). MS (APCI+)
m/z 552.0 (M + H).sup.+. Example 8-(2-fluoro-4-methylphenyl)-5-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-98 methoxy-N-(naphthalene-1- ppm 8.60 (d, J = 8.4 Hz, 1H),
8.21-8.08 (m, 2H), sulfonyl)-1,2,3,4- 8.04 (d, J = 7.7 Hz, 1H),
7.66-7.54 (m, 3H), tetrahydronaphthalene-1- 6.83-6.74 (m, 3H),
6.68-6.63 (m, 1H), carboxamide 6.46-6.41 (m, 1H), 3.76 (s, 3H),
3.42 (s, 1H), 2.51-2.34 (m, 2H), 2.25 (s, 3H), 1.89 (d, J = 22.3
Hz, 1H), 1.65-1.47 (m, 1H), 1.46-1.05 (m, 2H). MS (APCI+) m/z 504.0
(M + H).sup.+. Example 5-methoxy-N-(naphthalene-1- .sup.1H NMR (400
MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-99
sulfonyl)-8-(2-phenoxyphenyl)- ppm 8.79-8.58 (m, 1H), 8.16-7.84 (m,
3H), 1,2,3,4-tetrahydronaphthalene-1- 7.63-7.41 (m, 3H), 7.27-7.09
(m, 4H), 6.96 (t, J = 7.4 Hz, carboxamide 1H), 6.92-6.50 (m, 6H),
3.71 (s, 3H), 3.21-3.11 (m, 1H), 2.45-2.23 (m, 2H), 2.12-1.88 (m,
1H), 1.42-1.09 (m, 3H). MS (APCI+) m/z 564.0 (M + H).sup.+. Example
N-(3-bromo-2-methylbenzene-1- .sup.1H NMR (501 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-100
sulfonyl)-4-chloro-1-ethyl-2,3- ppm 7.98 (d, J = 8.1 Hz, 1H), 7.91
(d, J = 7.8 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.36 (t, J =
8.0 Hz, 1H), 7.33-7.27 (m, 1H), 7.27-7.20 (m, 2H), 2.86 (t, J = 7.3
Hz, 2H), 2.51 (s, 3H), 2.45 (dt, J = 13.1, 7.3 Hz, 1H), 2.14-1.99
(m, 2H), 1.76-1.62 (m, 1H), 0.68 (t, J = 7.3 Hz, 3H). MS (APCI+)
m/z 457.9 (M + H).sup.+. Example 4-chloro-1-ethyl-N-(3-fluoro-2-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-101 methylbenzene-1-sulfonyl)-2,3- ppm 7.84-7.76 (m, 1H),
7.56-7.42 (m, 2H), dihydro-1H-indene-1-carboxamide 7.35-7.20 (m,
3H), 2.86 (t, J = 7.3 Hz, 2H), 2.50-2.40 (m, 1H), 2.38 (d, J = 2.3
Hz, 3H), 2.13-1.98 (m, 2H), 1.81-1.67 (m, 1H), 0.68 (t, J = 7.3 Hz,
3H). MS (APCI+) m/z 396.1 (M + H).sup.+. Example
4-chloro-1-ethyl-N-[2- .sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O
= 9:1 (v/v)) .delta. II-102 (methoxymethyl)benzene-1- ppm 7.95 (dd,
J = 8.0, 1.3 Hz, 1H), 7.75-7.62 (m,
sulfonyl]-2,3-dihydro-1H-indene-1- 2H), 7.56-7.47 (m, 1H),
7.36-7.20 (m, 3H), carboxamide 4.73 (s, 2H), 3.36 (s, 3H),
2.94-2.76 (m, 2H), 2.49-2.37 (m, 1H), 2.11-1.98 (m, 2H), 1.79-1.65
(m, 1H), 0.66 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 408.1 (M +
H).sup.+. Example 4-chloro-N-(2,3-difluorobenzene-1- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-103
sulfonyl)-1-ethyl-2,3-dihydro-1H- ppm 7.85-7.75 (m, 1H), 7.73-7.66
(m, 1H), indene-1-carboxamide 7.50-7.40 (m, 1H), 7.35-7.19 (m, 3H),
2.91-2.78 (m, 2H), 2.51-2.39 (m, 1H), 2.14-2.00 (m, 2H), 1.81-1.67
(m, 1H), 0.70 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 400.0 (M +
H).sup.+. Example 4-chloro-N-[2-(2,2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-104
difluoroethoxy)benzene-1-sulfonyl]- ppm 7.86 (dd, J = 7.9, 1.7 Hz,
1H), 7.72-7.62 (m, 1-ethyl-2,3-dihydro-1H-indene-1- 1H), 7.34-7.15
(m, 5H), 6.34 (tt, J = 54.6, 3.8 Hz, carboxamide 1H), 4.40 (dd, J =
54.8, 3.9 Hz, 2H), 2.86 (t, J = 7.3 Hz, 2H), 2.50-2.37 (m, 1H),
2.14-1.93 (m, 2H), 1.82-1.68 (m, 1H), 0.67 (t, J = 7.3 Hz, 3H). MS
(APCI+) m/z 444.0 (M + H).sup.+. Example
4-chloro-1-ethyl-N-(quinoxaline-5- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-105
sulfonyl)-2,3-dihydro-1H-indene-1- ppm 9.07 (d, J = 1.8 Hz, 1H),
8.99 (d, J = 1.8 Hz, carboxamide 1H), 8.51 (dd, J = 7.4, 1.4 Hz,
1H), 8.43 (dd, J = 8.5, 1.4 Hz, 1H), 8.05 (dd, J = 8.5, 7.4 Hz,
1H), 7.27-7.18 (m, 1H), 7.17-7.08 (m, 2H), 2.86-2.66 (m, 2H),
2.46-2.34 (m, 1H), 2.11-1.96 (m,
2H), 1.74-1.60 (m, 1H), 0.53 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z
416.0 (M + H).sup.+. Example 4-chloro-N-(3-chloro-2- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-106
fluorobenzene-1-sulfonyl)-1-ethyl- ppm 7.94 (ddd, J = 8.2, 6.8, 1.7
Hz, 1H), 2,3-dihydro-1H-indene-1- 7.86 (ddd, J = 8.1, 6.5, 1.7 Hz,
1H), 7.51-7.41 (m, carboxamide 1H), 7.35-7.19 (m, 3H), 2.95-2.78
(m, 2H), 2.51-2.39 (m, 1H), 2.15-2.01 (m, 2H), 1.81-1.67 (m, 1H),
0.69 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z 416.0 (M + H).sup.+.
Example 4-chloro-N-(2,3-dichlorobenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-107
sulfonyl)-1-ethyl-2,3-dihydro-1H- ppm 8.07 (dd, J = 8.1, 1.5 Hz,
1H), 7.96 (dd, J = 8.1, indene-1-carboxamide 1.5 Hz, 1H), 7.61 (t,
J = 8.1 Hz, 1H), 7.33-7.19 (m, 3H), 2.95-2.82 (m, 2H), 2.52-2.40
(m, 1H), 2.16-1.99 (m, 2H), 1.84-1.70 (m, 1H), 0.70 (t, J = 7.3 Hz,
3H). MS (APCI+) m/z 433.9 (M + H).sup.+. Example
4-chloro-1-ethyl-N-(1-methyl-1H- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-108
indole-3-sulfonyl)-2,3-dihydro-1H- ppm 8.07 (s, 1H), 7.80 (d, J =
7.8 Hz, 1H), 7.57 (d, indene-1-carboxamide J = 8.2 Hz, 1H),
7.38-7.30 (m, 1H), 7.29-7.23 (m, 3H), 7.21-7.14 (m, 1H), 3.86 (s,
3H), 2.88-2.70 (m, 2H), 2.42-2.30 (m, 1H), 2.10-1.91 (m, 2H),
1.74-1.60 (m, 1H), 0.55 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 417.1
(M + H).sup.+. Example 5-[2-(1,3-dioxan-2-yl)ethyl]-8- .sup.1H NMR
(400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-109
methoxy-N-(naphthalene-1- ppm 8.69 (d, J = 8.7 Hz, 1H), 8.33-8.21
(m, 2H), sulfonyl)-1,2,3,4- 8.18-8.10 (m, 1H), 7.87-7.78 (m, 1H),
tetrahydronaphthalene-1- 7.77-7.63 (m, 2H), 6.87 (d, J = 8.4 Hz,
1H), 6.48 (d, J = 8.4 Hz, carboxamide 1H), 4.46 (t, J = 5.1 Hz,
1H), 3.97 (ddd, J = 11.8, 5.0, 1.4 Hz, 2H), 3.72-3.60 (m, 3H), 2.88
(s, 3H), 2.52-2.34 (m, 4H), 1.93-1.74 (m, 2H), 1.70-1.52 (m, 3H),
1.51-1.27 (m, 3H). MS (APCI+) m/z 510.0 (M + H).sup.+. Example
4-cyano-7-methoxy-N-(naphthalene- .sup.1H NMR (501 MHz,
DMSO-d.sub.6) .delta. ppm 12.64 (s, II-110
1-sulfonyl)-2,3-dihydro-1H-indene- 1H), 8.64 (dd, J = 8.7, 1.1 Hz,
1H), 8.31 (d, J = 8.3 Hz, 1-carboxamide 1H), 8.27 (dd, J = 7.4, 1.2
Hz, 1H), 8.15 (dt, J = 8.2, 0.9 Hz, 1H), 7.81 (ddd, J = 8.5, 6.9,
1.4 Hz, 1H), 7.74-7.66 (m, 2H), 7.61 (d, J = 8.3 Hz, 1H), 6.78 (d,
J = 8.6 Hz, 1H), 4.00 (dd, J = 9.2, 5.7 Hz, 1H), 3.17 (s, 3H), 2.91
(dt, J = 8.7, 6.1 Hz, 2H), 2.35 (dtd, J = 13.1, 8.8, 6.3 Hz, 1H),
1.86 (ddt, J = 12.7, 8.7, 6.3 Hz, 1H). MS (APCI+) m/z 407 (M +
H).sup.+. Example 5-cyano-8-methoxy-N-(naphthalene- .sup.1H NMR
(501 MHz, DMSO) .delta. ppm 12.58 (s, 1H), II-111
1-sulfonyl)-1,2,3,4- 8.68 (dd, J = 1.0, 8.7 Hz, 1H), 8.30 (d, J =
8.2 Hz, tetrahydronaphthalene-1- 1H), 8.24 (dd, J = 1.2, 7.4 Hz,
1H), 8.14 (d, J = 8.0 Hz, carboxamide 1H), 7.82 (ddd, J = 1.4, 6.9,
8.5 Hz, 1H), 7.72 (ddd, J = 1.1, 6.9, 8.1 Hz, 1H), 7.67 (dd, J =
7.4, 8.2 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 8.6 Hz,
1H), 3.69 (dd, J = 4.7, 6.7 Hz, 1H), 3.01 (s, 3H), 2.72-2.60 (m,
2H), 1.89-1.81 (m, 1H), 1.77-1.69 (m, 1H), 1.56-1.48 (m, 1H),
1.42-1.32 (m, 1H). LC/MS (ESI+) m/z 421 (M + H).sup.+. Example
4-chloro-N-(3-cyclobutyl-2- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-112
methylbenzene-1-sulfonyl)-1-ethyl- ppm 7.80 (dd, J = 7.9, 1.3 Hz,
1H), 7.48 (d, J = 7.7 Hz, 2,3-dihydro-1H-indene-1- 1H), 7.32 (t, J
= 7.9 Hz, 1H), 7.28-7.15 (m, carboxamide 3H), 3.74-3.59 (m, 1H),
2.90-2.83 (m, 2H), 2.53-2.48 (m, 1H), 2.41-2.30 (m, 5H), 2.13-1.93
(m, 5H), 1.88-1.65 (m, 2H), 0.72 (t, J = 7.4 Hz, 3H). MS (APCI+)
m/z 432.0 (M + H).sup.+. Example
4-chloro-1-ethyl-N-(isoquinoline-5- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-113
sulfonyl)-2,3-dihydro-1H-indene-1- ppm 9.39 (s, 1H), 8.62-8.46 (m,
1H), 8.42 (d, J = 6.1 Hz, carboxamide 1H), 8.40-8.27 (m, 2H), 7.80
(t, J = 7.8 Hz, 1H), 7.26-7.16 (m, 2H), 7.16-7.07 (m, 1H),
2.84-2.75 (m, 2H), 2.55-2.45 (m, 1H), 2.12-1.91 (m, 1H), 1.91-1.77
(m, 1H), 1.65-1.46 (m, 1H), 0.54 (t, J = 7.3 Hz, 3H). MS (APCI+)
m/z 415.6 (M + H).sup.+. Example 5-methoxy-N-(naphthalene-1-
.sup.1H NMR (500 MHz, DMSO) .delta. ppm 12.78 (s, 1H), II-114
sulfonyl)bicyclo[4.2.0]octa-1,3,5- 8.61 (dd, J = 1.0, 8.6 Hz, 1H),
8.32-8.28 (m, 2H), triene-7-carboxamide 8.14 (d, J = 8.0 Hz, 1H),
7.79 (ddd, J = 1.4, 6.9, 8.5 Hz, 1H), 7.73-7.67 (m, 2H), 7.10-7.07
(m, 1H), 6.61-6.57 (m, 2H), 4.38 (dd, J = 2.5, 5.8 Hz, 1H), 3.32
(s, 3H), 3.29 (dd, J = 5.8, 14.0 Hz, 1H), 2.76 (dd, J = 2.5, 14.0
Hz, 1H). LC/MS (ESI+) m/z 368 (M + H).sup.+. Example
8-methoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 12.44 (s, II-115 sulfonyl)-1,2,3,4- 1H), 8.70 (d, J =
8.6 Hz, 1H), 8.28 (d, J = 8.2 Hz, tetrahydronaphthalene-1- 1H),
8.24 (dd, J = 7.4, 1.2 Hz, 1H), 8.15-8.12 (m, carboxamide 1H), 7.81
(ddd, J = 8.6, 6.8, 1.4 Hz, 1H), 7.71 (ddd, J = 8.2, 6.8, 1.1 Hz,
1H), 7.66 (dd, J = 8.2, 7.4 Hz, 1H), 7.00 (dd, J = 8.0, 7.6 Hz,
1H), 6.59 (d, J = 7.6 Hz, 1H), 6.50 (d, J = 8.0 Hz, 1H), 3.69-3.65
(m, 1H), 2.91 (s, 3H), 2.56-2.51 (m, 2H), 1.88-1.79 (m, 1H),
1.71-1.62 (m, 1H), 1.47-1.33 (m, 2H). MS (ESI+) m/z 396 (M +
H).sup.+. Example 4-bromo-7-methoxy-N-(quinoline-8- .sup.1H NMR
(501 MHz, DMSO-d.sub.6) .delta. ppm 12.44 (s, II-116
sulfonyl)-2,3-dihydro-1H-indene-1- 1H), 9.16-9.02 (m, 1H), 8.57 (d,
J = 8.3 Hz, 1H), carboxamide 8.40 (dd, J = 7.4, 1.4 Hz, 1H), 8.34
(d, J = 8.2 Hz, 1H), 7.84-7.68 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H),
6.62 (d, J = 8.7 Hz, 1H), 4.12 (bs, 1H), 3.30 (s, 3H), 2.70 (ddd, J
= 16.2, 9.1, 5.2 Hz, 1H), 2.60 (td, J = 16.2, 14.8, 6.7 Hz, 1H),
2.32-2.20 (m, 1H), 1.84-1.74 (m, 1H). MS (APCI+) m/z 461 (M +
H).sup.+. Example 4-bromo-N-(8-fluoroquinoline-5- .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. ppm 12.71 (s, II-117
sulfonyl)-7-methoxy-2,3-dihydro- 1H), 9.15 (dd, J = 4.2, 1.5 Hz,
1H), 9.06 (d, J = 8.9 Hz, 1H-indene-1-carboxamide 1H), 8.36 (dd, J
= 8.4, 4.9 Hz, 1H), 7.95 (dd, J = 8.9, 4.2 Hz, 1H), 7.81 (dd, J =
10.0, 8.4 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.59 (d, J = 8.7 Hz,
1H), 4.02 (dd, J = 9.2, 5.7 Hz, 1H), 3.12 (s, 3H), 2.77 (t, J = 7.5
Hz, 2H), 2.30 (ddt, J = 13.1, 8.9, 7.3 Hz, 1H), 1.90-1.76 (m, 1H).
MS (APCI+) m/z 479 (M + H).sup.+. Example
7-ethyl-5-methoxy-N-(naphthalene- .sup.1H NMR (501 MHz,
DMSO-d.sub.6) .delta. ppm 12.18 (s, II-118
1-sulfonyl)bicyclo[4.2.0]octa-1,3,5- 1H), 8.62 (d, J = 8.6 Hz, 1H),
8.31-8.26 (m, 2H), triene-7-carboxamide 8.11 (d, J = 8.3 Hz, 1H),
7.75 (ddd, J = 1.3, 6.7, 8.5 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H),
7.67 (d, J = 7.1 Hz, 1H), 7.13 (dd, J = 7.2, 8.5 Hz, 1H), 6.72 (d,
J = 8.5 Hz, 1H), 6.62 (d, J = 7.2 Hz, 1H), 3.65 (s, 3H), 3.07 (d, J
= 14.3 Hz, 1H), 2.98 (d, J = 14.3 Hz, 1H), 2.05 (dq, J = 7.4, 14.7
Hz, 1H), 1.79 (dq, J = 7.3, 14.6 Hz, 1H), 0.58 (t, J = 7.4 Hz, 3H).
LC/MS (ESI+) m/z 396 (M + H).sup.+. Example
8-methoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-119 sulfonyl)-5-[3-
ppm 8.71 (dd, J = 8.6, 1.1 Hz, 1H), 8.33-8.24 (m,
(trifluoromethoxy)phenyl]-1,2,3,4- 2H), 8.19-8.11 (m, 1H),
7.88-7.80 (m, 1H), tetrahydronaphthalene-1- 7.77-7.66 (m, 2H), 7.52
(t, J = 8.0 Hz, 1H), carboxamide 7.33-7.27 (m, 1H), 7.26-7.22 (m,
1H), 7.15-7.11 (m, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 8.5
Hz, 1H), 3.78-3.74 (m, 1H), 2.92 (s, 3H), 2.49-2.26 (m, 2H),
1.98-1.80 (m, 1H), 1.76-1.61 (m, 1H), 1.52-1.24 (m, 2H). MS (APCI+)
m/z 556.0 (M + H).sup.+. Example 8-methoxy-N-(naphthalene-1-
.sup.1H NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta.
II-120 sulfonyl)-5-[(E)-2-phenylethenyl]- ppm 8.70 (d, J = 8.7 Hz,
1H), 8.27 (dd, J = 14.9, 1,2,3,4-tetrahydronaphthalene-1- 7.8 Hz,
2H), 8.14 (d, J = 8.2 Hz, 1H), 7.83 (t, J = 7.7 Hz, carboxamide
1H), 7.77-7.59 (m, 3H), 7.58-7.51 (m, 2H), 7.47-7.18 (m, 5H), 6.87
(d, J = 16.1 Hz, 1H), 6.62 (d, J = 8.6 Hz, 1H), 3.72-3.68 (m, 1H),
2.98 (s, 3H), 2.74-2.57 (m, 2H), 1.76 (d, J = 33.3 Hz, 2H),
1.59-1.28 (m, 2H). MS (APCI+) m/z 497.8 (M + H).sup.+. Example
5-(3,6-dihydro-2H-pyran-4-yl)-8- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-121
methoxy-N-(naphthalene-1- ppm 8.70 (d, J = 8.7 Hz, 1H), 8.33-8.22
(m, 2H), sulfonyl)-1,2,3,4- 8.14 (dt, J = 8.2, 0.9 Hz, 1H),
7.88-7.79 (m, 1H), tetrahydronaphthalene-1- 7.78-7.63 (m, 2H), 6.84
(d, J = 8.4 Hz, 1H), carboxamide 6.52 (d, J = 8.5 Hz, 1H),
5.49-5.43 (m, 1H), 4.11 (q, J = 2.8 Hz, 2H), 3.74 (t, J = 10.7 Hz,
2H), 3.70-3.65 (m, 1H), 2.87 (s, 3H), 2.47 (t, J = 6.2 Hz, 2H),
2.22-2.04 (m, 2H), 1.91-1.79 (m, 1H), 1.63 (d, J = 13.6 Hz, 1H),
1.50-1.28 (m, 2H). MS (APCI+) m/z 478.0 (M + H).sup.+. Example
5-methoxy-8-(6-methylpyridin-3- .sup.1H NMR (501 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-122
yl)-N-(naphthalene-1-sulfonyl)- ppm 8.55-8.48 (m, 1H), 8.31 (d, J =
8.3 Hz, 1H), 1,2,3,4-tetrahydronaphthalene-1- 8.23-8.14 (m, 2H),
8.08 (d, J = 2.4 Hz, 1H), carboxamide 7.80-7.71 (m, 2H), 7.68 (t, J
= 7.8 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.88-6.79 (m, 2H), 6.50
(d, J = 8.0 Hz, 1H), 3.75 (s, 3H), 3.51 (s, 1H), 2.51-2.24 (m, 5H),
1.81-1.66 (m, 1H), 1.66-1.52 (m, 2H), 1.41-1.31 (m, 1H), 0.96-0.79
(m, 1H). MS (APCI+) m/z 487.0 (M + H).sup.+. Example
4-bromo-N-(2-ethoxyquinoline-5- .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 12.62 (s, II-123 sulfonyl)-7-methoxy-2,3-dihydro- 1H),
8.90 (dd, J = 9.3, 0.7 Hz, 1H), 8.12 (dd, J = 7.5,
1H-indene-1-carboxamide 1.2 Hz, 1H), 8.09 (dt, J = 8.4, 1.1 Hz,
1H), 7.83 (dd, J = 8.4, 7.5 Hz, 1H), 7.31 (dd, J = 9.3, 1.6 Hz,
2H), 6.62 (d, J = 8.7 Hz, 1H), 4.58-4.46 (m, 2H), 4.04 (dd, J =
9.2, 5.6 Hz, 1H), 3.22 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 2.33-2.25
(m, 1H), 1.89-1.76 (m, 1H), 1.41 (t, J = 7.1 Hz, 3H). MS (APCI+)
m/z 505 (M + H).sup.+. Example 8-methoxy-N-(naphthalene-1- .sup.1H
NMR (501 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-124
sulfonyl)-5-(pyrrolidin-1-yl)-1,2,3,4- ppm 8.75-8.62 (m, 1H), 8.31
(d, J = 8.3 Hz, 1H), tetrahydronaphthalene-1- 8.25 (dd, J = 7.3,
1.2 Hz, 1H), 8.15 (d, J = 8.2 Hz, carboxamide 1H), 7.84 (ddd, J =
8.5, 6.9, 1.3 Hz, 1H), 7.74 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.68
(dd, J = 8.2, 7.4 Hz, 1H), 7.35 (d, J = 8.9 Hz, 1H), 6.71 (d, J =
9.2 Hz, 1H), 3.51 (s, 3H), 2.95 (s, 3H), 2.66-2.55 (m, 4H),
2.20-2.00 (m, 4H), 1.95-1.78 (m, 1H), 1.78-1.65 (m, 1H), 1.61-1.48
(m, 1H), 1.46-1.31 (m, 1H). MS (APCI+) m/z 465.1 (M + H).sup.+.
Example 4-chloro-1-ethyl-N-[2-methyl-3- .sup.1H NMR (501 MHz,
pyridine-d.sub.5) .delta. ppm 8.39 (dd, II-125
(piperidin-1-yl)benzene-1-sulfonyl]- J = 8.0, 1.3 Hz, 1H),
7.36-7.32 (m, 2H), 7.22 (d, 2,3-dihydro-1H-indene-1- J = 1.1 Hz,
1H), 7.19 (d, J = 1.0 Hz, 1H), 7.13 (t, J = 7.7 Hz, carboxamide
1H), 2.84 (s, 3H), 2.82-2.78 (m, 2H), 2.77-2.71 (m, 1H), 2.69-2.59
(m, 4H), 2.12-2.00 (m, 2H), 1.98-1.90 (m, 1H), 1.58 (p, J = 5.7 Hz,
4H), 1.47-1.37 (m, 2H), 0.79 (t, J = 7.4 Hz, 3H). MS (APCI+) m/z
461.3 (M + H).sup.+. Example 4-chloro-N-[3-(3,3-difluoroazetidin-
.sup.1H NMR (501 MHz, pyridine-d.sub.5) .delta. ppm 8.26 (d, J =
7.8 Hz, II-126 1-yl)-2-methylbenzene-1-sulfonyl]- 1H), 7.42-7.36
(m, 1H), 7.26 (t, J = 8.0 Hz, 1-ethyl-2,3-dihydro-1H-indene-1- 1H),
7.19 (d, J = 1.1 Hz, 1H), 7.14 (t, J = 7.6 Hz, carboxamide 1H),
6.78 (dd, J = 8.1, 1.2 Hz, 1H), 4.24 (td, J = 12.0, 3.2 Hz, 4H),
2.87-2.74 (m, 3H), 2.67 (s, 3H), 2.13-2.04 (m, 2H), 1.95 (dq, J =
14.6, 7.4 Hz, 1H), 0.81 (t, J = 7.3 Hz, 3H). MS (APCI+) m/z 469.2
(M + H).sup.+. Example 4-chloro-N-[3-(3,3- .sup.1H NMR (501 MHz,
Pyridine-d.sub.5) .delta. ppm 8.54 (dd, II-127
difluoropyrrolidin-1-yl)-2- J = 7.9, 1.3 Hz, 1H), 7.37-7.31 (m,
2H), 7.20 (d, methylbenzene-1-sulfonyl]-1-ethyl- J = 1.1 Hz, 1H),
7.18 (d, J = 1.1 Hz, 1H), 7.13 (td, 2,3-dihydro-1H-indene-1- J =
7.8, 3.7 Hz, 2H), 3.47-3.39 (m, 1H), 3.14 (t, J = 6.9 Hz,
carboxamide 1H), 2.91 (s, 2H), 2.88-2.80 (m, 3H), 2.79 (s, 2H),
2.79-2.74 (m, 1H), 2.39 (tt, J = 14.5, 6.9 Hz, 1H), 2.13-2.02 (m,
3H),
1.99-1.86 (m, 1H), 0.80 (td, J = 7.4, 4.4 Hz, 4H). MS (APCI+) m/z
483.2 (M + H).sup.+. Example 5-chloro-8-hydroxy-N-(naphthalene-
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 9.04 (bs, 1H), II-128
1-sulfonyl)-1,2,3,4- 8.51 (dd, J = 7.4, 1.2 Hz, 1H), 8.40-8.36 (m,
1H), tetrahydronaphthalene-1- 8.12 (d, J = 8.2 Hz, 1H), 7.98-7.94
(m, 1H), carboxamide 7.64-7.56 (m, 3H), 7.16-7.11 (m, 1H), 6.52 (d,
J = 8.5 Hz, 1H), 3.75-3.71 (m, 1H), 2.72-2.62 (m, 1H), 2.57-2.46
(m, 1H), 2.03? (m, 1H), 1.69-1.55 (m, 3H). MS (ESI+) m/z 416 (M +
H).sup.+. Example 5-methoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-129 sulfonyl)-8-[6-
ppm 8.53-8.42 (m, 2H), 8.35-8.27 (m, 1H),
(trifluoromethyl)pyridin-3-yl]- 8.22-8.10 (m, 2H), 7.78-7.59 (m,
3H), 1,2,3,4-tetrahydronaphthalene-1- 7.45-7.28 (m, 2H), 6.96 (d, J
= 8.4 Hz, 1H), 6.91 (d, J = 8.5 Hz, carboxamide 1H), 3.77 (s, 3H),
3.65-3.60 (m, 1H), 2.50-2.27 (m, 2H), 1.71-1.52 (m, 2H), 1.38-1.31
(m, 1H), 1.03-0.75 (m, 1H). MS (APCI+) m/z 541.0 (M + H).sup.+.
Example 8-(3,6-dihydro-2H-pyran-4-yl)-5- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-130
methoxy-N-(naphthalene-1- ppm 8.67 (d, J = 8.6 Hz, 1H), 8.41-8.03
(m, 2H), sulfonyl)-1,2,3,4- 7.90-7.51 (m, 4H), 6.88-6.65 (m, 2H),
5.14 (s, tetrahydronaphthalene-1- 1H), 3.83 (d, J = 23.4 Hz, 4H),
3.68-3.42 (m, carboxamide 4H), 2.46-2.20 (m, 2H), 2.10-1.82 (m,
2H), 1.70-1.55 (m, 2H), 1.40-1.26 (m, 1H), 1.01-0.81 (m, 1H). MS
(APCI+) m/z 478.0 (M + H).sup.+. Example
8-(6-cyclopropylpyridin-3-yl)-5- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. II-131
methoxy-N-(naphthalene-1- ppm 8.50-8.43 (m, 1H), 8.34-8.27 (m, 1H),
sulfonyl)-1,2,3,4- 8.22 (d, J = 2.1 Hz, 1H), 8.19-8.10 (m, 2H),
tetrahydronaphthalene-1- 7.80-7.70 (m, 2H), 7.67 (dd, J = 8.2, 7.5
Hz, 1H), carboxamide 7.54 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 8.3 Hz,
1H), 6.95 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.4 Hz, 1H), 3.76 (s,
3H), 3.64 (t, J = 5.3 Hz, 1H), 2.49-2.30 (m, 2H), 2.29-2.18 (m,
1H), 1.71-1.58 (m, 1H), 1.53-1.43 (m, 1H), 1.37-1.31 (m, 1H),
1.30-1.22 (m, 2H), 1.16-1.03 (m, 2H), 0.96 (s, 1H). MS (APCI+) m/z
513.0 (M + H).sup.+. Example 4-bromo-7-methoxy-N-[2-(propan-2-
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 12.66 (s, II-132
yl)quinoline-5-sulfonyl]-2,3- 1H), 8.95 (dd, J = 9.0, 0.8 Hz, 1H),
8.29 (d, J = 8.4 Hz, dihydro-1H-indene-1-carboxamide 1H), 8.25 (dd,
J = 7.5, 1.2 Hz, 1H), 7.88 (dd, J = 8.4, 7.5 Hz, 1H), 7.79 (d, J =
9.0 Hz, 1H), 7.29 (d, J = 8.7 Hz, 1H), 6.57 (d, J = 8.7 Hz, 1H),
4.03 (dd, J = 9.2, 5.8 Hz, 1H), 3.29 (dt, J = 13.8, 7.2 Hz, 1H),
3.05 (s, 3H), 2.78 (t, J = 7.5 Hz, 2H), 2.31 (ddt, J = 13.1, 9.1,
7.4 Hz, 1H), 1.87 (dtd, J = 13.4, 8.1, 6.3 Hz, 1H), 1.36 (dd, J =
6.9, 1.6 Hz, 6H). MS (APCI+) m/z 503 (M + H).sup.+. Example
4-bromo-7-methoxy-N-(5- .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 12.56 (s, II-133 methoxynaphthalene-1-sulfonyl)- 1H), 8.53 (d,
J = 8.4 Hz, 1H), 8.27 (dd, J = 7.4, 1.3 Hz,
2,3-dihydro-1H-indene-1- 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.71 (dd, J
= 8.7, carboxamide 7.8 Hz, 1H), 7.65 (dd, J = 8.5, 7.4 Hz, 1H),
7.29 (dd, J = 8.7, 0.7 Hz, 1H), 7.18 (dd, J = 7.9, 0.7 Hz, 1H),
6.60 (d, J = 8.7 Hz, 1H), 4.05 (dd, J = 9.2, 5.6 Hz, 1H), 4.02 (s,
3H), 3.18 (s, 3H), 2.74 (ddd, J = 9.3, 6.6, 3.2 Hz, 2H), 2.27 (dtd,
J = 13.1, 8.8, 6.6 Hz, 1H), 1.80 (dddd, J = 13.2, 8.4, 6.6, 5.6 Hz,
1H). MS (APCI+) m/z 490 (M + H).sup.+. Example methyl
7-methoxy-1-[(naphthalene- .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm II-134
1-sulfonyl)carbamoyl]-2,3-dihydro- 12.59 (s, 1H), 8.66 (dd, J =
8.7, 1.1 Hz, 1H), 1H-indene-4-carboxylate 8.30 (d, J = 8.2 Hz, 1H),
8.26 (dd, J = 7.4, 1.3 Hz, 1H), 8.17-8.10 (m, 1H), 7.84-7.78 (m,
1H), 7.76 (d, J = 8.6 Hz, 1H), 7.74-7.71 (m, 1H), 7.68 (dd, J =
8.2, 7.4 Hz, 1H), 6.73 (d, J = 8.7 Hz, 1H), 3.95 (dd, J = 9.4, 5.6
Hz, 1H), 3.74 (s, 3H), 3.16 (s, 3H), 3.06 (t, J = 7.6 Hz, 2H),
2.35-2.21 (m, 1H), 1.80 (td, J = 13.1, 7.2 Hz, 1H). MS (APCI+) m/z
440 (M + H).sup.+. Example methyl 5-[(4-bromo-7-methoxy-2,3-
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm
II-135 dihydro-1H-indene-1- 12.68 (s, 1H), 9.13-8.91 (m, 2H), 8.30
(ddd, J = 40.1, carbonyl)sulfamoyl]naphthalene-1- 7.4, 1.1 Hz, 2H),
7.86 (ddd, J = 25.6, 8.8, 7.4 Hz, carboxylate 2H), 7.29 (d, J = 8.7
Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.04 (dd, J = 9.2, 5.6 Hz, 1H),
3.98 (s, 3H), 3.12 (s, 3H), 2.75 (t, J = 7.5 Hz, 2H), 2.28 (ddt, J
= 15.0, 9.3, 7.4 Hz, 1H), 1.82 (dtd, J = 13.0, 7.4, 5.6 Hz, 1H).
MS(ESI-) m/z 515.8 (M - H).sup.-. Example
5-chloro-8-[2-(morpholin-4- .sup.1H NMR (501 MHz, CD.sub.2Cl.sub.2)
.delta. ppm II-136 yl)ethoxy]-N-(naphthalene-1- 8.57-8.54 (m, 1/H),
8.38 (dd, J = 7.4, 1.2 Hz, 1H), 8.18 (d, J = 8.3 Hz,
sulfonyl)-1,2,3,4- 1H), 8.02-8.00 (m, 1H), 7.73 (ddd, J = 8.5,
tetrahydronaphthalene-1- 6.9, 1.4 Hz, 1H), 7.66 (ddd, J = 8.1, 6.9,
1.2 Hz, carboxamide 1H), 7.63-7.59 (m, 1H), 7.25 (d, J = 8.7 Hz,
1H), 6.59 (d, J = 8.7 Hz, 1H), 4.38-4.32 (m, 1H), 4.10-4.05 (m,
4H), 3.94-3.89 (m, 1H), 3.83-3.78 (m, 1H), 3.78-3.74 (m, 1H),
3.69-3.64 (m, 1H), 3.60-3.54 (m, 1H), 3.30-3.25 (m, 1H), 3.15-3.08
(m, 1H), 3.00-2.93 (m, 1H), 2.66-2.49 (m, 2H), 1.77-1.68 (m, 1H),
1.49-1.39 (m, 3H). MS (ESI) m/z 529 (M + H).sup.+. Example
4-chloro-1-methyl-N- III-3 (phenylmethanesulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example
4-chloro-N-(1,3,5-trimethyl-1H- III-4
pyrazole-4-sulfonyl)-2,3-dihydro- 1H-indene-1-carboxamide Example
4-chloro-N-(2- III-5 methoxyethanesulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example
4-chloro-N-(propane-1-sulfonyl)- III-6 2,3-dihydro-1H-indene-1-
carboxamide Example 8-methoxy-N-(2-methylbenzene-1- MS (APCI+) m/z
360.1 (M + H).sup.+. III-7 sulfonyl)-1,2,3,4-
tetrahydronaphthalene-2- carboxamide Example
5-methoxy-N-(2-methylbenzene-1- MS (APCI+) m/z 346.1 (M + H).sup.+.
III-9 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
N-(2-methylbenzene-1-sulfonyl)- MS (APCI+) m/z 330.2 (M + H).sup.+.
III-10 1,2,3,4-tetrahydronaphthalene-2- carboxamide Example
4-methoxy-N-(1,3,5-trimethyl-1H- MS (ESI+) m/z 364 (M + H).sup.+.
III-11 pyrazole-4-sulfonyl)-2,3-dihydro- 1H-indene-1-carboxamide
Example 4-methoxy-N-(2-methoxybenzene-1- MS (ESI+) m/z 362 (M +
H).sup.+. III-12 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide
Example 4-methoxy-N-(5-methylpyridine-2- MS (ESI+) m/z 347 (M +
H).sup.+. III-13 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide
Example 4-methoxy-N-(oxane-4-sulfonyl)- MS (ESI+) m/z 340 (M +
H).sup.+. III-14 2,3-dihydro-1H-indene-1- carboxamide Example
4-methoxy-N-(3-methoxypropane-1- MS (ESI+) m/z 328 (M + H).sup.+.
III-15 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
4-methoxy-N-(2- MS (ESI+) m/z 314 (M + H).sup.+. III-16
methoxyethanesulfonyl)-2,3- dihydro-1H-indene-1-carboxamide Example
4-methoxy-N-(propane-1-sulfonyl)- III-17 2,3-dihydro-1H-indene-1-
carboxamide Example 4-chloro-N-(2-methoxybenzene-1- III-18
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-N-(5-methylpyridine-2- III-19
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
N-(4-hydroxybenzene-1-sulfonyl)-4- MS (APCI+) m/z 347.9 (M +
H).sup.+. III-20 methoxy-2,3-dihydro-1H-indene-1- carboxamide
Example 4-methoxy-N- MS (APCI+) m/z 345.9 (M + H).sup.+. III-21
(phenylmethanesulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example N-(6-hydroxynaphthalene-2- MS (APCI+) m/z 398.0 (M +
H).sup.+. III-22 sulfonyl)-4-methoxy-2,3-dihydro-
1H-indene-1-carboxamide Example 4-methoxy-N-(4-methylbenzene-1- MS
(APCI+) m/z 345.9 (M + H).sup.+. III-23
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
N-(5-acetamido-1,3,4-thiadiazole-2- MS (APCI+) m/z 397.0 (M +
H).sup.+. III-24 sulfonyl)-4-methoxy-2,3-dihydro-
1H-indene-1-carboxamide Example 4-methoxy-N-[5-methyl-2-(propan- MS
(APCI+) m/z 388.0 (M + H).sup.+. III-25
2-yl)benzene-1-sulfonyl]-2,3- dihydro-1H-indene-1-carboxamide
Example N-[4-(methanesulfonyl)benzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6: D.sub.2O = 9:1 (v/v)) .delta. III-26
sulfonyl]-4-methoxy-2,3-dihydro- ppm 8.17 (s, 4H), 7.14 (t, J = 7.9
Hz, 1H), 1H-indene-1-carboxamide 6.89-6.67 (m, 2H), 4.01 (dd, J =
8.3, 5.8 Hz, 1H), 3.74 (s, 3H), 3.29 (s, 3H), 2.88-2.64 (m, 2H),
2.25-2.06 (m, 2H). Example 4-methoxy-N-(3-nitrobenzene-1- .sup.1H
NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. III-27
sulfonyl)-2,3-dihydro-1H-indene-1- ppm 8.64-8.58 (m, 1H), 8.53
(ddd, J = 8.2, 2.3, carboxamide 1.0 Hz, 1H), 8.34 (ddd, J = 7.9,
1.8, 1.0 Hz, 1H), 7.93 (t, J = 8.1 Hz, 1H), 7.11 (t, J = 7.9 Hz,
1H), 6.79 (dd, J = 7.9, 5.4 Hz, 2H), 4.00 (dd, J = 8.2, 5.8 Hz,
1H), 3.74 (s, 3H), 2.86-2.64 (m, 2H), 2.25-2.04 (m, 2H). Example
N-(4-chloro-3-nitrobenzene-1- .sup.1H NMR (400 MHz, DMSO-d.sub.6:
D.sub.2O = 9:1 (v/v)) .delta. III-28
sulfonyl)-4-methoxy-2,3-dihydro- ppm 8.49 (d, J = 2.2 Hz, 1H), 8.17
(dd, J = 8.5, 2.3 Hz, 1H-indene-1-carboxamide 1H), 8.01 (d, J = 8.5
Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.8 Hz, 2H), 3.98
(t, J = 7.0 Hz, 1H), 3.75 (s, 3H), 2.87-2.64 (m, 2H), 2.22-2.08 (m,
2H). Example N-(6-chloro-1,1-dioxo-1,2-dihydro- MS (APCI+) m/z
369.9 (M + H).sup.+. III-29 1.lamda..sup.6,2,4-benzothiadiazine-7-
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
4-methoxy-N-(2-methyl-5- .sup.1H NMR (400 MHz, DMSO-d.sub.6:
D.sub.2O = 9:1 (v/v)) .delta. III-30 nitrobenzene-1-sulfonyl)-2,3-
ppm 8.64 (d, J = 2.5 Hz, 1H), 8.39 (dd, J = 8.4, 2.5 Hz,
dihydro-1H-indene-1-carboxamide 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.15
(t, J = 7.9 Hz, 1H), 6.82 (t, J = 7.6 Hz, 2H), 4.03 (dd, J = 8.5,
5.4 Hz, 1H), 3.74 (s, 3H), 2.91-2.63 (m, 5H), 2.27-2.11 (m, 1H),
2.15-2.03 (m, 1H). Example N-(4-acetamido-2-methylbenzene-1- MS
(APCI+) m/z 403.0 (M + H).sup.+. III-31
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-(4-chlorobenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6: D.sub.2O = 9:1 (v/v)) .delta. III-32
methoxy-2,3-dihydro-1H-indene-1- ppm 7.96-7.88 (m, 2H), 7.73-7.65
(m, 2H), carboxamide 7.13 (t, J = 7.8 Hz, 1H), 6.79 (dd, J = 14.2,
7.9 Hz, 2H), 4.01-3.93 (m, 1H), 3.75 (s, 3H), 2.87-2.64 (m, 2H),
2.24-2.04 (m, 2H). Example N-(4-chloro-2-nitrobenzene-1- .sup.1H
NMR (400 MHz, DMSO-d.sub.6: D.sub.2O = 9:1 (v/v)) .delta. III-33
sulfonyl)-4-methoxy-2,3-dihydro- ppm 8.23 (d, J = 2.0 Hz, 1H), 8.13
(d, J = 8.6 Hz, 1H-indene-1-carboxamide 1H), 7.94 (dd, J = 8.7, 2.1
Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.81
(d, J = 8.1 Hz, 1H), 4.04 (t, J = 7.1 Hz, 1H), 3.75 (s, 3H),
2.89-2.66 (m, 2H), 2.29-2.08 (m, 2H). Example
4-methoxy-N-(naphthalene-2- MS (APCI+) m/z 382.0 (M + H).sup.+.
III-34 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
N-(3-chlorobenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6: D.sub.2O = 9:1 (v/v)) .delta. III-35
methoxy-2,3-dihydro-1H-indene-1- ppm 7.92-7.84 (m, 2H), 7.81-7.74
(m, 1H), carboxamide 7.66 (t, J = 8.2 Hz, 1H), 7.14 (t, J = 7.9 Hz,
1H),
6.79 (dd, J = 12.2, 7.9 Hz, 2H), 4.03-3.94 (m, 1H), 3.75 (s, 3H),
2.87-2.65 (m, 2H), 2.25-2.05 (m, 2H). Example 4-methoxy-N-[4-(3- MS
(APCI+) m/z 431.0 (M + H).sup.+. III-36 oxobutanamido)benzene-1-
sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example
N-(2,4-dichlorobenzene-1-sulfonyl)- MS (APCI+) m/z 400.2 (M +
H).sup.+. III-37 4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide
Example N-(4-amino-2-chloro-5- MS (APCI+) m/z 395.1 (M + H).sup.+.
III-38 methylbenzene-1-sulfonyl)-4-
methoxy-2,3-dihydro-1H-indene-1- carboxamide Example
N-(2-chloro-5-methylbenzene-1- MS (APCI+) m/z 380.0 (M + H).sup.+.
III-39 sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide
Example N-(2-chloro-5-nitrobenzene-1- MS (APCI+) m/z 411.0 (M +
H).sup.+. III-40 sulfonyl)-4-methoxy-2,3-dihydro-
1H-indene-1-carboxamide Example N-(4-acetamidobenzene-1-sulfonyl)-
MS (APCI+) m/z 389.0 (M + H).sup.+. III-41
4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example
N-(4-acetamido-2-chlorobenzene-1- MS (APCI+) m/z 423. (M +
H).sup.+. III-42 sulfonyl)-4-methoxy-2,3-dihydro-
1H-indene-1-carboxamide Example N-(4-butanamidobenzene-1- MS
(APCI+) m/z 417.0 (M + H).sup.+. III-43
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-(5-chloro-1,3-dimethyl-1H- MS (APCI+) m/z 384.0 (M + H).sup.+.
III-44 pyrazole-4-sulfonyl)-4-methoxy-2,3-
dihydro-1H-indene-1-carboxamide Example N-(2,4-dihydroxy-6- .sup.1H
NMR (400 MHz, DMSO-d.sub.6: D.sub.2O = 9:1 (v/v)) .delta. III-45
methylpyrimidine-5-sulfonyl)-4- ppm 7.14 (t, J = 7.9 Hz, 1H), 6.83
(dd, J = 12.6, methoxy-2,3-dihydro-1H-indene-1- 7.8 Hz, 2H), 4.04
(t, J = 7.2 Hz, 1H), 3.76 (s, 3H), carboxamide 2.93-2.67 (m, 2H),
2.46 (s, 3H), 2.25-2.08 (m, 2H). Example
N-(4-cyanobenzene-1-sulfonyl)-4- .sup.1H NMR (400 MHz,
DMSO-d.sub.6: D.sub.2O = 9:1 (v/v)) .delta. III-46
methoxy-2,3-dihydro-1H-indene-1- ppm 8.08 (s, 4H), 7.14 (t, J = 7.9
Hz, 1H), carboxamide 6.79 (dd, J = 14.1, 7.8 Hz, 2H), 3.99 (dd, J =
8.3, 5.9 Hz, 1H), 3.75 (s, 3H), 2.86-2.64 (m, 2H), 2.24-2.03 (m,
2H). Example 4-methoxy-N-(2-oxo-2H-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6: D.sub.2O = 9:1 (v/v)) .delta. III-47
benzopyran-6-sulfonyl)-2,3-dihydro- ppm 8.29 (d, J = 2.3 Hz, 1H),
8.18 (d, J = 9.7 Hz, 1H-indene-1-carboxamide 1H), 8.08 (dd, J =
8.8, 2.4 Hz, 1H), 7.58 (d, J = 8.7 Hz, 1H), 7.12 (t, J = 7.8 Hz,
1H), 6.80 (t, J = 8.0 Hz, 2H), 6.61 (d, J = 9.6 Hz, 1H), 3.96 (t, J
= 7.1 Hz, 1H), 3.73 (s, 3H), 2.86-2.63 (m, 2H), 2.19-2.07 (m, 2H).
Example ethyl 4-[(4-methoxy-2,3-dihydro- MS (APCI+) m/z 404.1 (M +
H).sup.+. III-48 1H-indene-1- carbonyl)sulfamoyl]benzoate Example
N-(2,4-dimethyl-3-nitrobenzene-1- MS (APCI+) m/z 405.0 (M +
H).sup.+. III-49 sulfonyl)-4-methoxy-2,3-dihydro-
1H-indene-1-carboxamide Example N-{2-chloro-5-[(2,6- MS (APCI+) m/z
528.9 (M + H).sup.+. III-50 dimethylphenyl)carbamoyl]-4-
hydroxybenzene-1-sulfonyl}-4- methoxy-2,3-dihydro-1H-indene-1-
carboxamide Example N-[1-(2-chloroethyl)-3,5-dimethyl- MS (APCI+)
m/z 412.0 (M + H).sup.+. III-51 1H-pyrazole-4-sulfonyl]-4-methoxy-
2,3-dihydro-1H-indene-1- carboxamide Example
N-[3-({[(2S)-1-ethylpyrrolidin-2- MS (APCI+) m/z 516.0 (M +
H).sup.+. III-52 yl]methyl}carbamoyl)-4-
methoxybenzene-1-sulfonyl]-4- methoxy-2,3-dihydro-1H-indene-1-
carboxamide Example N-(6-ethoxy-1,3-benzothiazole-2- MS (APCI+) m/z
433.0 (M + H).sup.+. III-53 sulfonyl)-4-methoxy-2,3-dihydro-
1H-indene-1-carboxamide Example N-(4-hexanoylbenzene-1-sulfonyl)-
MS (APCI+) m/z 430.3 (M + H).sup.+. III-54
4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example
N-[4-(4-{2-[(1S)-3,4-dihydro-1H-2- MS (APCI+) m/z 576.1 (M +
H).sup.+. III-55 benzopyran-1-yl]ethyl}piperazin-1-
yl)benzene-1-sulfonyl]-4-methoxy- 2,3-dihydro-1H-indene-1-
carboxamide Example propan-2-yl 2-[(4-methoxy-2,3- MS (APCI+) m/z
418.0 (M + H).sup.+. III-56 dihydro-1H-indene-1-
carbonyl)sulfamoyl]benzoate Example N-{4-[(3-hydroxy-3- MS (APCI+)
m/z 478.0 (M + H).sup.+. III-57 methylbutyl)amino]-3-nitrobenzene-
1-sulfonyl}-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-[2-chloro-5-(1,3-dimethyl-2,6- MS (APCI+) m/z 543.8 (M +
H).sup.+. III-58 dioxo-2,3,6,7-tetrahydro-1H-purin-
8-yl)benzene-1-sulfonyl]-4- methoxy-2,3-dihydro-1H-indene-1-
carboxamide Example N-{7-[(4-chlorophenyl)methyl]-1,3- MS (APCI+)
m/z 557.8 (M + H).sup.+. III-59 dimethyl-2,6-dioxo-2,3,6,7-
tetrahydro-1H-purine-8-sulfonyl}-4-
methoxy-2,3-dihydro-1H-indene-1- carboxamide Example
N-(9-benzyl-1,3-dimethyl-2,6-dioxo- MS (APCI+) m/z 524.0 (M +
H).sup.+. III-60 2,3,6,9-tetrahydro-1H-purine-8-
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-{4- MS (APCI+) m/z 389.0 (M + H).sup.+. III-61
[(dimethylamino)methyl]benzene-1- sulfonyl}-4-methoxy-2,3-dihydro-
1H-indene-1-carboxamide Example N-(2-cyano-3-fluorobenzene-1- MS
(APCI+) m/z 374.3 (M + H).sup.+. III-62
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-(4-hydroxy-3-nitrobenzene-1- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. III-63
sulfonyl)-4-methoxy-2,3-dihydro- ppm 8.36 (d, J = 2.4 Hz, 1H), 8.01
(dd, J = 8.9, 2.4 Hz, 1H-indene-1-carboxamide 1H), 7.27 (d, J = 8.9
Hz, 1H), 7.12 (t, J = 7.9 Hz, 1H), 6.79 (dd, J = 14.2, 7.9 Hz, 2H),
3.98 (dd, J = 8.2, 5.9 Hz, 1H), 3.75 (s, 3H), 2.87-2.65 (m, 2H),
2.25-2.05 (m, 2H). Example N-(3-cyanobenzene-1-sulfonyl)-4- .sup.1H
NMR (400 MHz, DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. III-64
methoxy-2,3-dihydro-1H-indene-1- ppm 8.29 (t, J = 1.8 Hz, 1H),
8.26-8.19 (m, 1H), carboxamide 8.19-8.12 (m, 1H), 7.84 (t, J = 7.9
Hz, 1H), 7.14 (t, J = 7.9 Hz, 1H), 6.80 (dd, J = 9.9, 7.9 Hz, 2H),
4.00 (dd, J = 8.2, 5.9 Hz, 1H), 3.75 (s, 3H), 2.87-2.65 (m, 2H),
2.25-2.04 (m, 2H). Example N-(5-bromopyridine-3-sulfonyl)-4- MS
(APCI+) m/z 410.8 (M + H).sup.+. III-65
methoxy-2,3-dihydro-1H-indene-1- carboxamide Example
N-(6-hydroxypyridine-3-sulfonyl)-4- MS (APCI+) m/z 348.9 (M +
H).sup.+. III-66 methoxy-2,3-dihydro-1H-indene-1- carboxamide
Example N-(4-cyano-1,3-dimethyl-1H- .sup.1H NMR (400 MHz,
DMSO-d.sub.6:D.sub.2O = 9:1 (v/v)) .delta. III-67
pyrazole-5-sulfonyl)-4-methoxy-2,3- ppm 8.06 (d, J = 8.6 Hz, 1H),
7.89 (d, J = 2.1 Hz, dihydro-1H-indene-1-carboxamide 1H), 7.66 (dd,
J = 8.6, 2.1 Hz, 1H), 7.16 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 7.6
Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 4.06 (dd, J = 8.5, 5.6 Hz, 1H),
3.75 (s, 3H), 2.87-2.66 (m, 2H), 2.29-2.04 (m, 2H). Example
tert-butyl 5-[(4-methoxy-2,3- MS (APCI+) m/z 450.0 (M + H).sup.+.
III-68 dihydro-1H-indene-1- carbonyl)sulfamoyl]-1,3-dimethyl-
1H-pyrazole-4-carboxylate Example
N-[4-(hydroxymethyl)-1,3-dimethyl- MS (APCI+) m/z 380.0 (M +
H).sup.+. III-69 1H-pyrazole-5-sulfonyl]-4-methoxy-
2,3-dihydro-1H-indene-1- carboxamide Example
N-(3-chloro-2-fluorobenzene-1- III-70
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-(2,6-difluorobenzene-1-sulfonyl)- III-71
4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example
4,5-dimethoxy-N-(2-methylbenzene- III-72
1-sulfonyl)-2,3-dihydro-1H-indene- 1-carboxamide Example
N-(5-chloro-2-fluorobenzene-1- III-73
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-(2,5-difluorobenzene-1-sulfonyl)- III-74
4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example
N-(2-chloro-5-fluorobenzene-1- III-75
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-(2,6-dichlorobenzene-1-sulfonyl)- III-76
4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example
N-(2,4-difluorobenzene-1-sulfonyl)- III-77
4-methoxy-2,3-dihydro-1H-indene- 1-carboxamide Example
4-methoxy-N-[1-(2-methoxyethyl)- III-78
1H-pyrazole-4-sulfonyl]-2,3- dihydro-1H-indene-1-carboxamide
Example N-(3,5-dimethyl-1,2-oxazole-4- III-79
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
N-(2,4-dimethyl-1,3-thiazole-5- III-80
sulfonyl)-4-methoxy-2,3-dihydro- 1H-indene-1-carboxamide Example
4-methoxy-N-(pyridine-3-sulfonyl)- III-81 2,3-dihydro-1H-indene-1-
carboxamide Example 2-[(4-methoxy-2,3-dihydro-1H- III-82
indene-1-carbonyl)sulfamoyl]-N,N- dimethylpyridine-3-carboxamide
Example N-(2-cyanopyridine-3-sulfonyl)-4- III-83
methoxy-2,3-dihydro-1H-indene-1- carboxamide Example
4-methoxy-N-(pyridine-2-sulfonyl)- III-84 2,3-dihydro-1H-indene-1-
carboxamide Example 4-(6-methoxypyridin-3-yl)-N-(2- III-85
methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example N-(2-methylbenzene-1-sulfonyl)-4- III-86
[6-(piperidin-1-yl)pyridin-3-yl]-2,3-
dihydro-1H-indene-1-carboxamide Example
N-(2-methylbenzene-1-sulfonyl)-4- III-87
[6-(4-methylpiperazin-1-yl)pyridin- 3-yl]-2,3-dihydro-1H-indene-1-
carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- III-88
(2-methylpyridin-3-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example
4-(6-fluoropyridin-3-yl)-N-(2- III-89
methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example 4-[6-(dimethylamino)pyridin-3-yl]- III-90
N-(2-methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example 4-(5-fluoropyridin-3-yl)-N-(2- III-91
methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example N-(2-methylbenzene-1-sulfonyl)-4- III-92
(5-methylpyridin-3-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example
4-(2-fluoropyridin-4-yl)-N-(2- III-93
methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example 4-(3-fluoropyridin-4-yl)-N-(2- III-94
methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example N-(2-methylbenzene-1-sulfonyl)-4-
III-95 (3-methylpyridin-4-yl)-2,3-dihydro- 1H-indene-1-carboxamide
Example N-(2-methylbenzene-1-sulfonyl)-4- III-96
(2-methylpyridin-4-yl)-2,3-dihydro- 1H-indene-1-carboxamide Example
N-(2-methylbenzene-1-sulfonyl)-4- III-97
(1H-pyrazol-4-yl)-2,3-dihydro-1H- indene-1-carboxamide Example
N-(2-methylbenzene-1-sulfonyl)-4- III-98
(1H-pyrazol-5-yl)-2,3-dihydro-1H- indene-1-carboxamide Example
N-(2-methylbenzene-1-sulfonyl)-4- III-99
(thiophen-3-yl)-2,3-dihydro-1H- indene-1-carboxamide Example
N-(2-methylbenzene-1-sulfonyl)-4- .sup.1H NMR 400 MHz (CDCl.sub.3)
.delta. ppm 8.26 (1H, d); III-100 [6-(morpholin-4-yl)pyridin-3-yl]-
8.16 (1H, d); 8.02 (1H, s); 7.52 (1H, t); 7.39 (1H,
2,3-dihydro-1H-indene-1- t); 7.27-7.33 (4H, m); 6.79 (1H, d); 6.73
(1H, s br); carboxamide 4.09 (1H, t); 3.87 (4H, m); 3.68 (4H, m);
3.07-3.14 (1H, m); 2.88-2.96 (1H, m); 2.63 (3H, s); 2.38-2.45 (1H,
m); 2.28-2.31 (1H, m). MS (ESI+) m/z 478 (M + H).sup.+. Example
N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M + H).sup.+.
III-101 (3-methyl-1H-pyrazol-4-yl)-2,3-
dihydro-1H-indene-1-carboxamide Example
N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M + H).sup.+.
III-102 (1-methyl-1H-pyrazol-4-yl)-2,3-
dihydro-1H-indene-1-carboxamide Example
N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M + H).sup.+.
III-103 (5-methylfuran-2-yl)-2,3-dihydro- 1H-indene-1-carboxamide
Example N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z 396 (M +
H).sup.+. III-104 (2-methylfuran-3-yl)-2,3-dihydro-
1H-indene-1-carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4-
MS (ESI+) m/z 424 (M + H).sup.+. III-105
(1,3,5-trimethyl-1H-pyrazol-4-yl)- 2,3-dihydro-1H-indene-1-
carboxamide Example N-(2-methylbenzene-1-sulfonyl)-4- MS (ESI+) m/z
396 (M + H).sup.+. III-106 (1-methyl-1H-pyrazol-5-yl)-2,3-
dihydro-1H-indene-1-carboxamide Example (1R)-N-(2-aminopyridine-3-
MS (APCI+) m/z 362 (M + H).sup.+. III-107
sulfonyl)-5-methoxy-1,2,3,4- tetrahydronaphthalene-1- carboxamide
Example N-(6-aminopyridine-2-sulfonyl)-1,5- MS (ESI+) m/z 346 (M +
H).sup.+. III-108 dimethyl-2,3-dihydro-1H-indene-1- carboxamide
Example (1R)-N-(6-aminopyridine-2- MS (APCI+) m/z 362 (M +
H).sup.+. III-109 sulfonyl)-5-methoxy-1,2,3,4-
tetrahydronaphthalene-1- carboxamide Example
N-(6-aminopyridine-2-sulfonyl)-8- MS (APCI+) m/z 366 (M + H).sup.+.
III-110 chloro-1,2,3,4- tetrahydronaphthalene-1- carboxamide
Example 4-chloro-N-(naphthalene-1- MS (ESI+) m/z 483 (M + H).sup.+.
III-111 sulfonyl)-1-[2-(pyrrolidin-1-
yl)ethyl]-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-1-{2-[(2- MS (ESI+) m/z 501 (M + H).sup.+. III-112
methoxyethyl)(methyl)amino]ethyl}- N-(naphthalene-1-sulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example
4-chloro-N-(2,4-dichlorobenzene-1- MS (APCI+) m/z 431.9 (M +
H).sup.+. III-113 sulfonyl)-1-ethyl-2,3-dihydro-1H-
indene-1-carboxamide Example 4-chloro-N-(2,4-dimethylbenzene-1- MS
(APCI+) m/z 392.1 (M + H).sup.+. III-114
sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example
4-chloro-N-(2,6-difluorobenzene-1- MS (APCI+) m/z 400.0 (M +
H).sup.+. III-115 sulfonyl)-1-ethyl-2,3-dihydro-1H-
indene-1-carboxamide Example 4-chloro-N-(2,5-dichlorobenzene-1- MS
(APCI+) m/z 431.9 (M + H).sup.+. III-116
sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example
4-chloro-N-(3-chlorobenzene-1- MS (APCI+) m/z 398.0 (M + H).sup.+.
III-117 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide
Example 4-chloro-N-(2-chloro-5- MS (APCI+) m/z 412.0 (M + H).sup.+.
III-118 methylbenzene-1-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1-
carboxamide Example 4-chloro-1-ethyl-N-[4- MS (APCI+) m/z 447.9 (M
+ H).sup.+. III-119 (trifluoromethoxy)benzene-1-
sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-N-(2-cyanobenzene-1- MS (APCI+) m/z 389.0 (M + H).sup.+.
III-120 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide
Example 4-chloro-N-(2,6-dimethoxybenzene- MS (APCI+) m/z 424.0 (M +
H).sup.+. III-121 1-sulfonyl)-1-ethyl-2,3-dihydro-1H-
indene-1-carboxamide Example 4-chloro-1-ethyl-N-[2- MS (APCI+) m/z
432.0 (M + H).sup.+. III-122 (trifluoromethyl)benzene-1-
sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-N-(2,3-dihydro-1,4- MS (APCI+) m/z 422.0 (M + H).sup.+.
III-123 benzodioxine-6-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1-
carboxamide Example 4-chloro-N-(2-chloro-6- MS (APCI+) m/z 412.0 (M
+ H).sup.+. III-124 methylbenzene-1-sulfonyl)-1-ethyl-
2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-N-(4-chlorobenzene-1- MS (APCI+) m/z 398.0 (M + H).sup.+.
III-125 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide
Example 4-chloro-1-ethyl-N-[2-methyl-6- MS (APCI+) m/z 445.9 (M +
H).sup.+. III-126 (trifluoromethyl)benzene-1-
sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-N-(2-cyano-3- MS (APCI+) m/z 407.0 (M + H).sup.+. III-127
fluorobenzene-1-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1-
carboxamide Example 4-chloro-1-ethyl-N-(1- MS (APCI+) m/z 342.1 (M
+ H).sup.+. III-128 methylcyclopropane-1-sulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example
N-([1,1'-biphenyl]-4-sulfonyl)-4- MS (APCI+) m/z 440.0 (M +
H).sup.+. III-129 chloro-1-ethyl-2,3-dihydro-1H-
indene-1-carboxamide Example 4-chloro-N-{4- MS (APCI+) m/z 421.0 (M
+ H).sup.+. III-130 [(dimethylamino)methyl]benzene-1-
sulfonyl}-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide Example
4-chloro-N-(5-chloro-1,3-dimethyl- MS (APCI+) m/z 416.0 (M +
H).sup.+. III-131 1H-pyrazole-4-sulfonyl)-1-ethyl-2,3-
dihydro-1H-indene-1-carboxamide Example
4-chloro-N-(2-chloropyridine-3- MS (APCI+) m/z 399.0 (M + H).sup.+.
III-132 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide
Example 4-chloro-1-ethyl-N-(quinoline-6- MS (APCI+) m/z 415.0 (M +
H).sup.+. III-133 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide
Example 4-chloro-N-(6-chloroimidazo[2,1- MS (APCI+) m/z 443.9 (M +
H).sup.+. III-134 b][1,3]thiazole-5-sulfonyl)-1-ethyl-
2,3-dihydro-1H-indene-1- carboxamide Example
2-[(4-chloro-1-ethyl-2,3-dihydro- MS (APCI+) m/z 436.0 (M +
H).sup.+. III-135 1H-indene-1-carbonyl)sulfamoyl]-
N,N-dimethylpyridine-3- carboxamide Example
4-chloro-N-(cyclohexanesulfonyl)-1- MS (APCI+) m/z 370.1 (M +
H).sup.+. III-136 ethyl-2,3-dihydro-1H-indene-1- carboxamide
Example 4-chloro-1-ethyl-N-{4-[4-(propan-2- MS (APCI+) m/z 491.0 (M
+ H).sup.+. III-137 yl)piperazin-1-yl]pyridine-3-
sulfonyl}-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-1-ethyl-N-{2-[2-(piperidin- MS (APCI+) m/z 491.0 (M +
H).sup.+. III-138 1-yl)ethoxy]benzene-1-sulfonyl}-
2,3-dihydro-1H-indene-1- carboxamide Example 4-chloro-1-ethyl-N-(4-
MS (APCI+) m/z 378.1 (M + H).sup.+. III-139
methylbenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example 4-chloro-1-ethyl-N- MS (APCI+) m/z 378.1 (M + H).sup.+.
III-140 (phenylmethanesulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example
4-chloro-1-ethyl-N-(2-methyl-1,3- MS (APCI+) m/z 446.9 (M +
H).sup.+. III-141 dioxo-2,3-dihydro-1H-isoindole-4-
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-1-ethyl-N-(4- MS (APCI+) m/z 394.1 (M + H).sup.+. III-142
methoxybenzene-1-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example 4-chloro-1-ethyl-N-(4- MS (APCI+) m/z 456.0 (M + H).sup.+.
III-143 phenoxybenzene-1-sulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example
4-chloro-N-(3-cyanobenzene-1- MS (APCI+) m/z 389.0 (M + H).sup.+.
III-144 sulfonyl)-1-ethyl-2,3-dihydro-1H- indene-1-carboxamide
Example 4-chloro-1-ethyl-N-(1H-pyrazole-3- MS (APCI+) m/z 354.1 (M
+ H).sup.+. III-145 sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide
Example 3-{4-chloro-1-[(naphthalene-1- MS (APCI+) m/z 386.0 (M +
H).sup.+. III-146 sulfonyl)carbamoyl]-2,3-dihydro-
1H-inden-1-yl}propanoic acid Example 4-chloro-N-(naphthalene-1- MS
(APCI+) m/z 476.9 (M + H).sup.+. III-147
sulfonyl)-1-[(pyridin-2-yl)methyl]- 2,3-dihydro-1H-indene-1-
carboxamide Example 5-methoxy-N-(naphthalene-1- MS (APCI+) m/z
556.0 (M + H).sup.+. III-148 sulfonyl)-8-[3-
(trifluoromethoxy)phenyl]-1,2,3,4- tetrahydronaphthalene-1-
carboxamide Example methyl 2-chloro-6-[(4-chloro-1- MS (APCI+) m/z
455.8 (M + H).sup.+. III-149 ethyl-2,3-dihydro-1H-indene-1-
carbonyl)sulfamoyl]benzoate Example 4-chloro-1-ethyl-N-methyl-N- MS
(ESI+) m/z 428 (M + H).sup.+. III-150 (naphthalene-1-sulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example
4-chloro-1-(methoxymethyl)-N- MS (ESI+) m/z 430 (M + H).sup.+.
III-151 (naphthalene-1-sulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example
4-bromo-7-hydroxy-N-(naphthalene- MS (APCI+) m/z 446.0 (M +
H).sup.+. III-152 1-sulfonyl)-2,3-dihydro-1H-indene- 1-carboxamide
Example 5-methoxy-8-(morpholin-4-yl)-N- MS (APCI+) m/z 481.0 (M +
H).sup.+. III-153 (naphthalene-1-sulfonyl)-1,2,3,4-
tetrahydronaphthalene-1- carboxamide Example
5-methoxy-N-(naphthalene-1- MS (APCI+) m/z 540.0 (M + H).sup.+.
III-154 sulfonyl)-8-[4- (trifluoromethyl)phenyl]-1,2,3,4-
tetrahydronaphthalene-1- carboxamide Example
4-chloro-1-(cyanomethyl)-N- MS (ESI+) m/z 442 (M + NH.sub.4).sup.+.
III-155 (naphthalene-1-sulfonyl)-2,3-
dihydro-1H-indene-1-carboxamide Example 4-chloro-N-(3-chloro-2- MS
(APCI+) m/z 412.0 (M + H).sup.+. III-156
methylbenzene-1-sulfonyl)-1-ethyl- 2,3-dihydro-1H-indene-1-
carboxamide Example 8-chloro-1-cyano-N-(naphthalene-1- MS (ESI+)
m/z 442 (M +
NH.sub.4).sup.+. III-157 sulfonyl)-1,2,3,4-
tetrahydronaphthalene-1- carboxamide Example
4-bromo-7-methoxy-N-(2- MS (APCI+) m/z 441 (M + H).sup.+. III-158
methoxypyridine-3-sulfonyl)-2,3- dihydro-1H-indene-1-carboxamide
Example N-(2-aminopyridine-3-sulfonyl)-4- MS (APCI+) m/z 426 (M +
H).sup.+. III-159 bromo-7-methoxy-2,3-dihydro-1H-
indene-1-carboxamide Example N-(6-aminopyridine-2-sulfonyl)-4- MS
(APCI+) m/z 426 (M + H).sup.+. III-160
bromo-7-methoxy-2,3-dihydro-1H- indene-1-carboxamide Example
4-bromo-N-(4-ethoxynaphthalene-1- MS (APCI+) m/z 504 (M + H).sup.+.
III-161 sulfonyl)-7-methoxy-2,3-dihydro- 1H-indene-1-carboxamide
Example 4-bromo-7-methoxy-N-(4- MS (APCI+) m/z 490 (M + H).sup.+.
III-162 methoxynaphthalene-1-sulfonyl)- 2,3-dihydro-1H-indene-1-
carboxamide Example 4-bromo-7-methoxy-N- MS (APCI+) 452 m/z (M +
H).sup.+. III-163 ([1,2,4]triazolo[4,3-a]pyridine-8-
sulfonyl)-2,3-dihydro-1H-indene-1- carboxamide Example
8-methoxy-N-(naphthalene-1- MS (APCI+) m/z 474.0 (M + H).sup.+.
III-164 sulfonyl)-5-(pyrimidin-5-yl)-1,2,3,4-
tetrahydronaphthalene-1- carboxamide Example
5-(6-cyclopropylpyridin-3-yl)-8- MS (APCI+) m/z 513.0 (M +
H).sup.+. III-165 methoxy-N-(naphthalene-1- sulfonyl)-1,2,3,4-
tetrahydronaphthalene-1- carboxamide Example
8-methoxy-N-(naphthalene-1- MS (APCI+) m/z 473.0 (M + H).sup.+.
III-166 sulfonyl)-5-(pyridin-4-yl)-1,2,3,4-
tetrahydronaphthalene-1- carboxamide Example
8-methoxy-5-(6-methylpyridin-3- MS (APCI+) m/z 487.0 (M + H).sup.+.
III-167 yl)-N-(naphthalene-1-sulfonyl)-
1,2,3,4-tetrahydronaphthalene-1- carboxamide Example
7-methoxy-4-(pyrimidin-5-yl)-N- MS (APCI+) m/z 461.0 (M + H).sup.+.
III-168 (quinoline-5-sulfonyl)-2,3-dihydro- 1H-indene-1-carboxamide
Example 4-(3,6-dihydro-2H-pyran-4-yl)-7- MS (APCI+) m/z 465.0 (M +
H).sup.+. III-169 methoxy-N-(quinoline-5-sulfonyl)-
2,3-dihydro-1H-indene-1- carboxamide Example
8-methoxy-5-(4-methylphenyl)-N- MS (APCI+) m/z 486.0 (M + H).sup.+.
III-170 (naphthalene-1-sulfonyl)-1,2,3,4- tetrahydronaphthalene-1-
carboxamide Example 8-methoxy-N-(naphthalene-1- MS (APCI+) m/z
541.0 (M + H).sup.+. III-171 sulfonyl)-5-[6-
(trifluoromethyl)pyridin-3-yl]- 1,2,3,4-tetrahydronaphthalene-1-
carboxamide Example 4-chloro-1-ethyl-N-[2-methyl-3- MS (APCI+) m/z
463.2 (M + H).sup.+. III-172 (morpholin-4-yl)benzene-1-
sulfonyl]-2,3-dihydro-1H-indene-1- carboxamide Example
4-chloro-1-ethyl-N-{3-[(2- MS (APCI+) m/z 465.2 (M + H).sup.+.
III-173 methoxyethyl)(methyl)amino]-2-
methylbenzene-1-sulfonyl}-2,3- dihydro-1H-indene-1-carboxamide
Example 5-methoxy-N-(naphthalene-1- MS (APCI+) m/z 465.1 (M +
H).sup.+. III-174 sulfonyl)-8-(pyrrolidin-1-yl)-1,2,3,4-
tetrahydronaphthalene-1- carboxamide Example 2,3-dimethoxy-N-(2- MS
(APCI+) m/z 362.1 (M + H).sup.+. III-175 methylbenzene-1-
sulfonyl)bicyclo[4.2.0]octa-1,3,5- triene-7-carboxamide Example
N-(2-methylbenzene-1- MS (APCI+) m/z 302.1 (M + H).sup.+. III-176
sulfonyl)bicyclo[4.2.0]octa-1,3,5- triene-7-carboxamide Example
2,3-dimethoxy-N-(naphthalene-1- MS (APCI+) m/z 398.0 (M + H).sup.+.
III-177 sulfonyl)bicyclo[4.2.0]octa-1,3,5- triene-7-carboxamide
Example 2-methoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz,
Chloroform-d) .delta. ppm III-178 sulfonyl)-6,7-dihydro-5H- 8.52
(ddd, J = 8.4, 4.0, 1.2 Hz, 2H), 8.14 (d, J = 8.2 Hz,
cyclopenta[b]pyridine-5- 1H), 7.98 (dd, J = 7.9, 1.5 Hz, 1H),
7.73-7.57 (m, carboxamide 3H), 7.13 (dd, J = 8.5, 0.8 Hz, 1H), 6.35
(d, J = 8.3 Hz, 1H), 3.86 (s, 3H), 3.83-3.79 (m, 1H), 3.00-2.88 (m,
1H), 2.81 (ddd, J = 16.7, 9.0, 6.6 Hz, 1H), 2.40-2.28 (m, 1H),
2.11-2.01 (m, 1H), 1.37-1.20 (m, 1H). MS (ESI+) m/z 383.2 (M +
H).sup.+. Example 2-chloro-6-[(4-chloro-1-ethyl-2,3- MS (APCI+) m/z
441.9 (M + H).sup.+. III-179 dihydro-1H-indene-1-
carbonyl)sulfamoyl]benzoic acid Example 1-methoxy-N-(naphthalene-1-
.sup.1H NMR (400 MHz, Chloroform-d) .delta. ppm III-180
sulfonyl)-6,7-dihydro-5H- 10.13 (s, 1H), 8.77 (dd, J = 6.9, 1.2 Hz,
1H), 8.35 (dd, J = 7.5, cyclopenta[c]pyridine-7- 1.2 Hz, 1H), 8.26
(s, 1H), 7.38 (d, J = 8.6 Hz, carboxamide 1H), 7.20 (t, J = 7.1 Hz,
1H), 6.75 (d, J = 8.6 Hz, 1H), 4.19-4.13 (m, 1H), 4.11 (s, 3H),
2.95-2.72 (m, 2H), 2.58 (ddt, J = 11.8, 7.5, 2.2 Hz, 1H), 2.11 (dq,
J = 12.5, 9.0 Hz, 1H). MS (APCI+) 452 m/z (M + H).sup.+. Example
5-[(4-bromo-7-methoxy-2,3- .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm III-181 dihydro-1H-indene-1- 12.67
(s, 1H), 9.14 (d, J = 8.7 Hz, 1H), 8.89 (d, J = 8.7 Hz,
carbonyl)sulfamoyl]naphthalene-1- 1H), 8.34 (d, J = 7.2 Hz, 1H),
8.26 (d, J = 7.0 Hz, carboxylic acid 1H), 7.94-7.79 (m, 2H), 7.29
(d, J = 8.7 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H), 4.04 (dd, J = 9.2,
5.6 Hz, 1H), 3.13 (s, 3H), 2.75 (t, J = 7.5 Hz, 2H), 2.28 (tt, J =
13.3, 4.7 Hz, 1H), 1.89-1.75 (m, 1H). MS (ESI-) m/z 515.8 (M -
H).sup.-. MS (ESI+) m/z = 504 (M + H).sup.+. Example
7-methoxy-N-(naphthalene-1- .sup.1H NMR (400 MHz, dimethyl
sulfoxide-d.sub.6) .delta. ppm III-182
sulfonyl)-2,3-dihydro-1H-indene-1- 12.52 (s, 1H), 8.67 (dd, J =
8.6, 1.0 Hz, 1H), carboxamide 8.30 (d, J = 8.3 Hz, 1H), 8.26 (dd, J
= 7.4, 1.3 Hz, 1H), 8.17-8.11 (m, 1H), 7.80 (ddd, J = 8.5, 6.8, 1.4
Hz, 1H), 7.74-7.70 (m, 1H), 7.68 (dd, J = 8.2, 7.4 Hz, 1H), 7.08
(t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.4 Hz, 1H), 6.56 (d, J = 8.0 Hz,
1H), 3.94 (dd, J = 9.0, 5.8 Hz, 1H), 3.10 (s, 3H), 2.78-2.71 (m,
2H), 2.29-2.16 (m, 1H), 1.85-1.72 (m, 1H). MS (APCI+) m/z 382 (M +
H).sup.+. Example 7-methoxy-1-[(naphthalene-1- .sup.1H NMR (400
MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm III-183
sulfonyl)carbamoyl]-2,3-dihydro- 12.57 (s, 1H), 12.42 (s, 1H), 8.66
(dd, J = 8.7, 1.1 Hz, 1H-indene-4-carboxylic acid 1H), 8.30 (d, J =
8.2 Hz, 1H), 8.26 (dd, J = 7.4, 1.2 Hz, 1H), 8.14 (dd, J = 8.3, 1.3
Hz, 1H), 7.80 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H), 7.74 (d, J = 8.6 Hz,
1H), 7.73-7.61 (m, 2H), 6.70 (d, J = 8.6 Hz, 1H), 3.94 (dd, J =
9.4, 5.6 Hz, 1H), 3.16 (s, 3H), 3.06 (t, J = 7.5 Hz, 2H), 2.25
(ddt, J = 13.1, 9.4, 7.5 Hz, 1H), 1.80 (dtd, J = 13.0, 7.4, 5.5 Hz,
1H). MS (APCI+) m/z 426 (M + H).sup.+. Example methyl
7-methoxy-3-[(naphthalene- MS (APCI+) m/z 440.0 (M + H).sup.+.
III-184 1-sulfonyl)carbamoyl]-2,3-dihydro- 1H-indene-4-carboxylate
Example 4-(hydroxymethyl)-7-methoxy-N- .sup.1H NMR (500 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm III-185
(naphthalene-1-sulfonyl)-2,3- 12.50 (s, 1H), 8.68 (d, J = 8.7 Hz,
1H), 8.30 (d, J = 8.2 Hz, dihydro-1H-indene-1-carboxamide 1H), 8.27
(d, J = 7.5 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.83-7.78 (m, 1H),
7.75-7.65 (m, 2H), 7.07 (d, J = 8.2 Hz, 1H), 6.55 (d, J = 8.3 Hz,
1H), 4.86 (s, 1H), 4.41-4.17 (m, 2H), 3.95 (dd, J = 9.1, 5.8 Hz,
1H), 3.10 (d, J = 1.1 Hz, 3H), 2.73 (q, J = 6.6 Hz, 2H), 2.23 (dq,
J = 14.9, 8.0 Hz, 1H), 1.79 (dq, J = 14.0, 6.8 Hz, 1H). MS (APCI+)
m/z 412 (M + H).sup.+. Example 7-methoxy-N.sup.4-methyl-N.sup.1-
.sup.1H NMR (501 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm
III-186 (naphthalene-1-sulfonyl)-2,3- 12.55 (s, 1H), 8.67 (dd, J =
8.7, 1.0 Hz, 1H), dihydro-1H-indene-1,4- 8.30 (d, J = 8.2 Hz, 1H),
8.26 (dd, J = 7.4, 1.2 Hz, 1H), dicarboxamide 8.18-8.13 (m, 1H),
7.93 (q, J = 4.5 Hz, 1H), 7.80 (ddd, J = 8.5, 6.9, 1.4 Hz, 1H),
7.72 (ddd, J = 8.0, 6.9, 1.1 Hz, 1H), 7.68 (dd, J = 8.2, 7.4 Hz,
1H), 7.41 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 3.93 (dd,
J = 9.2, 5.7 Hz, 1H), 3.13 (s, 3H), 2.97 (t, J = 7.5 Hz, 2H), 2.67
(d, J = 4.6 Hz, 3H), 2.29-2.15 (m, 1H), 1.77 (ddd, J = 13.3, 7.7,
5.8 Hz, 1H). MS (APCI+) m/z 439 (M + H).sup.+. Example
7-methoxy-N.sup.4,N.sup.4-dimethyl-N.sup.1- .sup.1H NMR (400 MHz,
dimethyl sulfoxide-d.sub.6) .delta. ppm III-187
(naphthalene-1-sulfonyl)-2,3- 12.58 (s, 1H), 8.69-8.65 (m, 1H),
8.31 (d, J = 8.3 Hz, dihydro-1H-indene-1,4- 1H), 8.27 (dd, J = 7.4,
1.3 Hz, 1H), dicarboxamide 8.17-8.13 (m, 1H), 7.81 (ddd, J = 8.5,
6.8, 1.4 Hz, 1H), 7.75-7.71 (m, 1H), 7.69 (dd, J = 8.2, 7.5 Hz,
1H), 7.05 (d, J = 8.3 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 3.97 (dd,
J = 9.0, 5.8 Hz, 1H), 3.11 (s, 3H), 2.89 (s, 3H), 2.76 (s, 3H),
2.68 (t, J = 7.4 Hz, 2H), 2.32-2.19 (m, 1H), 1.85-1.72 (m, 1H). MS
(APCI+) m/z 453 (M + H).sup.+. Example 7-methoxy-N-(naphthalene-1-
.sup.1H NMR (400 MHz, dimethyl sulfoxide-d.sub.6) .delta. ppm
III-188 sulfonyl)-4-[(pyrrolidin-1- 12.60 (s, 1H), 9.49 (s, 1H),
8.71-8.62 (m, 1H), yl)methyl]-2,3-dihydro-1H-indene- 8.31 (d, J =
8.3 Hz, 1H), 8.26 (dd, J = 7.4, 1.3 Hz, 1-carboxamide 1H), 8.15
(dd, J = 8.3, 1.3 Hz, 1H), 7.81 (ddd, J = 8.6, 6.9, 1.4 Hz, 1H),
7.76-7.64 (m, 2H), 7.27 (d, J = 8.4 Hz, 1H), 6.70 (d, J = 8.4 Hz,
1H), 4.17 (d, J = 5.3 Hz, 2H), 3.99 (dd, J = 9.0, 5.7 Hz, 1H), 3.33
(m, 2H), 3.16 (s, 3H), 3.03 (m, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.27
(dq, J = 12.9, 7.8 Hz, 1H), 1.99 (d, J = 7.8 Hz, 2H), 1.90-1.75 (m,
3H). MS (APCI+) m/z 465 (M + H).sup.+.
Determination of Biological Activity
[1347] Cell Surface Expression-Horse Radish Peroxidase (CSE-HRP)
Assay
[1348] A cellular assay for measuring the F508delCFTR cell surface
expression after correction with test compounds either without or
with a co-corrector (2 .mu.M of
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid), was
developed in human lung derived epithelial cell line (CFBE41o-)
(Veit G et al, (2012) Mol Biol Cell. 23(21): 4188-4202). The
development was achieved by expressing the F508delCFTR mutation
along with a horseradish peroxidase (HRP) in the fourth exofacial
loop, and then measuring the HRP activity using luminescence
readout from these cells, CFBE41o-F508delCFTR-HRP, that were
incubated overnight with the test corrector compounds, either
without or with the co-corrector. For this primary assay, the
CFBE41o-F508delCFTR-HRP cells were plated in 384-well plates
(Greiner Bio-one; Cat 781080) at 4,000 cells/well along with 0.5
.mu.g/mL doxycycline to induce the F508delCFTR-HRP expression and
further incubated at 37.degree. C., 5% CO.sub.2 for 72 hours. The
test compounds were then added either without or with a
co-corrector at the required concentrations and further incubated
for 18-24 hours at 33.degree. C. The highest concentration tested
was 20 .mu.M with an 8-point concentration response curve using a
3-fold dilution in both the test compound without or with the
co-corrector. Three replicate plates were run to determine one
EC.sub.50. All plates contained negative controls (dimethyl
sulfoxide, DMSO) and positive control (2 .mu.M of
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) as well
as on-plate concentration response of the positive control. Post
incubation, the plates were washed 5.times. times with Dulbecco's
phosphate buffered saline (DPBS), followed by the addition of the
HRP substrate, luminol (50 .mu.L), and measuring the HRP activity
using luminescence readout on EnVision.RTM. Multilabel Plate Reader
(Perkin Elmer; product number 2104-0010). The raw counts from the
experiment were analyzed using Accelrys.RTM. Assay Explorer
v3.3.
[1349] Z' greater than 0.5 was used as passing quality control
criteria for the plates.
[1350] The Z' is defined as:
1-[3*SD.sub.Positive Control+3*SD.sub.Negative Control/Absolute
(Mean.sub.Positive Control-Mean.sub.Negative Control)]
wherein "SD" is standard deviation.
[1351] The % activity measured at each of the 8 test concentrations
of the test compound added either without or with a co-corrector (2
.mu.M of
3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl-
}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) was
normalized to the on-plate positive control using the following
formulae:
% activity (Test compound without co-corrector)=[(test compound
without co-corrector response-DMSO response)/(positive control
response-DMSO response)]*100%
activity (Test compound with co-corrector)=[(test compound with
co-corrector response-DMSO response)/(positive control
response-DMSO response)]*100
[1352] The maximum % activity achieved for the test compound either
without or with a co-corrector at any tested concentration is
presented in Table 1 along with the respective EC.sub.50's
calculated using the following general sigmoidal curve with
variable Hill slope equation (described as Model 42 in the
Accelrys.RTM. Assay Explorer v3.3 software):
y=(a-d)/(1+(x/c) b)+d
[1353] General sigmoidal curve with concentration, response, top,
bottom, EC.sub.50 and Hill slope. This model describes a sigmoidal
curve with an adjustable baseline, a. The equation can be used to
fit curves where response is either increasing or decreasing with
respect to the independent variable, "x".
"x" is a concentration of drug under test. "y" is the response. "a"
is the maximum response, and "d" is the minimum response "c" is the
inflection point (EC.sub.50) for the curve. That is, "y" is halfway
between the lower and upper asymptotes when x=c. "b" is the
slope-factor or Hill coefficient. The sign of b is positive when
the response increases with increasing dose and is negative when
the response decreases with increasing dose (inhibition). The data
is presented with the qualifiers shown below:
TABLE-US-00003 Without/with co- corrector EC50 (.mu.M) <3 +++
.gtoreq.3 and <10 ++ .gtoreq.10 + Without co- Maximum %
corrector activity (%) <50 + .gtoreq.50 and <150 ++
.gtoreq.150 +++ Maximum % With co-corrector activity (%) <150 +
.gtoreq.150 and <350 ++ .gtoreq.350 +++
TABLE-US-00004 TABLE 1 EC50 Maximum % Maximum % (without activity
(without activity (with Exam- co-corrector) co-corrector) EC50
(with co- co-corrector) ple # (.mu.M) (%) corrector) (.mu.M) (%)
I-1 ++ +++ ++ +++ I-2 ++ +++ +++ +++ I-3 ++ +++ ++ +++ I-4 ++ +++
++ +++ I-5 +++ +++ +++ +++ I-6 ++ +++ ++ +++ I-7 +++ +++ +++ +++
I-8 ++ +++ ++ +++ I-9 +++ +++ +++ +++ I-10 ++ +++ +++ +++ I-11 +++
+++ +++ +++ I-12 ++ +++ +++ +++ I-13 + + +++ ++ I-14 +++ +++ +++
+++ I-15 +++ +++ +++ +++ I-16 +++ ++ +++ +++ I-17 +++ ++ +++ +++
I-18 +++ +++ +++ +++ I-19 ++ +++ +++ +++ I-20 ++ +++ ++ +++ I-21 ++
+++ ++ +++ I-22 ++ +++ +++ +++ I-23 ++ +++ +++ +++ I-24 ++ +++ +++
+++ I-26 +++ ++ +++ +++ I-27 +++ +++ +++ +++ I-28 +++ +++ +++ +++
I-29 +++ +++ +++ +++ I-30 +++ +++ I-31 +++ ++ +++ +++ I-32 +++ +++
+++ +++ I-33 +++ +++ +++ +++ I-34 +++ +++ +++ +++ I-35 +++ +++ +++
+++ I-36 ++ ++ +++ +++ I-37 ++ ++ ++ +++ I-38 ++ +++ +++ +++ I-39
+++ ++ +++ +++ I-40 +++ +++ +++ +++ I-41 +++ +++ +++ +++ I-42 +++
+++ +++ +++ I-43 +++ ++ +++ +++ I-44 +++ +++ +++ +++ I-45 +++ +++
+++ +++ I-46 ++ +++ +++ +++ I-47 +++ +++ +++ +++ I-48 ++ +++ +++
+++ I-49 +++ +++ +++ +++ I-50 +++ +++ +++ +++ I-51 ++ ++ ++ ++ I-52
+++ +++ +++ +++ I-53 +++ +++ +++ +++ I-54 ++ +++ +++ +++ I-55 +++
+++ +++ +++ I-56 +++ +++ +++ +++ I-57 +++ +++ +++ +++ I-58 +++ +++
+++ +++ I-59 ++ +++ +++ +++ I-60 +++ +++ +++ +++ I-61 +++ +++ +++
+++ I-62 ++ +++ +++ +++ I-63 +++ +++ +++ +++ I-64 +++ +++ +++ +++
I-65 +++ +++ +++ +++ I-66 +++ +++ +++ +++ I-67 +++ +++ +++ +++ I-68
+++ +++ +++ +++ I-69 +++ +++ +++ +++ I-70 +++ +++ +++ +++ I-71 ++
++ ++ ++ I-72 ++ +++ +++ +++ I-73 ++ +++ +++ +++ I-74 ++ +++ +++
+++ I-75 +++ +++ +++ +++ I-76 ++ +++ +++ +++ I-77 ++ +++ +++ +++
I-78 ++ +++ +++ +++ I-79 ++ +++ +++ +++ I-80 ++ ++ ++ +++ I-81 +++
+++ +++ +++ I-82 +++ +++ +++ +++ I-83 +++ +++ +++ +++ I-84 ++ +++
+++ +++ I-85 ++ ++ ++ +++ I-86 ++ +++ +++ +++ I-87 ++ ++ ++ +++
I-88 +++ +++ +++ +++ I-89 ++ ++ ++ ++ I-90 ++ +++ ++ +++ I-91 ++ ++
++ +++ I-92 ++ +++ +++ +++ I-93 ++ +++ ++ +++ I-94 +++ +++ +++ +++
I-95 ++ +++ +++ +++ I-96 +++ +++ +++ +++ I-97 +++ +++ +++ +++ I-98
+++ +++ +++ +++ I-99 ++ +++ +++ +++ I-100 +++ +++ +++ +++ I-101 +++
+++ +++ +++ I-102 +++ +++ +++ +++ I-103 ++ +++ ++ +++ I-104 ++ +++
+++ +++ I-105 ++ +++ +++ +++ I-106 ++ +++ +++ +++ I-107 +++ +++ +++
+++ I-108 ++ +++ ++ +++ I-109 ++ +++ +++ +++ I-110 ++ +++ ++ +++
I-111 ++ +++ ++ +++ I-112 ++ +++ ++ +++ I-113 ++ +++ +++ +++ I-114
+++ +++ +++ +++ I-115 ++ +++ +++ +++ I-116 +++ +++ +++ +++ I-117 ++
+++ ++ +++ I-118 +++ +++ +++ +++ I-119 ++ +++ ++ +++ I-120 +++ +++
+++ +++ I-121 ++ +++ ++ +++ I-122 ++ +++ ++ +++ I-123 ++ +++ +++
+++ I-124 +++ +++ +++ +++ I-125 ++ ++ ++ +++ I-126 +++ +++ +++ +++
I-127 ++ +++ +++ +++ I-128 ++ +++ +++ +++ I-129 +++ +++ +++ +++
I-130 ++ +++ ++ +++ I-131 +++ +++ +++ +++ I-132 +++ +++ +++ +++
I-133 +++ +++ +++ +++ I-134 +++ +++ +++ +++ I-135 ++ +++ +++ +++
I-136 +++ +++ +++ +++ I-138 ++ +++ +++ +++ I-139 ++ +++ +++ +++
I-140 +++ +++ +++ +++ I-141 ++ +++ +++ +++ I-142 +++ +++ +++ +++
I-143 ++ ++ +++ +++ I-144 +++ +++ +++ +++ I-145 ++ +++ ++ +++ I-146
+++ +++ +++ +++ I-147 ++ +++ +++ +++ I-148 +++ +++ +++ +++ I-149
+++ +++ +++ +++ I-151 ++ +++ +++ +++ I-152 ++ +++ +++ +++ I-153 ++
+++ +++ +++ I-154 ++ +++ +++ +++ I-155 ++ +++ +++ +++ II-1 ++ ++ ++
+++ II-3 ++ ++ ++ +++ II-4 ++ + ++ ++ II-5 ++ + +++ ++ II-6 ++ ++
++ ++ II-7 ++ + ++ ++ II-8 ++ ++ ++ ++ II-9 + + ++ ++ II-10 ++ ++
++ ++ II-11 + + ++ + II-12 ++ + ++ ++ II-13 ++ ++ ++ +++ II-14 ++ +
++ ++ II-15 + + ++ + II-16 ++ + ++ ++ II-17 ++ + ++ ++ II-18 ++ +
++ ++ II-19 ++ ++ ++ ++ II-20 ++ + ++ ++ II-21 ++ + ++ ++ II-22 ++
++ ++ ++ II-24 ++ + ++ ++ II-25 ++ ++ ++ ++ II-26 + + ++ ++ II-27 +
+ ++ ++ II-28 ++ + ++ ++ II-29 ++ ++ +++ ++ II-30 ++ + ++ ++ II-31
++ + ++ ++ II-32 +++ + +++ ++ II-33 ++ ++ ++ +++ II-34 ++ + ++ ++
II-35 ++ ++ ++ ++ II-36 ++ ++ ++ +++ II-37 ++ + ++ ++ II-38 + + ++
++ II-39 ++ + ++ ++ II-40 ++ ++ ++ ++ II-41 ++ ++ ++ +++ II-42 ++
++ ++ ++ II-43 ++ ++ ++ ++ II-44 ++ ++ ++ +++ II-45 ++ +++ ++ +++
II-46 ++ ++ ++ +++ II-47 ++ + ++ ++ II-48 ++ ++ ++ +++ II-49 ++ +++
+++ +++ II-50 ++ + ++ ++ II-51 ++ ++ ++ +++ II-52 ++ ++ ++ +++
II-53 ++ ++ ++ +++ II-54 +++ + +++ ++ II-55 + + + + II-56 +++ + +++
++ II-57 +++ + +++ ++ II-58 +++ + +++ ++ II-59 +++ + +++ ++ II-60 +
+ + + II-61 + + + + II-62 + + + + II-63 +++ + +++ ++ II-64 +++ +
+++ ++ II-65 ++ + ++ ++ II-66 +++ ++ +++ ++ II-67 + + + + II-68 ++
+ +++ ++ II-69 +++ ++ +++ +++ II-70 +++ ++ +++ ++ II-72 +++ ++ +++
++ II-74 + + + + II-75 ++ +++ +++ +++ II-76 +++ + +++ ++ II-77 +++
+ +++ ++ II-78 +++ ++ +++ +++ II-79 +++ ++ +++ ++ II-80 + + + +
II-81 ++ ++ +++ +++ II-82 + + ++ ++ II-83 ++ ++ ++ ++ II-84 ++ ++
++ ++ II-85 ++ + ++ ++ II-86 + + ++ ++ II-87 +++ + +++ ++ II-88 ++
++ +++ +++ II-89 ++ ++ ++ ++ II-90 + + + + II-91 ++ ++ +++ +++
II-92 ++ + +++ ++ II-93 + + +++ + II-94 ++ +++ +++ +++ II-95 +++
+++ +++ +++
II-96 +++ +++ +++ +++ II-97 +++ +++ +++ +++ II-98 +++ +++ +++ +++
II-99 +++ +++ +++ +++ II-100 ++ ++ ++ +++ II-101 +++ + +++ ++
II-102 ++ + +++ ++ II-103 + + +++ + II-104 +++ + +++ ++ II-105 + +
+++ + II-106 + + +++ ++ II-107 +++ + +++ ++ II-108 ++ ++ +++ +++
II-109 ++ +++ ++ +++ II-110 ++ +++ +++ +++ II-111 ++ +++ +++ +++
II-112 ++ + +++ ++ II-113 ++ +++ +++ +++ II-114 ++ +++ ++ +++
II-115 ++ +++ +++ +++ II-116 ++ +++ ++ +++ II-117 ++ +++ +++ +++
II-118 ++ +++ +++ +++ II-119 ++ +++ ++ +++ II-120 ++ + ++ ++ II-121
++ +++ +++ +++ II-122 ++ +++ +++ +++ II-123 ++ +++ ++ +++ II-124
+++ +++ +++ +++ II-125 ++ ++ ++ +++ II-126 ++ ++ ++ +++ II-127 ++
++ +++ +++ II-128 ++ ++ ++ +++ II-129 +++ +++ +++ +++ II-130 +++
+++ +++ +++ II-131 +++ +++ +++ +++ II-132 +++ +++ +++ +++ II-133 ++
+++ ++ +++ II-134 ++ +++ +++ +++ II-135 ++ +++ ++ +++ II-136 ++ +++
++ +++ III-3 + + + + III-4 + + + + III-5 + + + + III-6 + + + +
III-7 + + ++ ++ III-9 + + + + III-10 + + + + III-11 + + + + III-12
+ + ++ + III-13 + + + + III-14 + + + + III-15 + + + + III-16 + + +
+ III-17 + + + + III-18 + + + + III-19 + + + + III-20 + + + +
III-21 + + + + III-22 + + + + III-23 ++ + ++ ++ III-24 + + + +
III-25 + + ++ + III-26 + + + + III-27 + + + + III-28 + + + + III-29
+ + + + III-30 + + + + III-31 + + + + III-32 + + + + III-33 + + +++
++ III-34 + + + + III-35 + + ++ ++ III-36 + + + + III-37 + + + +
III-38 + + ++ ++ III-39 + + + + III-40 + + + + III-41 + + + +
III-42 + + + + III-43 + + + + III-44 + + + + III-45 + + + + III-46
+ + + + III-47 + + + + III-48 + + + + III-49 + + ++ ++ III-50 + + +
+ III-51 + + + + III-52 + + + + III-53 + + + + III-54 + + + +
III-55 + + ++ + III-56 ++ ++ ++ +++ III-57 + + + + III-58 ++ + ++
++ III-59 + + + + III-60 + + + + III-61 + + + + III-62 + + ++ +
III-63 + + + + III-64 + + + + III-65 + + + + III-66 + + + + III-67
+ + + + III-68 + + + + III-69 + + + + III-70 + + + + III-71 + + ++
++ III-72 + + + + III-73 + + + + III-74 + + + + III-75 + + + +
III-76 + + + + III-77 + + + + III-78 + + + + III-79 + + + + III-80
+ + + + III-81 + + + + III-82 + + + + III-83 + + + + III-84 + + + +
III-85 + + ++ ++ III-86 ++ ++ +++ ++ III-87 + + + + III-88 + + + +
III-89 + + ++ ++ III-90 + + + + III-91 + + + + III-92 + + + +
III-93 + + ++ ++ III-94 + + ++ ++ III-95 + + + + III-96 + + + +
III-97 + + + + III-98 + + + + III-99 ++ ++ ++ +++ III-100 + + ++ +
III-101 + + + + III-102 + + + + III-103 + + ++ ++ III-105 + + + +
III-106 + + + + III-107 ++ ++ ++ +++ III-108 ++ ++ ++ ++ III-109 +
+ + + III-110 + + + + III-111 + + ++ + III-112 ++ + ++ ++ III-113 +
+ +++ ++ III-114 ++ + +++ ++ III-115 +++ + +++ ++ III-116 + + + +
III-117 ++ + +++ ++ III-118 + + + + III-119 + + ++ + III-120 + + +
+ III-121 + + + + III-122 + + + + III-123 + + ++ ++ III-124 + + + +
III-125 ++ + ++ ++ III-126 + + + + III-127 + + + + III-128 ++ + ++
++ III-129 + + ++ ++ III-130 + + + + III-131 + + + + III-132 + + ++
++ III-133 + + ++ ++ III-134 + + + + III-135 + + + + III-136 + + +
+ III-137 + + + + III-138 ++ + ++ ++ III-139 +++ + +++ ++ III-140 +
+ + + III-141 + + + + III-142 ++ + ++ ++ III-143 + + + + III-144 +
+ ++ ++ III-145 ++ + ++ ++ III-146 + + ++ + III-147 ++ + ++ ++
III-148 +++ +++ +++ +++ III-149 + + +++ + III-150 + + + + III-151 +
+ + + III-152 ++ + ++ ++ III-153 + + + + III-154 +++ +++ +++ +++
III-155 ++ + ++ ++ III-156 ++ ++ +++ ++ III-157 + + ++ ++ III-158
++ ++ ++ ++ III-159 ++ +++ ++ +++ III-160 ++ ++ ++ +++ III-161 ++ +
++ ++ III-162 ++ ++ ++ +++ III-163 + + ++ ++ III-164 +++ ++ +++ +++
III-165 ++ ++ +++ ++ III-166 +++ ++ +++ ++ III-167 ++ + +++ ++
III-168 ++ ++ ++ +++ III-169 ++ +++ +++ +++ III-170 +++ ++ +++ +++
III-171 ++ ++ ++ +++ III-172 ++ + +++ ++ III-173 ++ ++ ++ +++
III-174 + + + + III-175 + + + + III-176 + + + + III-177 + + ++ ++
III-178 ++ + ++ ++ III-179 + + + + III-180 + + + + III-181 + + ++
++ III-182 +++ ++ +++ ++ III-183 + + ++ ++ III-184 ++ ++ ++ ++
III-185 ++ + ++ ++ III-186 + + + + III-187 + + + + III-188 + + ++
+
[1354] The data provided in the present application demonstrate
that the compounds of the invention demonstrate activity in vitro,
and may be useful in vivo in the treatment of cystic fibrosis.
[1355] Further benefits of Applicants' invention will be apparent
to one skilled in the art from reading this patent application.
[1356] It is to be understood that the foregoing detailed
description and accompanying examples are merely illustrative and
are not to be taken as limitations upon the scope of the invention,
which is defined solely by the appended claims and their
equivalents. Various changes and modifications to the disclosed
embodiments will be apparent to those skilled in the art. Such
changes and modifications, including without limitation those
relating to the chemical structures, substituents, derivatives,
intermediates, syntheses, formulations, or methods, or any
combination of such changes and modifications of use of the
invention, may be made without departing from the spirit and scope
thereof.
* * * * *