U.S. patent application number 14/435954 was filed with the patent office on 2015-10-15 for heteroaromatic compounds and their use as dopamine d1 ligands.
The applicant listed for this patent is PFIZER INC.. Invention is credited to JOHN ARTHUR ALLEN, JOTHAM WADSWORTH COE, JENNIFER ELIZABETH DAVOREN, AMY BETH DOUNAY, IVAN VIKTOROVICH EFREMOV, DAVID LAWRENCE FIRMAN GRAY, EDWARD RAYMOND GUILMETTE, ANTHONY RICHARD HARRIS, CHRIS JOHN HELAL, JACLYN LOUISE HENDERSON, SCOT RICHARD MENTE, DEANE MILFORD NASON, STEVEN VICTOR O'NEIL, CHAKRAPANI SUBRAMANYAM, WENJIAN XU.
Application Number | 20150291625 14/435954 |
Document ID | / |
Family ID | 49955423 |
Filed Date | 2015-10-15 |
United States Patent
Application |
20150291625 |
Kind Code |
A1 |
COE; JOTHAM WADSWORTH ; et
al. |
October 15, 2015 |
Heteroaromatic Compounds and their Use as Dopamine D1 Ligands
Abstract
The present invention provides, in part, compounds of Formula I:
and pharmaceutically acceptable salts thereof and N-oxides thereof;
processes and intermediates for preparation of; and compositions
and uses thereof. The present invention further provides D1
agonists with reduced D1R desensitization, D1 agonists with a
reduced .beta.-arrestin recruitment activity relative to Dopamine,
D1 agonists interacting significantly with the Ser188 but not
significantly with the Ser202 of a D1R when binding to the D1R, D1
agonists interacting less strongly with the Asp103 and interacting
less strongly with the Ser198 of a D1R when binding to the D1R, and
their uses. ##STR00001##
Inventors: |
COE; JOTHAM WADSWORTH;
(NIANTIC, CT) ; ALLEN; JOHN ARTHUR; (BILLERICA,
MA) ; DAVOREN; JENNIFER ELIZABETH; (CAMBRIDGE,
MA) ; DOUNAY; AMY BETH; (COLORADO SPRINGS, CO)
; EFREMOV; IVAN VIKTOROVICH; (BROOKLINE, MA) ;
GRAY; DAVID LAWRENCE FIRMAN; (GROTON, MA) ;
GUILMETTE; EDWARD RAYMOND; (FRANKLIN, MA) ; HARRIS;
ANTHONY RICHARD; (NARRAGANSETT, RI) ; HELAL; CHRIS
JOHN; (MYSTIC, CT) ; HENDERSON; JACLYN LOUISE;
(CAMBRIDGE, MA) ; MENTE; SCOT RICHARD; (ARLINGTON,
MA) ; NASON; DEANE MILFORD; (NORWICH, CT) ;
O'NEIL; STEVEN VICTOR; (EAST LYME, CT) ; SUBRAMANYAM;
CHAKRAPANI; (SOUTH GLASTONBURY, CT) ; XU;
WENJIAN; (WATERFORD, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PFIZER INC. |
New York |
NY |
US |
|
|
Family ID: |
49955423 |
Appl. No.: |
14/435954 |
Filed: |
October 29, 2013 |
PCT Filed: |
October 29, 2013 |
PCT NO: |
PCT/IB2013/059754 |
371 Date: |
April 15, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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61723966 |
Nov 8, 2012 |
|
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61881218 |
Sep 23, 2013 |
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Current U.S.
Class: |
514/210.21 ;
514/249; 514/252.04; 514/255.05; 514/256; 514/301; 514/302;
544/238; 544/333; 544/350; 544/405; 546/114; 546/115 |
Current CPC
Class: |
C07D 495/04 20130101;
A61P 25/18 20180101; A61P 25/24 20180101; C07D 519/00 20130101;
A61K 31/437 20130101; A61K 31/519 20130101; A61K 31/53 20130101;
A61K 31/497 20130101; A61K 31/501 20130101; A61K 31/4355 20130101;
A61K 31/506 20130101; A61P 25/30 20180101; A61K 31/4365 20130101;
A61P 25/14 20180101; A61K 31/4985 20130101; A61P 25/06 20180101;
C07D 491/04 20130101; A61P 25/00 20180101; A61P 25/28 20180101;
A61K 31/5025 20130101; A61P 25/16 20180101; C07D 519/04 20130101;
C07D 491/048 20130101 |
International
Class: |
C07D 519/00 20060101
C07D519/00; C07D 495/04 20060101 C07D495/04; C07D 491/048 20060101
C07D491/048 |
Claims
1. A compound of Formula I: ##STR00277## or an N-oxide thereof, or
a pharmaceutically acceptable salt of said compound or said
N-oxide, wherein: X.sup.1 is O or S; Y.sup.1 is O, S, or NR.sup.N;
Q.sup.1 is an N-containing 5- to 10-membered heterocycloalkyl, an
N-containing 5- to 10-membered heteroaryl, or phenyl, wherein the
heterocycloalkyl or heteroaryl is optionally substituted with 1, 2,
3, 4, or 5 independently selected R.sup.7; and the phenyl is
optionally substituted with 1, 2, 3, 4, or 5 independently selected
R.sup.7a; R.sup.T1 and R.sup.T2 are each independently selected
from the group consisting of H, C.sub.1-3 alkyl, C.sub.1-3
fluoroalkyl, cyclopropyl, fluorocyclopropyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkoxy, --C(.dbd.O)--O--(C.sub.1-3 alkyl), and
--C(.dbd.O)OH; R.sup.1 is selected from the group consisting of H,
F, --C(.dbd.O)OH, --C(.dbd.O)--O--(C.sub.1-3 alkyl), C.sub.1-3
alkyl, C.sub.1-3 fluoroalkyl, C.sub.3-6 cycloalkyl, and C.sub.3-6
fluorocycloalkyl, wherein said C.sub.3-6 cycloalkyl is optionally
substituted with 1, 2, 3, 4, or 5 substituents each independently
selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, and C.sub.1-4 haloalkoxy; R.sup.2 is selected from the
group consisting of H, halogen, --CN, --OH, C(.dbd.O)OH,
C(.dbd.O)--O--(C.sub.1-3 alkyl), C.sub.1-3 alkoxy, C.sub.1-3
haloalkoxy, --N(R.sup.8)(R.sup.9), C.sub.1-3 alkyl, C.sub.1-3
fluoroalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 fluorocycloalkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein said C.sub.3-6
cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5
substituents each independently selected from halo, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4
haloalkoxy; R.sup.3 and R.sup.4 are each independently selected
from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, --CN, C.sub.3-6
cycloalkyl, --C(.dbd.O)OH, C(.dbd.O)--O--(C.sub.1-4 alkyl), and
halogen, wherein each of said C.sub.1-6 alkyl and C.sub.3-6
cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5
substituents each independently selected from halo, --OH, --CN,
C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and
C.sub.1-4 haloalkoxy; R.sup.5 and R.sup.6 are each independently
selected from the group consisting of H, halogen, --OH, --NO.sub.2,
--CN, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, a 4- to
10-membered heterocycloalkyl, --N(R.sup.8)(R.sup.9),
--N(R.sup.10)(C(.dbd.O)R.sup.11), --C(.dbd.O)--N(R.sup.8)(R.sup.9),
--C(.dbd.O)--R.sup.12, --C(.dbd.O)--OR.sup.12, and --OR.sup.13,
wherein each of said C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and
heterocycloalkyl is optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, --CN, --OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, C.sub.1-3 haloalkoxy, C.sub.3-6 cycloalkyl,
--N(R.sup.14)(R.sup.15), --N(R.sup.16)(C(.dbd.O)R.sup.17),
--C(.dbd.O)--OR.sup.18, --O(.dbd.O)H, --O(.dbd.O)R.sup.18,
--O(.dbd.O)N(R.sup.14)(R.sup.15), and --OR.sup.19; or R.sup.5 and
R.sup.3 together with the two carbon atoms to which they are
attached form a fused N-containing 5- or 6-membered heteroaryl, a
fused N-containing 5- or 6-membered heterocycloalkyl, a fused 5- or
6-membered cycloalkyl, or a fused benzene ring, each optionally
substituted with 1, 2, or 3 substituents each independently
selected from the group consisting of halo, --CN, --OH, C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, and C.sub.1-3
haloalkoxy; R.sup.7 and R.sup.7a are each independently selected
from the group consisting of halogen, --OH, --CN, --NO.sub.2, oxo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxylalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.3-7 cycloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, a 4- to
10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,
heteroarylalkenyl, --CH.dbd.N--O--(C.sub.1-3 alkyl),
--N(R.sup.14)(R.sup.15), --N(R.sup.16)(C(.dbd.O)R.sup.17),
--S(.dbd.O).sub.2N(R.sup.14)(R.sup.15),
--O(.dbd.O)N(R.sup.14)(R.sup.15), --C(.dbd.O)--R.sup.12,
--O(.dbd.O)--OR.sup.18, and --OR.sup.19, wherein each of said
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,
heteroarylalkenyl, C.sub.6-10 aryl, heterocycloalkyl and heteroaryl
is optionally substituted with 1, 2, 3, or 4 substituents each
independently selected from the group consisting of halogen, OH,
--CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 hydroxylalkyl,
C.sub.1-4 alkoxy, --N(R.sup.14)(R.sup.15), --S--(C.sub.1-3 alkyl),
--S(.dbd.O).sub.2--(C.sub.1-4 alkyl), aryloxy, arylalkyloxy
optionally substituted with 1 or 2 C.sub.1-4 alkyl, oxo,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4 alkyl, --C(.dbd.O)O--C.sub.1-4
alkyl, --C(.dbd.O)NH.sub.2, --NHC(.dbd.O)H,
--NHC(.dbd.O)--(C.sub.1-4 alkyl), C.sub.3-7 cycloalkyl, a 5- or
6-membered heteroaryl, C.sub.1-4 haloalkyl, and C.sub.1-4
haloalkoxy; or two adjacent R.sup.7a together with the two carbon
atoms to which they are attached form a fused 5- or 6-membered
cycloalkyl, a fused 5- or 6-membered heterocycloalkyl, or a fused
benzene ring, each optionally substituted with 1, 2, 3, or 4
R.sup.7b, wherein each R.sup.7b is independently selected from the
group consisting of halo, --CN, --NO.sub.2, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl,
pyrrolidin-1-yl, pyridin-1-yl, OH, oxo, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 hydroxylalkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
haloalkoxy; R.sup.8 and R.sup.9 are each independently selected
from the group consisting of H, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.3-10 cycloalkyl, a 4- to 10-membered
heterocycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl,
arylalkyl, and heteroarylalkyl, wherein each of said C.sub.1-6
alkyl, C.sub.3-10 cycloalkyl, 4- to 10-membered heterocycloalkyl,
cycloalkylalkyl, arylalkyl, and heteroarylalkyl is optionally
substituted with 1, 2, 3, or 4 substituents each independently
selected from the group consisting of --OH, --CN, C.sub.1-3 alkyl,
C.sub.3-7 cycloalkyl, C.sub.1-3 hydroxylalkyl, --S--C.sub.1-3
alkyl, --C(.dbd.O)H, --C(.dbd.O)--C.sub.1-3 alkyl,
--C(.dbd.O)--O--C.sub.1-3 alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--N(C.sub.1-3 alkyl).sub.2, C.sub.1-3 haloalkyl,
C.sub.1-3 alkoxy, and C.sub.1-3 haloalkoxy; or R.sup.8 and R.sup.9
together with the N atom to which they are attached form a 4- to
10-membered heterocycloalkyl or heteroaryl optionally substituted
with 1, 2, 3, or 4 substituents each independently selected from
the group consisting of halogen, --OH, oxo, --C(.dbd.O)H,
--C(.dbd.O)OH, --C(.dbd.O)--C.sub.1-3 alkyl, --C(.dbd.O)--NH.sub.2,
--C(.dbd.O)--N(C.sub.1-3 alkyl).sub.2, --CN, C.sub.1-3 alkyl,
C.sub.1-3 alkoxy, C.sub.1-3 hydroxylalkyl, C.sub.1-3 haloalkyl, and
C.sub.1-3 haloalkoxy; R.sup.10 is selected from the group
consisting of H, C.sub.1-3 alkyl, and C.sub.3-7 cycloalkyl;
R.sup.11 is selected from the group consisting of C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl,
C.sub.6-10 aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen,
--CF.sub.3, --CN, --OH, oxo, --S--C.sub.1-3 alkyl, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy;
R.sup.12 is H or is selected from the group consisting of
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, a 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl, a 5- to 10-membered heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, each optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, --CF.sub.3, --CN, --OH, --C(.dbd.O)OH, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy;
R.sup.13 is selected from the group consisting of C.sub.1-10 alkyl,
C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, a 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl, a 5- to 10-membered heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, each optionally substituted with 1, 2, 3, or 4
substituents each independently selected from the group consisting
of halogen, --N(R.sup.14)(R.sup.15),
--C(.dbd.O)N(R.sup.14)(R.sup.15), --N(R.sup.16)(C(.dbd.O)R.sup.17),
--C(.dbd.O)H, --C(.dbd.O)N(R.sup.16)(OR.sup.18),
--C(.dbd.O)--R.sup.18, --C(.dbd.O)--OR.sup.18,
--O--C(.dbd.O)R.sup.18, --CF.sub.3, --CN, --OH, --O--(C.sub.1-6
hydroxylalkyl), C.sub.1-6 alkyl, oxo, C.sub.1-6 hydroxylalkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy;
R.sup.14 and R.sup.15 are each independently selected from the
group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.3-10 cycloalkyl, a 4- to 14-membered heterocycloalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, wherein each of said C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl is
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of --OH, --CN,
oxo, --NHC(.dbd.O)--(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --O--(C.sub.1-6 hydroxylalkyl),
--S(.dbd.O).sub.2--C.sub.1-3 alkyl, --S--C.sub.1-3 alkyl, C.sub.1-3
alkyl, C.sub.3-7 cycloalkyl, C.sub.1-3 hydroxylalkyl, a 5- to
10-membered heteroaryl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, and
C.sub.1-3 haloalkoxy; or R.sup.14 and R.sup.15 together with the N
atom to which they are attached form a 4- to 10-membered
heterocycloalkyl or 5- to 10-membered heteroaryl optionally
substituted with 1, 2, or 3 substituents each independently
selected from the group consisting of halogen, oxo, --OH, C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, C.sub.1-3 haloalkoxy,
C.sub.1-3 hydroxylalkyl, C.sub.2-4 alkoxyalkyl, oxo, a 5- to
6-membered heteroaryl, --NH.sub.2, --N(C.sub.1-3 alkyl).sub.2,
--S(.dbd.O).sub.2--C.sub.1-3 alkyl, --S--C.sub.1-3 alkyl,
--C(.dbd.O)H, --C(.dbd.O)OH, --C(.dbd.O)NH.sub.2, and
--C(.dbd.O)--C.sub.1-3 alkyl; R.sup.16 is selected from the group
consisting of H, C.sub.1-3 alkyl, and C.sub.3-7 cycloalkyl;
R.sup.17 is selected from the group consisting of C.sub.1-6 alkyl,
C.sub.3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl,
C.sub.6-10 aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen,
--CF.sub.3, --CN, --OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy; R.sup.18 is H or is
selected from the group consisting of C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, a 4- to 14-membered heterocycloalkyl, C.sub.6-10 aryl,
a 5- to 10-membered heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen,
--CF.sub.3, --CN, --OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-6 alkenyl, C.sub.3-7 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy; R.sup.19 is selected
from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl,
C.sub.6-10 aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen,
--N(R.sup.14)(R.sup.15), --C(.dbd.O)N(R.sup.14)(R.sup.15),
--N(R.sup.16)(C(.dbd.O)R.sup.17), --C(.dbd.O)--R.sup.18,
--C(.dbd.O)--OR.sup.18, --CF.sub.3, --CN, --OH, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy;
and R.sup.N is selected from the group consisting of H, C.sub.1-6
alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 fluorocycloalkyl,
heteroarylalkyl, and arylalkyl, wherein each of said C.sub.3-6
cycloalkyl, heteroarylalkyl, and arylalkyl is optionally
substituted with 1, 2, 3, 4, or 5 substituents each independently
selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, and C.sub.1-4 haloalkoxy.
2. The compound of claim 1, or an N-oxide thereof or a
pharmaceutically acceptable salt of said compound or said N-oxide,
wherein Y.sup.1 is O.
3. The compound of claim 1, or an N-oxide thereof or a
pharmaceutically acceptable salt of said compound or said N-oxide,
wherein X.sup.1 is O.
4. The compound of claim 1, or an N-oxide thereof or a
pharmaceutically acceptable salt of said compound or said N-oxide,
wherein Q.sup.1 is selected from quinolinyl, isoquinolinyl,
1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
1H-pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyrazinyl,
imidazo[2,1-c][1,2,4]triazinyl, imidazo[1,5-a]pyrazinyl,
imidazo[1,2-a]pyrimidinyl, 1H-indazolyl, 9H-purinyl, pyrimidinyl,
pyrazinyl, pyridinyl, pyridazinyl, 1H-pyrazolyl, 1H-pyrrolyl,
4H-pyrazolyl, 4H-imidazolyl, imidazo[1,2-a]pyrimidinyl,
[1,2,4]triazolo[1,5-a]pyrimidinyl,
[1,2,4]triazolo[4,3-b]pyridazinyl, 1H-imidazolyl,
3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl,
2,4(1H,3H)-dioxo-pyrimidinyl, and 1H-2-oxo-pyrazinyl, each
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.7.
5. The compound of claim 1, or an N-oxide thereof or a
pharmaceutically acceptable salt of said compound or said N-oxide,
wherein Q.sup.1 is selected from: ##STR00278## and each m is
independently 0, 1, 2, or 3.
6. The compound of claim 1, or an N-oxide thereof or a
pharmaceutically acceptable salt of said compound or said N-oxide,
wherein R.sup.T1 and R.sup.T2 are both H; R.sup.1 is H; and R.sup.2
is H, --CN, Br, C.sub.1-3 alkyl, or cyclopropyl.
7. The compound of claim 1, or an N-oxide thereof or a
pharmaceutically acceptable salt of said compound or said N-oxide,
wherein R.sup.3 and R.sup.4 are each independently selected from
the group consisting of H, F, Cl, and C.sub.1-3 alkyl.
8. The compound of claim 1, or an N-oxide thereof or a
pharmaceutically acceptable salt of said compound or said N-oxide,
wherein one of R.sup.5 and R.sup.6 is H; and the other of R.sup.5
and R.sup.6 is selected from the group consisting of H, --OH, --CN,
Cl, F, methyl, ethyl, CF.sub.3, CH.sub.2F, and --OCH.sub.3.
9. The compound of claim 1, or an N-oxide thereof or a
pharmaceutically acceptable salt of said compound or said N-oxide,
wherein each of R.sup.7 and R.sup.7a is independently selected from
the group consisting of C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl,
oxo, --OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy; wherein the
C.sub.1-4 alkyl is optionally substituted with 1, 2, 3, 4, or 5
substituents each independently selected from halogen, OH,
C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and pyridin-1-yl.
10. A compound of claim 1 selected from:
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridine;
2-(4,6-dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)benzonitrile-
;
5-[2-fluoro-4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-4,6-dimethylpyridazin--
3(2H)-one;
5-[4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-4,6-dimethylpyridazin--
3(2H)-one;
(+)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimet-
hylpyridazin-3(2H)-one;
(-)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridaz-
in-3(2H)-one;
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3-
(2H)-one;
(+)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylim-
idazo[1,2-a]pyrazine;
(-)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-
-a]pyrazine;
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-a]p-
yrazine;
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]furo[3,2-c]pyri-
dine; 4-[4-(4,6-dimethylpyrimidin-5-yl)phenoxy]furo[3,2-c]pyridine;
(-)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-
-2(1H)-one;
(+)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-
-2(1H)-one;
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1-
H)-one;
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyri-
midin-2(1H)-one;
4-[4-(4,6-dimethylpyrimidin-5-yl)-2-fluorophenoxy]furo[3,2-c]pyridine;
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-2,4,6-trimethylpyridazi-
n-3(2H)-one;
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4-methylpyridazin-3(2H)-
-one;
(+)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyr-
idine;
(-)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]py-
ridine;
4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyrid-
ine;
4-[4-(3,5-dimethyl-6-oxo-1,6-dihydropyridazin-4-yl)phenoxy]furo[3,2-c-
]pyridine-3-carbonitrile;
(-)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2-c]pyridin-
e;
(+)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2-c]pyrid-
ine;
4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2-c]pyridin-
e;
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimidin-
e-2,4(1H,3H)-dione;
(-)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimid-
ine-2,4(1H,3H)-dione;
(+)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimid-
ine-2,4(1H,3H)-dione; and
6-[4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H-
)-dione, or an N-oxide thereof or a pharmaceutically acceptable
salt of said compound or said N-oxide.
11. A pharmaceutical composition comprising a compound according to
claim 1 or an N-oxide thereof or a pharmaceutically acceptable salt
of said compound or said N-oxide, and a pharmaceutically acceptable
carrier.
12. A method for treating a disorder in a human, which method
comprises administering to said human a therapeutically effective
amount of a compound according to claim 1 or an N-oxide thereof or
a pharmaceutically acceptable salt of said compound or said
N-oxide, wherein the disorder is selected from schizophrenia,
cognitive impairment, attention deficit hyperactivity disorder
(ADHD), impulsivity, compulsive gambling, overeating, autism
spectrum disorder, mild cognitive impairment (MCI), age-related
cognitive decline, dementia, restless leg syndrome (RLS),
Parkinson's disease, Huntington's chorea, anxiety, depression,
major depressive disorder (MDD), treatment-resistant depression
(TRD), bipolar disorder, chronic apathy, anhedonia, chronic
fatigue, post-traumatic stress disorder, seasonal affective
disorder, social anxiety disorder, post-partum depression,
serotonin syndrome, substance abuse and drug dependence, drug abuse
relapse, Tourette's syndrome, tardive dyskinesia, drowsiness,
excessive daytime sleepiness, cachexia, inattention, a movement
disorder, a therapy-induced movement disorder, sexual dysfunction,
migraine, systemic lupus erythematosus (SLE), hyperglycemia,
atherosclerosis, dislipidemia, obesity, diabetes, sepsis,
post-ischemic tubular necrosis, renal failure, hyponatremia,
resistant edema, narcolepsy, hypertension, congestive heart
failure, postoperative ocular hypotonia, sleep disorders, and
pain.
13. A D1 agonist with reduced D1R desensitization, wherein the D1
agonist desensitizes D1R cAMP signaling less than about 25%
relative to Control; and wherein the D1 agonist with reduced D1R
desensitization is not a catechol derivative.
14. A D1 agonist with a reduced .beta.-arrestin recruitment
activity relative to Dopamine, wherein a D1R, after binding to the
D1 agonist with a reduced .beta.-arrestin recruitment activity,
recruits less than about 70% of .beta.-arrestin relative to the D1R
binding to Dopamine; and wherein the D1 agonist with a reduced
.beta.-arrestin recruitment activity is not a catechol
derivative.
15. The D1 agonist of claim 14 wherein the D1 agonist interacts
significantly with the Ser188 but not significantly with the Ser202
of a D1R when binding to the D1R.
16. The D1 agonist of claim 15 wherein the D1 agonist interacts
less strongly with the Asp103 or the Ser198 of the D1R when binding
to the D1R.
17. The D1 agonist of claim 14 wherein the D1 agonist is a partial
D1 agonist.
18. The D1 agonist of claim 14 wherein the D1 agonist is a full D1
agonist.
19. A pharmaceutical composition comprising a therapeutically
effective amount of a compound or salt thereof and a
pharmaceutically acceptable carrier, wherein the compound or salt
thereof is a D1 agonist of claim 14.
20. A method for treating a disorder in a human, which method
comprises administering to said human a therapeutically effective
amount of a compound or salt thereof wherein the compound or salt
thereof is a D1 agonist of claim 14, and wherein the disorder is
selected from schizophrenia, cognitive impairment, attention
deficit hyperactivity disorder (ADHD), impulsivity, compulsive
gambling, overeating, autism spectrum disorder, mild cognitive
impairment (MCI), age-related cognitive decline, dementia, restless
leg syndrome (RLS), Parkinson's disease, Huntington's chorea,
anxiety, depression, major depressive disorder (MDD),
treatment-resistant depression (TRD), bipolar disorder, chronic
apathy, anhedonia, chronic fatigue, post-traumatic stress disorder,
seasonal affective disorder, social anxiety disorder, post-partum
depression, serotonin syndrome, substance abuse and drug
dependence, drug abuse relapse, Tourette's syndrome, tardive
dyskinesia, drowsiness, excessive daytime sleepiness, cachexia,
inattention, a movement disorder, a therapy-induced movement
disorder sexual dysfunction, migraine, systemic lupus erythematosus
(SLE), hyperglycemia, atherosclerosis, dislipidemia, obesity,
diabetes, sepsis, post-ischemic tubular necrosis, renal failure,
hyponatremia, resistant edema, narcolepsy, hypertension, congestive
heart failure, postoperative ocular hypotonia, sleep disorders, and
pain.
Description
FIELD OF THE INVENTION
[0001] The present invention generally relates to heteroaromatic
compounds, which are dopamine D1 ligands, for example dopamine D1
agonists or partial agonists.
BACKGROUND OF THE INVENTION
[0002] Dopamine acts upon neurons through two families of dopamine
receptors, D1-like receptors (D1Rs) and D2-like receptors (D2Rs).
The D1-like receptor family consists of D1 and D5 receptors (D1),
which are highly expressed in many regions of the brain. D1 mRNA
has been found in the striatum and nucleus accumbens. See e.g.,
Missale C, Nash S R, Robinson S W, Jaber M, Caron M G "Dopamine
receptors: from structure to function", Physiological Reviews
78:189-225 (1998).
[0003] Pharmacological studies have reported that D1 and D5
receptors (D1/D5), namely D1-like receptors, are linked to
stimulation of adenylyl cyclase, whereas D2, D3, and D4 receptors,
namely D2-like receptors, are linked to inhibition of cAMP
production See, e.g., Jose P A, et. al, "Dopamine D1 receptor
regulation of phospholipase C", Hypertension Research 18 Suppl
1:S39-42 (1995).
[0004] Dopamine D1 receptors are implicated in numerous
neuropharmacological and neurobiological functions. For example, D1
receptors are involved in different types of memory function and
synaptic plasticity. See e.g., Goldman-Rakic P S, Castner S A,
Svensson T H, Siever L J, Williams G V "Targeting the dopamine D1
receptor in schizophrenia: insights for cognitive dysfunction",
Psychopharmacology 174(1):3-16 (2004); Castner S A, Williams G V
"Tuning the engine of cognition: a focus on NMDA/D1 receptor
interactions in prefrontal cortex", Brain Cognition 63(2):94-122
(2007). In addition, D1 receptors have been implicated in a variety
of psychiatric, neurological, neurodevelopmental,
neurodegenerative, mood, motivational, metabolic, cardiovascular,
renal, ophthalmic, endocrine, and/or other disorders described
herein including schizophrenia (e.g., cognitive and negative
symptoms in schizophrenia), cognitive impairment associated with D2
antagonist therapy, ADHD, impulsivity, autism spectrum disorder,
Mild cognitive impairment (MCI), age-related cognitive decline,
Alzheimer's dementia, Parkinson's disease, Huntington's chorea,
depression, anxiety, treatment-resistant depression (TRD), bipolar
disorder, chronic apathy, anhedonia, chronic fatigue,
post-traumatic stress disorder, seasonal affective disorder, social
anxiety disorder, post-partum depression, serotonin syndrome,
substance abuse and drug dependence, Tourette's syndrome, tardive
dyskinesia, drowsiness, sexual dysfunction, migraine, systemic
lupus erythematosus (SLE), hyperglycemia, dislipidemia, obesity,
diabetes, sepsis, post-ischemic tubular necrosis, renal failure,
resistant edema, narcolepsy, hypertension, congestive heart
failure, postoperative ocular hypotonia, sleep disorders, pain, and
other disorders in a mammal. See e.g., Goulet M, Madras B K "D(1)
dopamine receptor agonists are more effective in alleviating
advanced than mild parkinsonism in
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys",
Journal of Pharmacology and Experimental Therapy 292(2):714-24
(2000); Surmeier D J, et. al, "The role of dopamine in modulating
the structure and function of striatal circuits", Prog. Brain
Research 183:149-67 (2010); Umrani D N, Goyal R K "Fenoldopam
treatment improves peripheral insulin sensitivity and renal
function in STZ-induced type2 diabetic rats", Clin. Exp.
Hypertension 25(4):221-233 (2003); Bina K G et al., "Dopaminergic
agonists normalize elevated hypothalamic neuropeptide Y and
corticotropin-releasing hormone, body weight gain, and
hyperglycemia in ob/ob mice", Neuroendocrinology 71(1):68-78
(2000).
[0005] G protein-coupled receptors (GPCRs, including D1Rs)
desensitize via a common mechanism involving G protein-coupled
receptor kinase (GRK) phosphorylation followed by .beta.-arrestin
binding which prevents G protein-coupling (and thus G protein
activation). See Louis M. Luttrell et. al., "The role of
.beta.-arrestins in the termination and transduction of
G-protein-coupled receptor signals"; J. Cell Sci., 115, 455-465
(2002). For example, D1 receptor desensitization involves
agonist-induced phosphorylation of the receptor (i.e., preferential
phosphorylation of the receptor that are in the agonist-occupied
conformation) and .beta.-arrestin recruitment
(.beta.-arrestin-receptor binding) that prevents G protein coupling
and in turn leads to desensitization of D1 receptor's canonical G
protein pathway/activation signaling [which can be measured, for
example, by cyclic adenosine monophosphate (CAMP)
accumulation/production]. See M. M. Lewis et. al, "Homologous
Desensitization of the D1A Dopamine Receptor: Efficacy in Causing
Desensitization Dissociates from Both Receptor Occupancy and
Functional Potency"; JPET 286: 345-353, 1998.
[0006] In addition to their well-established role in GPCR
desensitization, .beta.-arrestins may also enable GPCR-mediated
"arrestinergic" signaling by functioning as scaffolds for
downstream effector molecules such as the extracellular regulated
kinases (ERKs). See; Nikhil M Urs, et. al, "A Dopamine D1
Receptor-Dependent .beta.-Arrestin Signaling Complex Potentially
Regulates Morphine-Induced Psychomotor Activation but not Reward in
Mice," Neuropsychopharmacology (2011) 36, 551-558; Reiter E, et.
al, "Molecular mechanism of beta-arrestin-biased agonism at
seven-transmembrane receptors," Annual review of pharmacology and
toxicology. 2012; 52:179-97; and Allen J A, et al. "Discovery of
beta-arrestin-biased dopamine D2 ligands for probing signal
transduction pathways essential for antipsychotic efficacy,"
Proceedings of the National Academy of Sciences of the United
States of America. 2011; 108(45):18488-93.
[0007] New or improved agents that modulate (such as agonize or
partially agonize) D1 are needed for developing new and more
effective pharmaceuticals to treat diseases or conditions
associated with dysregulated activation of D1, such as those
described herein.
SUMMARY OF THE INVENTION
[0008] The present invention provides, in part, a compound of
Formula I:
##STR00002##
or an N-oxide thereof, or a pharmaceutically acceptable salt of
said compound or said N-oxide, wherein:
[0009] X.sup.1 is O or S;
[0010] Y.sup.1 is O, S, or NR.sup.N;
[0011] Q.sup.1 is an N-containing 5- to 10-membered
heterocycloalkyl, an N-containing 5- to 10-membered heteroaryl, or
phenyl, wherein the heterocycloalkyl or heteroaryl is optionally
substituted with 1, 2, 3, 4, or 5 independently selected R.sup.7;
and the phenyl is optionally substituted with 1, 2, 3, 4, or 5
independently selected R.sup.7a;
[0012] R.sup.T1 and R.sup.T2 are each independently selected from
the group consisting of H, C.sub.1-3 alkyl, C.sub.1-3 fluoroalkyl,
cyclopropyl, fluorocyclopropyl, C.sub.1-3 alkoxy, C.sub.1-3
haloalkoxy, --C(.dbd.O)--O--(C.sub.1-3 alkyl), and
--C(.dbd.O)OH;
[0013] R.sup.1 is selected from the group consisting of H, F,
--C(.dbd.O)OH, --C(.dbd.O)--O--(C.sub.1-3 alkyl), C.sub.1-3 alkyl,
C.sub.1-3 fluoroalkyl, C.sub.3-6 cycloalkyl, and C.sub.3-6
fluorocycloalkyl, wherein said C.sub.3-6 cycloalkyl is optionally
substituted with 1, 2, 3, 4, or 5 substituents each independently
selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, and C.sub.1-4 haloalkoxy;
[0014] R.sup.2 is selected from the group consisting of H, halogen
(e.g., F, Cl, Br, or I), --CN, --OH, C(.dbd.O)OH,
C(.dbd.O)--O--(C.sub.1-3 alkyl), C.sub.1-3 alkoxy, C.sub.1-3
haloalkoxy, --N(R.sup.8)(R.sup.9), C.sub.1-3 alkyl, C.sub.1-3
fluoroalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 fluorocycloalkyl,
C.sub.2-6 alkenyl, and C.sub.2-6 alkynyl, wherein said C.sub.3-6
cycloalkyl is optionally substituted with 1, 2, 3, 4, or 5
substituents each independently selected from halo, C.sub.1-4
alkyl, C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4
haloalkoxy;
[0015] R.sup.3 and R.sup.4 are each independently selected from the
group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, --CN, C.sub.3-6 cycloalkyl,
--C(.dbd.O)OH, C(.dbd.O)--O--(C.sub.1-4 alkyl), and halogen,
wherein each of said C.sub.1-6 alkyl and C.sub.3-6 cycloalkyl is
optionally substituted with 1, 2, 3, 4, or 5 substituents each
independently selected from halo, --OH, --CN, C.sub.1-4 alkyl,
C.sub.1-4 haloalkyl, C.sub.1-4 alkoxy, and C.sub.1-4
haloalkoxy;
[0016] R.sup.5 and R.sup.6 are each independently selected from the
group consisting of H, halogen, --OH, --NO.sub.2, --CN, C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, a 4- to
10-membered heterocycloalkyl, --N(R.sup.8)(R.sup.9),
--N(R.sup.10)(C(.dbd.O)R.sup.11), --C(.dbd.O)--N(R.sup.8)(R.sup.9),
--C(.dbd.O)--R.sup.12, --C(.dbd.O)--OR.sup.12, and --OR.sup.13,
wherein each of said C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, and
heterocycloalkyl is optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, --CN, --OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy,
C.sub.1-3 haloalkyl, C.sub.1-3 haloalkoxy, C.sub.3-6 cycloalkyl,
--N(R.sup.14)(R.sup.15), --N(R.sup.16)(C(.dbd.O)R.sup.17),
--C(.dbd.O)--OR.sup.18, --C(.dbd.O)H, --C(.dbd.O)R.sup.15,
--C(.dbd.O)N(R.sup.14)(R.sup.15), and --OR.sup.19;
[0017] or R.sup.5 and R.sup.3 together with the two carbon atoms to
which they are attached form a fused N-containing 5- or 6-membered
heteroaryl, a fused N-containing 5- or 6-membered heterocycloalkyl,
a fused 5- or 6-membered cycloalkyl, or a fused benzene ring, each
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halo, --CN,
--OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, and
C.sub.1-3 haloalkoxy;
[0018] R.sup.7 and R.sup.7a are each independently selected from
the group consisting of halogen, --OH, --CN, --NO.sub.2, oxo,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 hydroxylalkyl,
C.sub.1-6 alkoxy, C.sub.1-6 haloalkoxy, C.sub.3-7 cycloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.6-10 aryl, a 4- to
10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,
heteroarylalkenyl, --CH.dbd.N--O--(C.sub.1-3 alkyl),
--N(R.sup.14)(R.sup.15), --N(R.sup.16)(C(.dbd.O)R.sup.17),
--S(.dbd.O).sub.2N(R.sup.14)(R.sup.15),
--C(.dbd.O)N(R.sup.14)(R.sup.15), --C(.dbd.O)--R.sup.12,
--C(.dbd.O)--OR.sup.15, and --OR.sup.19, wherein each of said
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, heteroarylalkyl,
heteroarylalkenyl, C.sub.6-10 aryl, heterocycloalkyl and heteroaryl
is optionally substituted with 1, 2, 3, or 4 substituents each
independently selected from the group consisting of halogen, OH,
--CN, --NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 hydroxylalkyl,
C.sub.1-4 alkoxy, --N(R.sup.14)(R.sup.15), --S--(C.sub.1-3 alkyl),
--S(.dbd.O).sub.2--(C.sub.1-4 alkyl), aryloxy, arylalkyloxy
optionally substituted with 1 or 2 C.sub.1-4 alkyl, oxo,
--C(.dbd.O)H, --C(.dbd.O)--C.sub.1-4 alkyl, --C(.dbd.O)O--C.sub.1-4
alkyl, --C(.dbd.O)NH.sub.2, --NHC(.dbd.O)H,
--NHC(.dbd.O)--(C.sub.1-4 alkyl), C.sub.3-7 cycloalkyl, a 5- or
6-membered heteroaryl, C.sub.1-4 haloalkyl, and C.sub.1-4
haloalkoxy;
[0019] or two adjacent R.sup.7a together with the two carbon atoms
to which they are attached form a fused 5- or 6-membered
cycloalkyl, a fused 5- or 6-membered heterocycloalkyl, or a fused
benzene ring, each optionally substituted with 1, 2, 3, or 4
R.sup.7b, wherein each R.sup.7b is independently selected from the
group consisting of halo, --CN, --NO.sub.2, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl,
pyrrolidin-1-yl, pyridin-1-yl, OH, oxo, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 hydroxylalkyl, C.sub.1-4 haloalkyl, and C.sub.1-4
haloalkoxy;
[0020] R.sup.8 and R.sup.9 are each independently selected from the
group consisting of H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.3-10 cycloalkyl, a 4- to 10-membered heterocycloalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, wherein each of said C.sub.1-6 alkyl, C.sub.3-10
cycloalkyl, 4- to 10-membered heterocycloalkyl, cycloalkylalkyl,
arylalkyl, and heteroarylalkyl is optionally substituted with 1, 2,
3, or 4 substituents each independently selected from the group
consisting of --OH, --CN, C.sub.1-3 alkyl, C.sub.3-7 cycloalkyl,
C.sub.1-3 hydroxylalkyl, --S--C.sub.1-3 alkyl, --C(.dbd.O)H,
--C(.dbd.O)--C.sub.1-3 alkyl, --C(.dbd.O)--O--C.sub.1-3 alkyl,
--C(.dbd.O)--NH.sub.2, --C(.dbd.O)--N(C.sub.1-3 alkyl).sub.2,
C.sub.1-3 haloalkyl, C.sub.1-3 alkoxy, and C.sub.1-3
haloalkoxy;
[0021] or R.sup.8 and R.sup.9 together with the N atom to which
they are attached form a 4- to 10-membered heterocycloalkyl or
heteroaryl optionally substituted with 1, 2, 3, or 4 substituents
each independently selected from the group consisting of halogen,
--OH, oxo, --C(.dbd.O)H, --C(.dbd.O)OH, --C(.dbd.O)--C.sub.1-3
alkyl, --C(.dbd.O)--NH.sub.2, --C(.dbd.O)--N(C.sub.1-3
alkyl).sub.2, --CN, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3
hydroxylalkyl, C.sub.1-3 haloalkyl, and C.sub.1-3 haloalkoxy;
[0022] R.sup.10 is selected from the group consisting of H,
C.sub.1-3 alkyl, and C.sub.3-7 cycloalkyl;
[0023] R.sup.11 is selected from the group consisting of C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl,
C.sub.6-10 aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen,
--CF.sub.3, --CN, --OH, oxo, --S--C.sub.1-3 alkyl, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0024] R.sup.12 is H or is selected from the group consisting of
C.sub.1-10 alkyl, C.sub.3-7 cycloalkyl, a 4-14 membered
heterocycloalkyl, C.sub.6-10 aryl, a 5- to 10-membered heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, each optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, --CF.sub.3, --CN, --OH, --C(.dbd.O)OH, C.sub.1-6 alkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0025] R.sup.13 is selected from the group consisting of C.sub.1-10
alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, a 4- to
14-membered heterocycloalkyl, C.sub.6-10 aryl, a 5- to 10-membered
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, each optionally substituted with 1, 2, 3, or 4
substituents each independently selected from the group consisting
of halogen, --N(R.sup.14)(R.sup.15),
--C(.dbd.O)N(R.sup.14)(R.sup.15), --N(R.sup.16)(C(.dbd.O)R.sup.17),
--C(.dbd.O)H, --C(.dbd.O)N(R.sup.16)(OR.sup.18),
--C(.dbd.O)--R.sup.18, --C(.dbd.O)--OR.sup.18,
--O--C(.dbd.O)R.sup.18, --CF.sub.3, --CN, --OH, --O--(C.sub.1-6
hydroxylalkyl), C.sub.1-6 alkyl, oxo, C.sub.1-6 hydroxylalkyl,
C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl,
C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, and C.sub.1-6
haloalkoxy;
[0026] R.sup.14 and R.sup.15 are each independently selected from
the group consisting of H, C.sub.1-6 alkyl, C.sub.2-6 alkenyl,
C.sub.3-10 cycloalkyl, a 4- to 14-membered heterocycloalkyl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, wherein each of said C.sub.1-6 alkyl, C.sub.3-7
cycloalkyl, cycloalkylalkyl, arylalkyl, and heteroarylalkyl is
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of --OH, --CN,
oxo, --NHC(.dbd.O)--(C.sub.1-3 alkyl), --C(.dbd.O)N(C.sub.1-3
alkyl).sub.2, --O--(C.sub.1-6 hydroxylalkyl),
--S(.dbd.O).sub.2--C.sub.1-3 alkyl, --S--C.sub.1-3 alkyl, C.sub.1-3
alkyl, C.sub.3-7 cycloalkyl, C.sub.1-3 hydroxylalkyl, a 5- to
10-membered heteroaryl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, and
C.sub.1-3 haloalkoxy;
[0027] or R.sup.14 and R.sup.15 together with the N atom to which
they are attached form a 4- to 10-membered heterocycloalkyl or 5-
to 10-membered heteroaryl optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, oxo, --OH, C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3
haloalkyl, C.sub.1-3 haloalkoxy, C.sub.1-3 hydroxylalkyl, C.sub.2-4
alkoxyalkyl, oxo, a 5- to 6-membered heteroaryl, --NH.sub.2,
--N(C.sub.1-3 alkyl).sub.2, --S(.dbd.O).sub.2--C.sub.1-3 alkyl,
--S--C.sub.1-3 alkyl, --C(.dbd.O)H, --C(.dbd.O)OH,
--C(.dbd.O)NH.sub.2, and --C(.dbd.O)--C.sub.1-3 alkyl;
[0028] R.sup.16 is selected from the group consisting of H,
C.sub.1-3 alkyl, and C.sub.3-7 cycloalkyl;
[0029] R.sup.17 is selected from the group consisting of C.sub.1-6
alkyl, C.sub.3-7 cycloalkyl, a 4- to 14-membered heterocycloalkyl,
C.sub.6-10 aryl, a 5- to 10-membered heteroaryl, cycloalkylalkyl,
heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, each
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen,
--CF.sub.3, --CN, --OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl,
C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl,
C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy;
[0030] R.sup.18 is H or is selected from the group consisting of
C.sub.1-6 alkyl, C.sub.3-7 cycloalkyl, a 4- to 14-membered
heterocycloalkyl, C.sub.6-10 aryl, a 5- to 10-membered heteroaryl,
cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, each optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, --CF.sub.3, --CN, --OH, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7
cycloalkyl, C.sub.1-6 alkoxy, and C.sub.1-6 haloalkoxy;
[0031] R.sup.19 is selected from the group consisting of C.sub.1-6
alkyl, C.sub.1-6 haloalkyl, C.sub.3-7 cycloalkyl, a 4- to
14-membered heterocycloalkyl, C.sub.6-10 aryl, a 5- to 10-membered
heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, and
heteroarylalkyl, each optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, --N(R.sup.14)(R.sup.15),
--C(.dbd.O)N(R.sup.14)(R.sup.15), --N(R.sup.16)(C(.dbd.O)R.sup.17),
--C(.dbd.O)--R.sup.18, --C(.dbd.O)--OR.sup.18, --CF.sub.3, --CN,
--OH, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.1-6 alkoxy, and
C.sub.1-6 haloalkoxy; and
[0032] R.sup.N is selected from the group consisting of H,
C.sub.1-6 alkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 fluorocycloalkyl,
heteroarylalkyl, and arylalkyl, wherein each of said C.sub.3-6
cycloalkyl, heteroarylalkyl, and arylalkyl is optionally
substituted with 1, 2, 3, 4, or 5 substituents each independently
selected from halo, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.1-4
alkoxy, and C.sub.1-4 haloalkoxy.
[0033] As used herein, the term "adjacent" in describing the
relative positions of two substituent groups on a ring structure
refers to two substituent groups that are respectively attached to
two ring-forming atoms of the same ring, wherein the two-ring
forming atoms are directly connected through a chemical bond. For
example, in each of the following structures:
##STR00003##
either of the two R.sup.70 groups is an adjacent group of
R.sup.60.
[0034] As used herein, the term "n-membered" where n is an integer
typically describes the number of ring-forming atoms in a moiety
where the number of ring-forming atoms is n. For example, pyridine
is an example of a 6-membered heteroaryl ring and thiophene is an
example of a 5-membered heteroaryl group.
[0035] At various places in the present specification, substituents
of compounds of the invention are disclosed in groups or in ranges.
It is specifically intended that the invention include each and
every individual subcombination of the members of such groups and
ranges. For example, the term "C.sub.1-6 alkyl" is specifically
intended to include methyl, ethyl, C.sub.3 alkyl, C.sub.4 alkyl,
C.sub.5 alkyl, and C.sub.6 alkyl. For another example, the term "a
5- to 10-membered heteroaryl group" is specifically intended to
include any 5-, 6-, 7-, 8-, 9- or 10-membered heteroaryl group.
[0036] As used herein, the term "alkyl" is defined to include
saturated aliphatic hydrocarbons including straight chains and
branched chains. In some embodiments, the alkyl group has 1 to 10,
e.g., 1 to 6, carbon atoms. For example, as used herein, the term
"C.sub.1-6 alkyl," as well as the alkyl moieties of other groups
referred to herein (e.g., C.sub.1-6alkoxy) refers to linear or
branched radicals of 1 to 6 carbon atoms (e.g., methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, or n-hexyl), optionally substituted by 1 or more (such as
1 to 5) suitable substituents. The term "C.sub.1-4 alkyl" refers to
linear or branched aliphatic hydrocarbons chains of 1 to 4 carbon
atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl). The term "C.sub.1-3 alkyl" refers to linear
or branched aliphatic hydrocarbons chains of 1 to 3 carbon
atoms
[0037] As used herein, the term "alkenyl" refers to aliphatic
hydrocarbons having at least one carbon-carbon double bond,
including straight chains and branched chains having at least one
carbon-carbon double bond. In some embodiments, the alkenyl group
has 2 to 6 carbon atoms. In some embodiments, the alkenyl group has
2 to 4 carbon atoms. For example, as used herein, the term
"C.sub.2-6 alkenyl" means straight or branched chain unsaturated
radicals of 2 to 6 carbon atoms, including, but not limited to,
ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl,
2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like, optionally
substituted by 1 to 5 suitable substituents. When the compounds of
Formula I contain an alkenyl group, the alkenyl group may exist as
the pure E form, the pure Z form, or any mixture thereof.
[0038] As used herein, the term "alkynyl" refers to aliphatic
hydrocarbons having at least one carbon-carbon triple bond,
including straight chains and branched chains having at least one
carbon-carbon triple bond. In some embodiments, the alkynyl group
has 2 to 6 carbon atoms. For example, as used herein, the term
"C.sub.2-6 alkynyl" is used herein to mean straight or branched
hydrocarbon chain alkynyl radicals as defined above, having 2 to 6
carbon atoms and one triple bond, optionally substituted by 1 or
more (such as 1 to 5) suitable substituents.
[0039] As used herein, the term "cycloalkyl" refers to saturated or
unsaturated, non-aromatic, monocyclic or polycyclic (such as
bicyclic) hydrocarbon rings (e.g., monocyclics such as cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
cyclononyl, or bicyclics including spiro, fused, or bridged systems
(such as bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl,
bicyclo[3.2.1]octanyl or bicyclo[5.2.0]nonanyl,
decahydronaphthalenyl, etc.), optionally substituted by 1 or more
(such as 1 to 5) suitable substituents. The cycloalkyl group has 3
to 15 carbon atoms. In some embodiments the cycloalkyl may
optionally contain one, two or more non-cumulative non-aromatic
double or triple bonds and/or one to three oxo groups. In some
embodiments, the bicycloalkyl group has 6 to 15 carbon atoms. For
example, the term "C.sub.3-7 cycloalkyl" refers to saturated or
unsaturated, non-aromatic, monocyclic or polycyclic (such as
bicyclic) hydrocarbon rings of 3 to 7 ring-forming carbon atoms
(e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or
bicyclo[1.1.1]pentanyl). The term "C.sub.3-6 cycloalkyl" refers to
saturated or unsaturated, non-aromatic, monocyclic or polycyclic
(such as bicyclic) hydrocarbon rings of 3 to 6 ring-forming carbon
atoms. Also included in the definition of cycloalkyl are moieties
that have one or more aromatic rings (including aryl and
heteroaryl) fused to the cycloalkyl ring, for example, benzo or
thienyl derivatives of cyclopentane, cyclopentene, cyclohexane, and
the like (e.g., 2,3-dihydro-1H-indene-1-yl, or
1H-inden-2(3H)-one-1-yl). The cycloalkyl group is optionally
substituted by 1 or more (such as 1 to 5) suitable
substituents.
[0040] As used herein, the term "aryl" refers to all-carbon
monocyclic or fused-ring polycyclic aromatic groups having a
conjugated pi-electron system. The aryl group has 6, 8, or 10
carbon atoms in the ring(s). More commonly, the aryl group has 6 or
10 carbon atoms in the ring(s). Most commonly, the aryl group has 6
carbon atoms in the ring. For example, as used herein, the term
"C.sub.6-10 aryl" means aromatic radicals containing from 6 to 10
carbon atoms such as phenyl, naphthyl, tetrahydronaphthyl, indanyl
and the like. The aryl group is optionally substituted by 1 or more
(such as 1 to 5) suitable substituents.
[0041] As used herein, the term "heteroaryl" refers to monocyclic
or fused-ring polycyclic aromatic heterocyclic groups with one or
more heteroatom ring members (ring-forming atoms) each
independently selected from O, S and N in at least one ring. The
heteroaryl group has 5 to 14 ring-forming atoms, including 1 to 13
carbon atoms, and 1 to 8 heteroatoms selected from O, S, and N. In
some embodiments, the heteroaryl group has 5 to 10 ring-forming
atoms including one to four heteroatoms. The heteroaryl group can
also contain one to three oxo groups. In some embodiments, the
heteroaryl group has 5 to 8 ring-forming atoms including one, two
or three heteroatoms. Examples of monocyclic heteroaryls include
those with 5 ring-forming atoms including one to three heteroatoms
or those with 6 ring-forming atoms including one or two nitrogen
heteroatoms. Examples of fused bicyclic heteroaryls include two
fused 5- and/or 6-membered monocyclic rings including one to four
heteroatoms.
[0042] Examples of heteroaryl groups include pyridinyl, pyrazinyl,
pyrimidinyl, pyridazinyl, thienyl, furyl, imidazolyl, pyrrolyl,
oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl (e.g.,
1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl, triazolyl
(e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,
1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl),
quinolyl, isoquinolyl, benzothienyl, benzofuryl, indolyl, pyridone,
pyrimidone, pyrazinone, pyrimidinone, 1H-imidazol-2(3H)-one,
1H-pyrrole-2,5-dione, and the like. The heteroaryl group is
optionally substituted by 1 or more (such as 1 to 5) suitable
substituents.
[0043] As used herein, the term "N-containing" when used in
connection with a heteroaryl or heterocycloalkyl means that the
heteroaryl or heterocycloalkyl comprises at least one ring-forming
nitrogen (N) atom and optionally one or more (e.g. 1, 2, 3, or 4)
ring-forming heteroatoms each independently selected from O, S and
N. The term "N-containing 5- to 10-membered heteroaryl" refers to a
5- to 10-membered heteroaryl group (including monocyclic or
bi-cyclic) comprising at least one ring-forming nitrogen (N) atom
and optionally one or more (e.g. 1, 2, 3, or 4) ring-forming
heteroatoms each independently selected from O, S and N. The term
"N-containing 5- or 6-membered heteroaryl" refers to a 5- or
6-membered heteroaryl group comprising at least one ring-forming
nitrogen (N) atom and optionally one or more (e.g. 1, 2, 3, or 4)
ring-forming heteroatoms each independently selected from O, S and
N. Examples of N-containing 5- to 10-membered heteroaryl groups
include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl,
pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl
(e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl,
triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl
(e.g., 1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl),
quinolyl, isoquinolyl, pyridone, pyrimidone, pyrazinone,
pyrimidinone, 1H-imidazol-2(3H)-one, 1H-pyrrole-2,5-dione, and the
like. Examples of N-containing 5- or 6-membered heteroaryl groups
include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl,
pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl), thiazolyl
(e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl,
triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl
(e.g., 1,2,3-oxadiazolyl), and thiadiazolyl (e.g.,
1,3,4-thiadiazolyl), The N-containing 5- to 10-membered heteroaryl
group or the N-containing 5- or 6-membered heteroaryl is optionally
substituted by 1 or more (such as 1 to 5) suitable
substituents.
[0044] As used herein, the term "heterocycloalkyl" refers to a
monocyclic or polycyclic [including 2 or more rings that are fused
together, including spiro, fused, or bridged systems, for example,
a bicyclic ring system], saturated or unsaturated, non-aromatic 3-
to 15-membered ring system (such as a 4- to 14-membered ring
system, 4- to 10-membered ring system, or 5- to 10-membered ring
system), including 1 to 14 ring-forming carbon atoms and 1 to 10
ring-forming heteroatoms each independently selected from O, S and
N. The heterocycloalkyl group can also include one to three oxo
groups. Examples of such heterocycloalkyl rings include azetidinyl,
tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl,
piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl,
thiomorpholinyl, tetrahydrothiazinyl, tetrahydrothiadiazinyl,
morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl,
indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl,
benzoxazinyl, 2-azabicyclo[2.2.1]heptanonyl,
3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl and the
like. Further examples of heterocycloalkyl rings include
tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, imidazolidin-1-yl,
imidazolidin-2-yl, imidazolidin-4-yl, pyrrolidin-1-yl,
pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl,
piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl,
1,3-oxazolidin-3-yl, 1,4-oxazepan-1-yl, isothiazolidinyl,
1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl,
1,2-tetrahydrothiazin-2-yl, 1,3-thiazinan-3-yl,
1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl,
1,4-oxazin-4-yl, oxazolidinonyl, and the like. Also included in the
definition of heterocycloalkyl are moieties that have one or more
aromatic rings (including aryl and heteroaryl) fused to the
nonaromatic heterocycloalkyl ring, for example pyridinyl,
pyrimidinyl, thiophenyl, pyrazolyl, phthalimidyl, naphthalimidyl,
and benzo derivatives of heterocycles such as indolene,
isoindolene, isoindolin-1-one-3-yl,
5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl,
6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-6-yl,
4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-yl,
5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one-5-yl,
1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-yl, and
3,4-dihydroisoquinolin-1(2H)-one-3-yl groups. The heterocycloalkyl
group is optionally substituted by 1 or more (such as 1 to 5)
suitable substituents. Examples of heterocycloalkyl groups include
5- or 6-membered monocyclic rings and 9- or 10-membered fused
bicyclic rings.
[0045] As used herein, the term "N-containing 5- to 10-membered
heterocycloalkyl" refers to a 5- to 10-membered heterocycloalkyl
group comprising at least one ring-forming nitrogen (N) atom and
optionally one or more ring-forming heteroatoms each independently
selected from 0, S and N. The term "N-containing 5- or 6-membered
heterocycloalkyl" refers to a 5- or 6-membered heterocycloalkyl
group comprising at least one ring-forming nitrogen (N) atom and
optionally one or more ring-forming heteroatoms each independently
selected from O, S and N. Examples of N-containing 5- to
10-membered heterocycloalkyl groups include piperidin-1-yl,
piperidin-4-yl, piperazin-1-yl, 1,3-thiazinan-3-yl,
1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-5-yl, and
3,4-dihydroisoquinolin-1(2H)-one-3-yl. Examples of N-containing 5-
or 6-membered heterocycloalkyl groups include piperidin-1-yl,
piperidin-4-yl, piperazin-1-yl, 1,3-thiazinan-3-yl, and morpholino.
The N-containing 5- to 10-membered heterocycloalkyl or the
N-containing 5- or 6-membered heterocycloalkyl is optionally
substituted by 1 or more (such as 1 to 5) suitable
substituents.
[0046] As used herein, the term "halo" or "halogen" group is
defined to include fluorine, chlorine, bromine or iodine.
[0047] As used herein, the term "haloalkyl" refers to an alkyl
group having one or more halogen substituents (up to perhaloalkyl,
i.e., every hydrogen atom of the alkyl group has been replaced by a
halogen atom). For example, the term "C.sub.1-6 haloalkyl" refers
to a C.sub.1-6 alkyl group having one or more halogen substituents
(up to perhaloalkyl, i.e., every hydrogen atom of the alkyl group
has been replaced by a halogen atom). The term "C.sub.1-4
haloalkyl" refers to a C.sub.1-4 alkyl group having one or more
halogen substituents (up to perhaloalkyl, i.e., every hydrogen atom
of the alkyl group has been replaced by a halogen atom). The term
"C.sub.1-3 haloalkyl" refers to a C.sub.1-3 alkyl group having one
or more halogen substituents (up to perhaloalkyl, i.e., every
hydrogen atom of the alkyl group has been replaced by a halogen
atom). Examples of haloalkyl groups include CF.sub.3,
C.sub.2F.sub.5, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2Cl
and the like.
[0048] As used herein, the term "alkoxy" or "alkyloxy" refers to an
--O-alkyl group. The term "C.sub.1-6 alkoxy" or "C.sub.1-6
alkyloxy" refers to an --O--(C.sub.1-6 alkyl) group. The term
"C.sub.1-4 alkoxy" or "C.sub.1-4 alkyloxy" refers to an
--O--(C.sub.1-4 alkyl) group. The term "C.sub.1-3 alkoxy" or
"C.sub.1-3 alkyloxy" refers to an --O--(C.sub.1-3 alkyl) group.
Examples of alkoxy include methoxy, ethoxy, propoxy (e.g.,
n-propoxy and isopropoxy), tert-butoxy, and the like.
[0049] As used here, the term "haloalkoxy" refers to an
--O-haloalkyl group. The term "C.sub.1-6 haloalkoxy" refers to an
--O--(C.sub.1-6 haloalkyl) group. The term "C.sub.1-4 haloalkoxy"
refers to an --O--(C.sub.1-4 haloalkyl) group. The term "C.sub.1-3
haloalkoxy" refers to an --O--(C.sub.1-3 haloalkyl) group. An
example of a haloalkoxy group is --OCF.sub.3.
[0050] As used here, the term "aryloxy" refers to an
--O--(C.sub.6-10 aryl) group. An example of an aryloxy group is
--O-phenyl [i.e., phenoxy].
[0051] As used here, the term "arylalkyloxy" or "arylalkoxy" refers
to an --O--C.sub.1-6 alkyl-C.sub.6-10 aryl group. Examples of
arylalkyloxy groups include --O--C.sub.1-4 alkyl-C.sub.6-10 aryl,
--O--C.sub.1-2 alkyl-C.sub.6 aryl, or --O--CH.sub.2-phenyl [i.e.,
benzyloxy].
[0052] As used herein, the term "fluoroalkyl" refers to an alkyl
group having one or more fluorine substituents (up to
perfluoroalkyl, i.e., every hydrogen atom of the alkyl group has
been replaced by fluorine). For example, the term "C.sub.1-6
fluoroalkyl" refers to a C.sub.1-6 alkyl group having one or more
fluorine substituents (up to perfluoroalkyl, i.e., every hydrogen
atom of the C.sub.1-6 alkyl group has been replaced by fluorine).
The term "C.sub.1-4 fluoroalkyl" refers to a C.sub.1-4 alkyl group
having one or more fluorine substituents (up to perfluoroalkyl,
i.e., every hydrogen atom of the C.sub.1-4 alkyl group has been
replaced by fluorine). The term "C.sub.1-3 fluoroalkyl" refers to a
C.sub.1-3 alkyl group having one or more fluorine substituents (up
to perfluoroalkyl, i.e., every hydrogen atom of the C.sub.1-3 alkyl
group has been replaced by fluorine). The term "C.sub.1
fluoroalkyl" refers to a C.sub.1 alkyl group (i.e., methyl) having
one or more fluorine substituents (up to perfluoromethyl, i.e.,
CF.sub.3). Examples of fluoroalkyl groups include CF.sub.3,
C.sub.2F.sub.5, CH.sub.2CF.sub.3, CHF.sub.2, CH.sub.2F, and the
like.
[0053] As used herein, the term "fluorocycloalkyl" refers to a
cycloalkyl group having one or more fluorine substituents (up to
perfluorocycloalkyl, i.e., every hydrogen atom of the cycloalkyl
group has been replaced by fluorine). For example, the term
"C.sub.3-6fluorocycloalkyl" refers to a C.sub.3-6 cycloalkyl group
having one or more fluorine substituents (up to C.sub.3-6
perfluorocycloalkyl, i.e., every hydrogen atom of the C.sub.3-6
cycloalkyl group has been replaced by fluorine). Examples of
fluorocycloalkyl groups include fluorocyclopropyl [i.e., a
cyclopropyl group having one or more fluorine substituents (up to
perfluorocyclopropyl, i.e., every hydrogen atom of the cyclopropyl
group has been replaced by fluorine), for example,
2-fluoro-cyclopropan-1-yl or 2,3-difluorocycloproan-1-y] and
fluorocyclobutyl [i.e., a cyclobutyl group having one or more
fluorine substituents (up to perfluorocyclobutyl, i.e., every
hydrogen atom of the cyclobutyl group has been replaced by
fluorine)],
[0054] As used herein, the term "hydroxylalkyl" or "hydroxyalkyl"
refers to an alkyl group having one or more (e.g., 1, 2, or 3) OH
substituents. The term "C.sub.1-6 hydroxylalkyl" or "C.sub.1-6
hydroxyalkyl" refers to a C.sub.1-6 alkyl group having one or more
(e.g., 1, 2, or 3) OH substituents. Examples of hydroxylalkyl
groups are --CH.sub.2OH and --CH.sub.2CH.sub.2OH.
[0055] As used herein, the term "alkoxyalkyl" refers to an alkyl
group having one or more alkoxy (e.g., 1, 2, or 3) substituents.
The term "C.sub.2-4 alkoxyalkyl" refers to a C.sub.1-3 alkyl group
substituted by a C.sub.1-3 alkoxy group wherein the total carbon
numbers of the alkyl and alkoxy moieties of the alkoxyalkyl is 2,
3, or 4. One example of a hydroxylalkyl group is
--CH.sub.2OCH.sub.3.
[0056] As used herein, the term "cyanoalkyl" refers to an alkyl
group having one or more (e.g., 1, 2, or 3) cyano substituents. The
term "C.sub.1-6 cyanoalkyl" refers to a C.sub.1-6 alkyl group
having one or more (e.g., 1, 2, or 3) CN substituents. The term
"C.sub.1-3 cyanoalkyl" refers to a C.sub.1-3 alkyl group having one
or more (e.g., 1, 2, or 3) CN substituents. One example of a
cyanoalkyl group is --CH.sub.2CN.
[0057] As used herein, the term "heteroarylalkenyl" refers to a
--C.sub.2-6 alkenyl-(heteroaryl) group. Examples of such a
heteroarylalkenyl group include 2-(thiophen-2-yl)ethen-1-yl and
1-(pyridin-2-yl)-prop-1-en-3-yl.
[0058] As used herein, the term "arylalkyl" refers to
--C.sub.1-6alkyl-C.sub.6-10aryl and "cycloalkylalkyl" refers to
--C.sub.1-6alkyl-C.sub.3-14cycloalkyl. Examples of arylalkyl groups
include --C.sub.1-4 alkyl-C.sub.6-10 aryl, --C.sub.1-2
alkyl-C.sub.6-10 aryl, and benzyl. Examples of cycloalkylalkyl
groups include --C.sub.1-4 alkyl-C.sub.3-7 cycloalkyl, cycloalkyl,
and cyclopropylmethyl-.
[0059] As used herein, the term "heteroarylalkyl" refers to
--C.sub.1-6alkyl-(a 5- to 14-membered heteroaryl) and the term
"heterocycloalkylalkyl" refers to --C.sub.1-6 alkyl-(a 3- to
14-membered heterocycloalkyl). Examples of heteroarylalkyl groups
include --C.sub.1-4 alkyl-(a 5- to 14-membered heteroaryl),
--C.sub.1-2 alkyl-(a 5- to 10-membered heteroaryl), --C.sub.1-2
alkyl-(a 5- or 6-membered heteroaryl), and (pyridin-2-yl)-methyl-.
Examples of heterocycloalkylalkyl groups include-C.sub.1-4 alkyl-(a
3- to 14-membered heterocycloalkyl), --C.sub.1-2 alkyl-(a 3- to
10-membered heterocycloalkyl), and 2-(piperidin-4-yl)-ethyl-.
[0060] As used herein, the term "oxo" refers to .dbd.O. When an oxo
is substituted on a carbon atom, they together form a carbonyl
moiety [--C(.dbd.O)--]. When an oxo is substituted on a sulfur
atom, they together form a sulfinyl moiety [--S(.dbd.O)--]; when
two oxo groups are substituted on a sulfur atom, they together form
a sulfonyl moiety [--S(.dbd.O).sub.2--].
[0061] As used herein, the term "optionally substituted" means that
substitution is optional and therefore includes both unsubstituted
and substituted atoms and moieties. A "substituted" atom or moiety
indicates that any hydrogen on the designated atom or moiety can be
replaced with a selection from the indicated substituent group (up
to that every hydrogen atom on the designated atom or moiety is
replaced with a selection from the indicated substituent group),
provided that the normal valency of the designated atom or moiety
is not exceeded, and that the substitution results in a stable
compound. For example, if a methyl group (i.e., CH.sub.3) is
optionally substituted, then up to 3 hydrogen atoms on the carbon
atom can be replaced with substituent groups.
[0062] As used herein, unless specified, the point of attachment of
a substituent can be from any suitable position of the substituent.
For example, piperidinyl can be piperidin-1-yl (attached through
the N atom of the piperidinyl), piperidin-2-yl (attached through
the C atom at the 2-position of the piperidinyl), piperidin-3-yl
(attached through the C atom at the 3-position of the piperidinyl),
or piperidin-4-yl (attached through the C atom at the 4-position of
the piperidinyl). For another example, pyridinyl (or pyridyl) can
be 2-pyridinyl (or pyridin-2-yl), 3-pyridinyl (or pyridin-3-yl), or
4-pyridinyl (or pyridin-4-yl).
[0063] When a bond to a substituent is shown to cross a bond
connecting two atoms in a ring, then such substituent may be bonded
to any of the ring-forming atoms that are substitutable (i.e.,
linking to one or more hydrogen atoms). For example, as shown in
formula a-101 below, R.sup.7 may be bonded to the amide nitrogen
atom or one of the two ring carbon atoms each of which links to a
hydrogen atom. For another example, as shown in formula a-102 below
(when a bond to a substituent is shown to cross a bond in each of
the two rings in a bicyclic ring system), R.sup.7 may be bonded to
any ring-forming atom that is substitutable (i.e., linking to one
or more hydrogen atoms) either in the benzene ring or the pyrazole
ring of the indazole. For yet another example, as shown I formula
a-103 below, substitution of R.sup.7a is on the benzene ring and
substitution R.sup.7b is on the 5-membered ring.
##STR00004##
[0064] When a substituent is listed without indicating the atom via
which such substituent is bonded to the rest of the compound of a
given formula, then such substituent may be bonded via any atom in
such substituent. For example, a substituent on an arylalkyl can be
bonded to any atom on the alkyl part or on the aryl part of the
arylalkyl. Combinations of substituents and/or variables are
permissible only if such combinations result in stable
compounds.
[0065] As noted above, the compounds of Formula I may exist in the
form of pharmaceutically acceptable salts such as, e.g., acid
addition salts and/or base addition salts of the compounds of
Formula I. The phrase "pharmaceutically acceptable salt(s)", as
used herein, unless otherwise indicated, includes acid addition or
base salts which may be present in the compounds of Formula I.
[0066] Pharmaceutically acceptable salts of the compounds of
Formula I include the acid addition and base salts thereof.
[0067] Suitable acid addition salts are formed from acids which
form non-toxic salts. Examples include the acetate, adipate,
aspartate, benzoate, besylate, bicarbonate/carbonate,
bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate,
edisylate, esylate, formate, fumarate, gluceptate, gluconate,
glucuronate, hexafluorophosphate, hibenzate,
hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide,
isethionate, lactate, malate, maleate, malonate, mesylate,
methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate,
orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
phosphate/dihydrogen phosphate, pyroglutamate, saccharate,
stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate
and xinofoate salts.
[0068] Suitable base salts are formed from bases which form
non-toxic salts. Examples include the aluminium, arginine,
benzathine, calcium, choline, diethylamine, diolamine, glycine,
lysine, magnesium, meglumine, olamine, potassium, sodium,
tromethamine and zinc salts.
[0069] Hemisalts of acids and bases may also be formed, for
example, hemisulfate and hemicalcium salts.
[0070] For a review on suitable salts, see "Handbook of
Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and
Wermuth (Wiley-VCH, 2002). Methods for making pharmaceutically
acceptable salts of compounds of Formula I are known to one of
skill in the art.
[0071] As used herein the terms "Formula I", "Formula I or
pharmaceutically acceptable salts thereof", "pharmaceutically
acceptable salts of the compound or the salt [of Formula I]" are
defined to include all forms of the compound of Formula I,
including hydrates, solvates, isomers (including for example
rotational stereoisomers), crystalline and non-crystalline forms,
isomorphs, polymorphs, metabolites, and prodrugs thereof.
[0072] As it is known to the person skilled in the art, amine
compounds (i.e., those comprising one or more nitrogen atoms), for
example tertiary amines, can form N-oxides (also known as amine
oxides or amine N-oxides). An N-oxide has the formula of
(R.sup.100R.sup.200R.sup.300)N.sup.+--O.sup.- wherein the parent
amine (R.sup.100R.sup.200R.sup.300)N can be for example, a tertiary
amine (for example, each of R.sup.100, R.sup.200, R.sup.300 is
independently alkyl, arylalkyl, aryl, heteroaryl, or the like), a
heterocyclic or heteroaromatic amine [for example,
(R.sup.100R.sup.200R.sup.300)N together forms 1-alkylpiperidine,
1-alkylpyrrolidine, 1-benzylpyrrolidine, or pyridine]. For
instance, an imine nitrogen, especially heterocyclic or
heteroaromatic imine nitrogen, or pyridine-type nitrogen
##STR00005##
atom [such as a nitrogen atom in pyridine, pyridazine, or
pyrazine], can be N-oxidized to form the N-oxide comprising the
group
##STR00006##
Thus, a compound according to the present invention comprising one
or more nitrogen atoms (e.g., an imine nitrogen atom), for example,
as a part of Q.sup.1 of Formula I, may be capable of forming an
N-oxide thereof (e.g., mono-N-oxides, bis-N-oxides or
multi-N-oxides, or mixtures thereof depending on the number of
nitrogen atoms suitable to form stable N-oxides). As used herein,
the term "N-oxide(s)" refer to all possible, and in particular all
stable, N-oxide forms of the amine compounds (e.g., compounds
comprising one or more imine nitrogen atoms) described herein, such
as mono-N-oxides (including different isomers when more than one
nitrogen atom of an amine compound can form a mono N-oxide) or
multi-N-oxides (e.g., bis-N-oxides), or mixtures thereof in any
ratio.
[0073] The compounds of Formula I can be converted, optionally,
into N-oxides thereof, for example, in the presence of a suitable
oxidizing reagent in a suitable solvent, for example in the
presence of hydrogen peroxide in methanol or in the presence of
m-chloroperoxybenzoic acid in dichloromethane. One skilled in the
art would readily recognize the reaction conditions suitable for
carrying out the N-oxidation reactions.
[0074] Compounds of Formula I described herein (Compounds of the
invention) include N-oxides thereof and pharmaceutically acceptable
salts of the compounds or the N-oxides.
[0075] Compounds of Formula I may exist in a continuum of solid
states ranging from fully amorphous to fully crystalline. The term
`amorphous` refers to a state in which the material lacks long
range order at the molecular level and, depending upon temperature,
may exhibit the physical properties of a solid or a liquid.
Typically such materials do not give distinctive X-ray diffraction
patterns and, while exhibiting the properties of a solid, are more
formally described as a liquid. Upon heating, a change from solid
to liquid properties occurs which is characterised by a change of
state, typically second order (glass transition'). The term
`crystalline` refers to a solid phase in which the material has a
regular ordered internal structure at the molecular level and gives
a distinctive X-ray diffraction pattern with defined peaks. Such
materials when heated sufficiently will also exhibit the properties
of a liquid, but the change from solid to liquid is characterized
by a phase change, typically first order (Melting point').
[0076] Compounds of Formula I may exist in unsolvated and solvated
forms. When the solvent or water is tightly bound, the complex will
have a well-defined stoichiometry independent of humidity. When,
however, the solvent or water is weakly bound, as in channel
solvates and hygroscopic compounds, the water/solvent content will
be dependent on humidity and drying conditions. In such cases,
non-stoichiometry will be the norm.
[0077] The compounds of Formula I may exist as clathrates or other
complexes (e.g., co-crystals). Included within the scope of the
invention are complexes such as clathrates, drug-host inclusion
complexes wherein the drug and host are present in stoichiometric
or non-stoichiometric amounts. Also included are complexes of the
compounds of Formula I containing two or more organic and/or
inorganic components which may be in stoichiometric or
non-stoichiometric amounts. The resulting complexes may be ionized,
partially ionized, or non-ionized. For a review of such complexes,
see J. K. Haleblian, J. Pharm. Sci. 1975, 64, 1269-1288.
Co-crystals are typically defined as crystalline complexes of
neutral molecular constituents which are bound together through
non-covalent interactions, but could also be a complex of a neutral
molecule with a salt. Co-crystals may be prepared by melt
crystallization, by recrystallisation from solvents, or by
physically grinding the components together--see 0. Almarsson and
M. J. Zaworotko, Chem. Commun. 2004, 17, 1889-1896. For a general
review of multi-component complexes, see Haleblian, J. Pharm. Sci.
1975, 64, 1269-1288.
[0078] The compounds of the invention may also exist in a
mesomorphic state (mesophase or liquid crystal) when subjected to
suitable conditions. The mesomorphic state is intermediate between
the true crystalline state and the true liquid state (either melt
or solution). Mesomorphism arising as the result of a change in
temperature is described as `thermotropic` and that resulting from
the addition of a second component, such as water or another
solvent, is described as lyotropie. Compounds that have the
potential to form lyotropic mesophases are described as
`amphiphilic` and consist of molecules which possess an ionic (such
as --COO.sup.-Na.sup.+, --COO.sup.-K.sup.+, or
--SO.sub.3.sup.-Na.sup.+) or non-ionic (such as
--N.sup.-N.sup.+(CH.sub.3).sub.3) polar head group. For more
information, see Crystals and the Polarizing Microscope by N. H.
Hartshorne and A. Stuart, 4.sup.th Edition (Edward Arnold,
1970).
[0079] The invention also relates to prodrugs of the compounds of
Formula I. Thus certain derivatives of compounds of Formula I which
may have little or no pharmacological activity themselves can, when
administered into or onto the body, be converted into compounds of
Formula I having the desired activity, for example, by hydrolytic
cleavage. Such derivatives are referred to as "prodrugs". Further
information on the use of prodrugs may be found in Pro-drugs as
Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi
and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon
Press, 1987 (Ed. E. B. Roche, American Pharmaceutical
Association).
[0080] Prodrugs in accordance with the invention can, for example,
be produced by replacing appropriate functionalities present in the
compounds of Formula I with certain moieties known to those skilled
in the art as `pro-moieties` as described, for example, in Design
of Prodrugs by H. Bundgaard (Elsevier, 1985).
[0081] Some non-limiting examples of prodrugs in accordance with
the invention include:
[0082] (i) where the compound of Formula I contains a carboxylic
acid functionality that is functionalized into a suitably
metabolically labile group (esters, carbamates, etc.);
[0083] (ii) where the compound of Formula I contains an alcohol
functionality that is functionalized into a suitably metabolically
labile group (ethers, esters, phosphonates, sulfonates, carbamates,
acetals, ketals, etc.); and
[0084] (iii) where the compound of Formula I contains a primary or
secondary amino functionality, or an amide, that is functionalized
into a suitably metabolically labile group, e.g., a hydrolyzable
group (amides, carbamates, ureas, etc.).
[0085] Further examples of replacement groups in accordance with
the foregoing examples and examples of other prodrug types may be
found in the aforementioned references.
[0086] Moreover, certain compounds of Formula I may themselves act
as prodrugs of other compounds of Formula I.
[0087] Also included within the scope of the invention are
metabolites of compounds of Formula I, that is, compounds formed in
vivo upon administration of the drug.
[0088] In some embodiments, the compounds of Formula I include
N-oxides thereof and pharmaceutically acceptable salts of the
compounds or the N-oxides.
[0089] The compounds of Formula I include all stereoisomers and
tautomers. Stereoisomers of Formula I include cis and trans
isomers, optical isomers such as R and S enantiomers,
diastereomers, geometric isomers, rotational isomers, atropisomers,
and conformational isomers of the compounds of Formula I, including
compounds exhibiting more than one type of isomerism; and mixtures
thereof (such as racemates and diastereomeric pairs). Also included
are acid addition or base addition salts wherein the counterion is
optically active, for example, D-lactate or L-lysine, or racemic,
for example, DL-tartrate or DL-arginine.
[0090] In some embodiments, the compounds of Formula I may have
asymmetric carbon atoms. The carbon-carbon bonds of the compounds
of Formula I may be depicted herein using a solid line (-), a solid
wedge () or a dotted wedge (). The use of a solid line to depict
bonds to asymmetric carbon atoms is meant to indicate that all
possible stereoisomers (e.g., specific enantiomers, racemic
mixtures, etc.) at that carbon atom are included. The use of either
a solid or dotted wedge to depict bonds to asymmetric carbon atoms
is meant to indicate that only the stereoisomer shown is meant to
be included. It is possible that compounds of Formula I may contain
more than one asymmetric carbon atom. In those compounds, the use
of a solid line to depict bonds to asymmetric carbon atoms is meant
to indicate that all possible stereoisomers are meant to be
included. For example, unless stated otherwise, it is intended that
the compounds of Formula I can exist as enantiomers and
diastereomers or as racemates and mixtures thereof. The use of a
solid line to depict bonds to one or more asymmetric carbon atoms
in a compound of Formula I and the use of a solid or dotted wedge
to depict bonds to other asymmetric carbon atoms in the same
compound is meant to indicate that a mixture of diastereomers is
present.
[0091] In some embodiments, the compounds of Formula I may exist in
and/or be isolated as atropisomers (e.g., one or more
atropenantiomers). Those skilled in the art would recognize that
atropisomerism may exist in a compound that has two or more
aromatic rings (for example, two aromatic rings linked through a
single bond). See e.g., Freedman, T. B. et al. Absolute
Configuration Determination of Chiral Molecules in the Solution
State Using Vibrational Circular Dichroism. Chirality 2003, 15,
743-758; and Bringmann, G. et al. Atroposelective Synthesis of
Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed. 2005, 44:
5384-5427.
[0092] When any racemate crystallizes, crystals of two different
types are possible. The first type is the racemic compound (true
racemate) referred to above wherein one homogeneous form of crystal
is produced containing both enantiomers in equimolar amounts. The
second type is the racemic mixture or conglomerate wherein two
forms of crystal are produced in equimolar amounts each comprising
a single enantiomer.
[0093] The compounds of Formula I may exhibit the phenomena of
tautomerism and structural isomerism. For example, the compounds of
Formula I may exist in several tautomeric forms, including the enol
and imine form, and the keto and enamine form and geometric isomers
and mixtures thereof. All such tautomeric forms are included within
the scope of the compounds of Formula I. Tautomers may exist as
mixtures of a tautomeric set in solution. In solid form, usually
one tautomer predominates. Even though one tautomer may be
described, the present invention includes all tautomers of the
compounds of Formula I. For example, when one of the following two
tautomers of the invention is disclosed in the experimental section
herein, those skilled in the art would readily recognize that the
invention also includes the other.
##STR00007##
[0094] The present invention 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.
[0095] Examples of isotopes suitable for inclusion in the compounds
of the invention 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.
[0096] 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.
[0097] 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.
[0098] 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.
[0099] Isotopically-labeled compounds of Formula I (or
pharmaceutically acceptable salts thereof or N-oxides of the
compounds or salts) can generally be prepared by conventional
techniques known to those skilled in the art or by processes
analogous to those described in the accompanying Examples and
Preparations using an appropriate isotopically-labeled reagent in
place of the non-labeled reagent previously employed.
[0100] Specific embodiments of the compounds of Formula I include
N-oxides thereof and pharmaceutically acceptable salts of the
compounds or the N-oxides.
[0101] An embodiment of the present invention is a compound of
Formula I wherein Y.sup.1 is O.
[0102] An embodiment of the present invention is a compound of
Formula I wherein Y.sup.1 is S.
[0103] An embodiment of the present invention is a compound of
Formula wherein Y.sup.1 is NH or N(CH.sub.3). In a further
embodiment, Y.sup.1 is NH. In another further embodiment, Y.sup.1
is N(CH.sub.3).
[0104] An embodiment of the present invention is a compound of
Formula I wherein X.sup.1 is O.
[0105] An embodiment of the present invention is a compound of
Formula I wherein X.sup.1 is S.
[0106] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is an N-containing 5- to 10-membered
heterocycloalkyl or N-containing 5- to 10-membered heteroaryl,
wherein each of the ring-forming atoms of the heterocycloalkyl or
heteroaryl is independently selected from N and C; and the
heterocycloalkyl or heteroaryl is optionally substituted with 1, 2,
3, or 4 independently selected R.sup.7. In a further embodiment,
Q.sup.1 is an N-containing 5- to 10-membered heterocycloalkyl
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.7, and wherein each of the ring-forming atoms of the
heterocycloalkyl is independently selected from N and C.
[0107] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is an N-containing 5- to 10-membered
heteroaryl optionally substituted with 1, 2, 3, or 4 independently
selected R.sup.7, and wherein each of the ring-forming atoms of the
heteroaryl is independently selected from N and C. In a further
specific embodiment, Q.sup.1 is selected from quinolinyl,
isoquinolinyl, 1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
1H-pyrrolo[3,2-c]pyridinyl, imidazo[1,2-a]pyrazinyl,
imidazo[2,1-c][1,2,4]triazinyl, imidazo[1,5-a]pyrazinyl,
imidazo[1,2-a]pyrimidinyl, 1H-indazolyl, 9H-purinyl, pyrimidinyl,
pyrazinyl, pyridinyl, pyridazinyl, 1H-pyrazolyl, 1H-pyrrolyl,
4H-pyrazolyl, 4H-imidazolyl, imidazo[1,2-a]pyrimidinyl,
[1,2,4]triazolo[1,5-a]pyrimidinyl,
[1,2,4]triazolo[4,3-b]pyridazinyl, 1H-imidazolyl,
3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyridinyl,
2,4(1H,3H)-dioxo-pyrimidinyl, and 1H-2-oxo-pyrazinyl, each
optionally substituted with 1, 2, 3, or 4 independently selected
R.sup.7.
[0108] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is selected from 1H-pyrazolyl,
1H-imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl,
3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrimidinyl, 1H-2-oxo-pyrazinyl,
2,4(1H,3H)-dioxo-pyrimidinyl, 1H-2-oxo-pyridinyl, isoquinolinyl,
1H-imidazo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,
imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, and
imidazo[1,2-a]pyrazinyl, each optionally substituted with 1, 2, 3,
or 4 independently selected R.sup.7.
[0109] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is selected from:
##STR00008##
[0110] each m is independently 0, 1, 2, or 3.
[0111] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is selected from:
##STR00009## ##STR00010##
and
[0112] each R.sup.7N is H or C.sub.1-3 alkyl, wherein the C.sub.1-3
alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents
each independent selected from halogen (e.g., F), OH, C.sub.1-4
alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, and --N(R.sup.14)(R.sup.15); and wherein R.sup.14 and
R.sup.15 together with the N atom to which they are attached form a
4- to 10-membered heterocycloalkyl optionally substituted with 1,
2, or 3 substituents each independently selected from the group
consisting of halogen, oxo, --OH, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, and C.sub.1-4
hydroxylalkyl. In a further embodiment, each R.sup.7N is H or
C.sub.1-3 alkyl, wherein the C.sub.1-3 alkyl is optionally
substituted with 1, 2, 3, 4, or 5 substituents each independent
selected from halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl,
pyrrolidin-1-yl, and pyridin-1-yl.
[0113] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is pyrimidinyl, pyrazinyl,
3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrazinyl,
2,4(1H,3H)-dioxo-pyrimidinyl, 1H-2-oxo-pyrimidinyl, or
imidazo[1,2-a]pyrazinyl, each optionally substituted with 1, 2, or
3 independently selected R.sup.7. In a further embodiment, each
R.sup.7 is independently C.sub.1-3 alkyl optionally substituted
with 1, 2, 3, 4, or 5 substituents each independent selected from
halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, and --N(R.sup.14)(R.sup.15);
wherein R.sup.14 and R.sup.15 together with the N atom to which
they are attached form a 4- to 10-membered heterocycloalkyl
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen, oxo,
--OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, and C.sub.1-4 hydroxylalkyl. In a yet further
embodiment, each R.sup.7 is independently C.sub.1-3 alkyl
optionally substituted with 1, 2, 3, 4, or 5 substituents each
independent selected from halogen (e.g., F), OH, C.sub.1-4 alkoxy,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
azetidin-1-yl, pyrrolidin-1-yl, and pyridin-1-yl. In a still
further embodiment, each R.sup.7 is methyl.
[0114] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is selected from:
##STR00011##
and m is 1, 2, or 3. Ina further embodiment, each R.sup.7 is
independently C.sub.1-3 alkyl optionally substituted with 1, 2, 3,
4, or 5 substituents each independent selected from halogen (e.g.,
F), OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, and --N(R.sup.14)(R.sup.15); wherein
R.sup.14 and R.sup.15 together with the N atom to which they are
attached form a 4- to 10-membered heterocycloalkyl optionally
substituted with 1, 2, or 3 substituents each independently
selected from the group consisting of halogen, oxo, --OH, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
and C.sub.1-4 hydroxylalkyl. In a yet further embodiment, each
R.sup.7 is independently C.sub.1-3 alkyl optionally substituted
with 1, 2, 3, 4, or 5 substituents each independent selected from
halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl,
and pyridin-1-yl. In a still further embodiment, m is 1 or 2. In a
yet still further embodiment, each R.sup.7 is methyl.
[0115] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is selected from:
##STR00012##
each R.sup.7 is independently H or C.sub.1-3 alkyl (e.g. methyl or
ethyl); and each R.sup.7N is H or C.sub.1-3 alkyl, wherein the
C.sub.1-3 alkyl is optionally substituted with 1, 2, 3, 4, or 5
substituents each independent selected from halogen (e.g., F), OH,
C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, and --N(R.sup.14)(R.sup.15), and wherein R.sup.14 and
R.sup.15 together with the N atom to which they are attached form a
4- to 10-membered heterocycloalkyl optionally substituted with 1,
2, or 3 substituents each independently selected from the group
consisting of halogen (e.g., F), oxo, --OH, C.sub.1-4 alkyl,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, and
C.sub.1-4 hydroxylalkyl. In a further embodiment, each R.sup.7 is
independently H, methyl, or ethyl; and each R.sup.7N is C.sub.1-3
alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents
each independent selected from halogen (e.g., F), OH, C.sub.1-4
alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and pyridin-1-yl. In
a further embodiment, each R.sup.7 is methyl or ethyl; and each
R.sup.7N is C.sub.1-3 alkyl optionally substituted with 1, 2, 3, 4,
or 5 substituents each independent selected from halogen (e.g., F),
OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and
pyridin-1-yl. In a yet further embodiment, each R.sup.7 is methyl
and each R.sup.7N is methyl.
[0116] An embodiment of the invention is a compound of Formula I
wherein Q.sup.1 is selected from:
##STR00013##
and each R.sup.7 is independently C.sub.1-3 alkyl (e.g. methyl or
ethyl). In a further embodiment, each R.sup.7 is independently
methyl or ethyl. In a yet further embodiment, each R.sup.7 is
methyl.
[0117] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is
##STR00014##
and each R.sup.7 is independently C.sub.1-3 alkyl (e.g. methyl or
ethyl). In a further embodiment, each R.sup.7 is methyl.
[0118] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is
##STR00015##
R.sup.7 is H or C.sub.1-3 alkyl (e.g. methyl or ethyl); and
R.sup.7N is C.sub.1-3 alkyl optionally substituted with 1, 2, 3, 4,
or 5 substituents each independent selected from halogen (e.g., F),
OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, and --N(R.sup.14)(R.sup.15); and
wherein R.sup.14 and R.sup.15 together with the N atom to which
they are attached form a 4- to 10-membered heterocycloalkyl
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen, oxo,
--OH, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl,
C.sub.1-4 haloalkoxy, and C.sub.1-4 hydroxylalkyl. In a further
embodiment, R.sup.7 is methyl or ethyl; and R.sup.7N is C.sub.1-3
alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents
each independent selected from halogen (e.g., F), OH, C.sub.1-4
alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and pyridin-1-yl. In
a yet further embodiment, R.sup.7 is methyl and R.sup.7N is
methyl.
[0119] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is
##STR00016##
R.sup.7 is H or C.sub.1-3 alkyl (e.g. methyl or ethyl); R.sup.7N is
C.sub.1-3 alkyl optionally substituted with 1, 2, 3, 4, or 5
substituents each independent selected from halogen (e.g., F), OH,
C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, and --N(R.sup.14)(R.sup.15); and R.sup.14 and
R.sup.15 together with the N atom to which they are attached form a
4- to 10-membered heterocycloalkyl optionally substituted with 1,
2, or 3 substituents each independently selected from the group
consisting of halogen, oxo, --OH, C.sub.1-4 alkyl, C.sub.1-4
alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, and C.sub.1-4
hydroxylalkyl. In a further embodiment, R.sup.7 is methyl or ethyl;
and R.sup.7N is C.sub.1-3 alkyl optionally substituted with 1, 2,
3, 4, or 5 substituents each independent selected from halogen
(e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and
pyridin-1-yl. In a yet further embodiment, R.sup.7 is methyl and
R.sup.7N is methyl.
[0120] An embodiment of the present invention is a compound of
Formula I wherein Q.sup.1 is phenyl optionally substituted with 1,
2, 3, 4, or 5 independently selected R.sup.7a.
[0121] An embodiment of the present invention is a compound of
Formula I wherein:
[0122] Q.sup.1 is a moiety of
##STR00017##
n1 is 0, 1, or 2; and n2 is 0, 1, 2, or 3.
[0123] An embodiment of the present invention is a compound of
Formula I (wherein R.sup.T1 and R.sup.T2 are each independently
selected from the group consisting of H, C.sub.1-3 alkyl, and
C.sub.1-3 fluoroalkyl. In a further embodiment, R.sup.T1 and
R.sup.T2 are each independently selected from the group consisting
of H, methyl, and C.sub.1 fluoroalkyl. In a yet further embodiment,
R.sup.T1 and R.sup.T2 are each independently selected from the
group consisting of H and methyl. In a still further embodiment,
R.sup.T1 and R.sup.T2 are both H.
[0124] An embodiment of the present invention is a compound of
Formula I wherein R.sup.1 is H or C.sub.1-3 alkyl (e.g., methyl).
In a further embodiment, R.sup.1 is H.
[0125] An embodiment of the present invention is a compound of
Formula I wherein R.sup.2 is H, --CN, Br, C.sub.1-3 alkyl (e.g.,
methyl), or cyclopropyl. In a further embodiment, R.sup.2 is H,
--CN, or Br. In a yet further embodiment, R.sup.2 is H or --CN. In
a still further embodiment, R.sup.2 is H. In another further
embodiment, R.sup.2 is --CN. In another further embodiment, R.sup.2
is Br.
[0126] An embodiment of the present invention is a compound of
Formula I wherein R.sup.3 and R.sup.4 are each independently
selected from the group consisting of H, F, Cl, and C.sub.1-3
alkyl. In a further embodiment, R.sup.3 and R.sup.4 are each
independently selected from the group consisting of H, methyl, and
F. In a yet further embodiment, one of R.sup.3 and R.sup.4 is H;
and the other of R.sup.3 and R.sup.4 is selected from the group
consisting of H, methyl, and F. In a still further embodiment,
R.sup.3 and R.sup.4 are both H.
[0127] An embodiment of the present invention is a compound of
Formula I wherein R.sup.3 and R.sup.4 are each independently H or
F. In a further embodiment, one of R.sup.3 and R.sup.4 is H; and
the other of R.sup.3 and R.sup.4 is H or F.
[0128] An embodiment of the present invention is a compound of
Formula I wherein R.sup.5 and R.sup.6 are each independently
selected from the group consisting of H, halogen, OH, --CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, a 4- to 10-membered
heterocycloalkyl, --N(R.sup.8)(R.sup.9),
--N(R.sup.10)(C(.dbd.O)R.sup.11), --C(.dbd.O)--N(R.sup.8)(R.sup.9),
--C(.dbd.O)--OR.sup.12, and --OR.sup.13, wherein each of said
C.sub.1-6 alkyl and 4- to 10-membered heterocycloalkyl is
optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halogen, --CN,
--OH, --N(R.sup.14)(R.sup.15), --N(R.sup.16)(C(.dbd.O)R.sup.17),
--C(.dbd.O)--OR.sup.18, --C(.dbd.O)H, --C(.dbd.O)R.sup.18, and
--C(.dbd.O)N(R.sup.14)(R.sup.15). In a further embodiment, R.sup.5
and R.sup.6 are each independently selected from the group
consisting of H, OH, --CN, Cl, F, methyl, ethyl, C.sub.1
fluoroalkyl, C.sub.1-3 cyanoalkyl, --OCH.sub.3, C.sub.1
fluoroalkoxy, --N(R.sup.8)(R.sup.9), and --OR.sup.13, wherein each
of said methyl or ethyl is optionally substituted with
--N(R.sup.14)(R.sup.15). In a yet further embodiment, one of
R.sup.5 and R.sup.6 is H, F, or methyl; and the other of R.sup.5
and R.sup.6 is selected from the group consisting of H, --OH, --CN,
Cl, F, methyl, ethyl, C.sub.1 fluoroalkyl, C.sub.1-3 cyanoalkyl,
--OCH.sub.3, C.sub.1 fluoroalkoxy, --N(R.sup.8)(R.sup.9), and
--OR.sup.13, wherein each of said methyl or ethyl is optionally
substituted with --N(R.sup.14)(R.sup.15).
[0129] An embodiment of the present invention is a compound of
Formula I wherein one of R.sup.5 and R.sup.6 is H, F, or methyl;
and the other of R.sup.5 and R.sup.6 is selected from the group
consisting of H, OH, --CN, Cl, F, methyl, ethyl, C.sub.1
fluoroalkyl (e.g., CF.sub.3 or CH.sub.2F), C.sub.1-3 cyanoalkyl,
--OCH.sub.3, C.sub.1 fluoroalkoxy (e.g., --OCF.sub.3), and
NH.sub.2. In a further embodiment, one of R.sup.5 and R.sup.6 is H,
F, or methyl; and the other of R.sup.5 and R.sup.6 is selected from
the group consisting of H, --OH, --CN, Cl, F, methyl, ethyl,
CF.sub.3, CH.sub.2F, and --OCH.sub.3. In a yet further embodiment,
one of R.sup.5 and R.sup.6 is H; and the other of R.sup.5 and
R.sup.6 is selected from the group consisting of H, --OH, --CN, Cl,
F, methyl, ethyl, CF.sub.3, CH.sub.2F, and --OCH.sub.3.
[0130] An embodiment of the present invention is a compound of
Formula I wherein one of R.sup.5 and R.sup.6 is H, F, or methyl;
and the other of R.sup.5 and R.sup.6 is selected from the group
consisting of H, --CN, F, methyl, and --OCH.sub.3. In a further
embodiment, one of R.sup.5 and R.sup.6 is H or F; and the other of
R.sup.5 and R.sup.6 is selected from the group consisting of H,
--CN, F, methyl, and --OCH.sub.3. In a yet further embodiment, one
of R.sup.5 and R.sup.6 is H; and the other of R.sup.5 and R.sup.6
is selected from the group consisting of H, --CN, F, methyl, and
--OCH.sub.3. In a still further embodiment, one of R.sup.5 and
R.sup.6 is H; and the other of R.sup.5 and R.sup.6 is --CN.
[0131] An embodiment of the present invention is a compound of
Formula I wherein one of R.sup.5 and R.sup.6 is H; and the other of
R.sup.5 and R.sup.6 is --OR.sup.13.
[0132] An embodiment of the present invention is a compound of
Formula I wherein one of R.sup.5 and R.sup.6 is H; and the other of
R.sup.5 and R.sup.6 is selected from the group consisting of
--N(R.sup.8)(R.sup.9) and --CH.sub.2--N(R.sup.14)(R.sup.15).
[0133] An embodiment of the present invention is a compound of
Formula I wherein R.sup.4 and R.sup.6 are each independently
selected from the group consisting of H, F, and C.sub.1-3 alkyl;
and R.sup.5 and R.sup.3 together with the two carbon atoms to which
they are attached form a fused N-containing 5- or 6-membered
heteroaryl, a fused N-containing 5- or 6-membered heterocycloalkyl,
or a fused benzene ring; wherein each of the fused heteroaryl, the
fused heterocycloalkyl, and the fused benzene ring is optionally
substituted with 1, 2, or 3 substituents each independently
selected from the group consisting of C.sub.1-3 alkyl, C.sub.1-3
alkoxy, C.sub.1-3 haloalkyl, and C.sub.1-3 haloalkoxy.
[0134] An embodiment of the present invention is a compound of
Formula I wherein R.sup.6 and R.sup.4 are both H; and R.sup.5 and
R.sup.3 together with the two carbon atoms to which they are
attached form a fused benzene ring; wherein the fused benzene ring
is optionally substituted with 1, 2, or 3 substituents each
independently selected from the group consisting of halo, C.sub.1-3
alkyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkyl, and C.sub.1-3
haloalkoxy.
[0135] An embodiment of the present invention is a compound of
Formula I wherein R.sup.6 and R.sup.4 are both H; and R.sup.5 and
R.sup.3 together with the two carbon atoms to which they are
attached form a fused N-containing 5- or 6-membered heteroaryl;
wherein the fused heteroaryl is optionally substituted with 1, 2,
or 3 substituents each independently selected from the group
consisting of C.sub.1-3 alkyl, C.sub.1-3 alkoxy, C.sub.1-3
haloalkyl, and C.sub.1-3 haloalkoxy.
[0136] An embodiment of the present invention is a compound of
Formula I wherein R.sup.6 and R.sup.4 are both H; and R.sup.5 and
R.sup.3 together with the two carbon atoms to which they are
attached form a fused N-containing 5- or 6-membered
heterocycloalkyl; wherein the fused heterocycloalkyl is optionally
substituted with 1 to 2 substituents each independently selected
from the group consisting of C.sub.1-3 alkyl.
[0137] An embodiment of the present invention is a compound of
Formula I wherein each of R.sup.7 and R.sup.7a is independently
selected from the group consisting of halogen, oxo, --OH, --CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-7
cycloalkyl, a 4- to 10-membered heterocycloalkyl, a 5- to
10-membered heteroaryl, arylalkyl, heteroarylalkyl, and
--N(R.sup.14)(R.sup.15), wherein the C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, 4, or 5 substituents each independently
selected from halogen (e.g., F), OH, C.sub.1-4 alkoxy, and
--N(R.sup.14)(R.sup.15); and wherein each of said C.sub.3-7
cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, and
heteroarylalkyl is optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, --OH, C.sub.1-4 alkyl, and C.sub.1-4 alkoxy.
[0138] An embodiment of the present invention is a compound of
Formula I wherein each of R.sup.7 and R.sup.7a is independently
selected from the group consisting of halogen, oxo, --OH, --CN,
C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, C.sub.3-7
cycloalkyl, a 4- to 10-membered heterocycloalkyl, a 5- to
10-membered heteroaryl, arylalkyl, heteroarylalkyl, and
--N(R.sup.14)(R.sup.15), wherein the C.sub.1-6 alkyl is optionally
substituted with 1, 2, 3, 4 or 5 substituents each independently
selected from the group consisting of halogen (e.g., F), OH,
C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and pyridin-1-yl; and
wherein each of said C.sub.3-7 cycloalkyl, heterocycloalkyl,
heteroaryl, arylalkyl, and heteroarylalkyl is optionally
substituted with 1, 2, or 3 substituents each independently
selected from the group consisting of halogen, --OH, C.sub.1-4
alkyl, and C.sub.1-4 alkoxy. In a further embodiment, each of
R.sup.7 and R.sup.7a is independently selected from the group
consisting of halogen, --OH, --CN, C.sub.1-6 alkyl, C.sub.1-6
haloalkyl, C.sub.1-6 alkoxy, C.sub.3-7 cycloalkyl, a 4- to
10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl,
arylalkyl, heteroarylalkyl, and --N(R.sup.14)(R.sup.15), wherein
the C.sub.1-6 alkyl is optionally substituted 1 with 1, 2, 3, 4 or
5 substituents each independently selected from the group
consisting of halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl,
pyrrolidin-1-yl, and pyridin-1-yl; and wherein each of said
C.sub.3-7 cycloalkyl, heterocycloalkyl, heteroaryl, arylalkyl, and
heteroarylalkyl is optionally substituted with 1, 2, or 3
substituents each independently selected from the group consisting
of halogen, --OH, C.sub.1-4 alkyl, and C.sub.1-4 alkoxy.
[0139] An embodiment of the present invention is a compound of
Formula I wherein each of R.sup.7 and R.sup.7a is independently
selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4
haloalkyl, oxo, --OH, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy,
halogen, --CN, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, and --N(R.sup.14)(R.sup.15); wherein the C.sub.1-4
alkyl is optionally substituted with 1, 2, 3, 4 or 5 substituents
each independently selected from the group consisting of halogen
(e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and
pyridin-1-yl; where R.sup.14 and R.sup.15 together with the N atom
to which they are attached form a 4- to 10-membered
heterocycloalkyl or a 5- to 10-membered heteroaryl optionally
substituted with 1, 2, or 3 substituents each independently
selected from the group consisting of halogen, oxo, --OH, --CN,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2,
C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4
haloalkoxy, and C.sub.1-4 hydroxylalkyl. In a further embodiment,
R.sup.14 and R.sup.15 together with the N atom to which they are
attached form a 4- to 10-membered heterocycloalkyl optionally
substituted with 1, 2, or 3 substituents each independently
selected from the group consisting of halogen, oxo, --OH, C.sub.1-4
alkyl, C.sub.1-4 alkoxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy,
and C.sub.1-4 hydroxylalkyl.
[0140] An embodiment of the present invention is a compound of
Formula I wherein each of R.sup.7 and R.sup.7a is independently
selected from the group consisting of C.sub.1-4 alkyl, C.sub.1-4
fluoroalkyl, oxo, --OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy;
wherein the C.sub.1-4 alkyl is optionally substituted with 1, 2, 3,
4 or 5 substituents each independently selected from the group
consisting of halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl,
pyrrolidin-1-yl, and pyridin-1-yl.
[0141] An embodiment of the present invention is a compound of
Formula I wherein each R.sup.7 is independently selected from the
group consisting of C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, oxo,
OH, C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, halogen, --CN,
--NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, and
azetidinyl, wherein the C.sub.1-4 alkyl of R.sup.7 is optionally
substituted with 1, 2, 3, 4 or 5 substituents each independently
selected from the group consisting of halogen (e.g., F), OH,
C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl), --N(C.sub.1-4
alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and pyridin-1-yl; and
wherein said azetidinyl of R.sup.7 is optionally substituted with
1, 2, or 3 substituents each independently selected from the group
consisting of F, C.sub.1-4 alkyl, C.sub.1-4 hydroxylalkyl, and
oxo.
[0142] An embodiment of the present invention is a compound of
Formula I wherein each R.sup.7 is independently selected from the
group consisting of C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, oxo,
OH, C.sub.1-4 alkoxy, and C.sub.1-4 haloalkoxy, wherein the
C.sub.1-4 alkyl is optionally substituted with 1, 2, 3, 4 or 5
substituents each independently selected from the group consisting
of halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl,
pyrrolidin-1-yl, and pyridin-1-yl. In a further embodiment, each
R.sup.7 is independently selected from the group consisting of
C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, and oxo; wherein the
C.sub.1-4 alkyl is optionally substituted with 1, 2, 3, 4 or 5
substituents each independently selected from the group consisting
of halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl,
pyrrolidin-1-yl, and pyridin-1-yl. In a yet further embodiment,
each R.sup.7 is independently selected from the group consisting of
C.sub.1-4 alkyl (e.g., methyl) and oxo; wherein the C.sub.1-4 alkyl
is optionally substituted with 1, 2, 3, 4 or 5 substituents each
independently selected from the group consisting of halogen (e.g.,
F), OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and
pyridin-1-yl.
[0143] An embodiment of the present invention is a compound of
Formula I wherein each R.sup.7a is independently selected from the
group consisting of C.sub.1-4 alkyl, C.sub.1-4 fluoroalkyl, OH,
C.sub.1-4 alkoxy, C.sub.1-4 haloalkoxy, halogen, --CN, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidinyl,
pyrrolidinyl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl,
2,5-dihydro-1H-pyrrolyl, thiomorpholino, piperidinyl, and
piperazinyl, wherein each of said azetidinyl, pyrrolidinyl,
1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 2,5-dihydro-1H-pyrrolyl,
thiomorpholino, piperidinyl, and piperazinyl is optionally
substituted with 1, 2, or 3 substituents each independently
selected from the group consisting of F, C.sub.1-4 alkyl, C.sub.1-4
hydroxylalkyl, and oxo.
[0144] An embodiment of the present invention is a compound of
Formula I wherein Y.sup.1 is O and X.sup.1 is O. An embodiment of
the present invention is a compound of Formula I wherein Y.sup.1 is
O; X.sup.1 is O; each of R.sup.T1, R.sup.T2, and R.sup.1 is H; and
R.sup.2 is H or --CN. An embodiment of the present invention is a
compound of Formula I wherein Y.sup.1 is O; X.sup.1 is O; each of
R.sup.T1, R.sup.T2, and R.sup.1 is H; R.sup.2 is H or --CN; and
R.sup.3 and R.sup.4 are each independently H or F. In a further
embodiment, one of R.sup.3 and R.sup.4 is H; and the other of
R.sup.3 and R.sup.4 is H or F. In a still further embodiment,
R.sup.2 is H; in another still further embodiment, R.sup.2 is
--CN.
[0145] An embodiment of the present invention is a compound of
Formula I wherein Y.sup.1 is O; X.sup.1 is O; each of R.sup.T1,
R.sup.T2, and R.sup.1 is H; R.sup.2 is H or --CN; one of R.sup.3
and R.sup.4 is H, and the other of R.sup.3 and R.sup.4 is H or F;
and one of R.sup.5 and R.sup.6 is H or F, and the other of R.sup.5
and R.sup.6 is selected from the group consisting of H, --CN, F,
methyl, and --OCH.sub.3. In a further embodiment, one of R.sup.5
and R.sup.6 is H. In a still further embodiment, R.sup.2 is H; in
another still further embodiment, R.sup.2 is --CN.
[0146] An embodiment of the present invention is a compound of
Formula I wherein Y.sup.1 is O; X.sup.1 is O; each of R.sup.T1,
R.sup.T2, and R.sup.1 is H; R.sup.2 is H or --CN; one of R.sup.3
and R.sup.4 is H, and the other of R.sup.3 and R.sup.4 is H or F;
one of R.sup.5 and R.sup.6 is H or F, and the other of R.sup.5 and
R.sup.6 is selected from the group consisting of H, --CN, F,
methyl, and --OCH.sub.3; and Q.sup.1 is pyrimidinyl, pyrazinyl,
3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrazinyl, 1H-2-oxo-pyrimidinyl, or
imidazo[1,2-a]pyrazinyl, each optionally substituted with 1, 2, or
3 independently selected R.sup.7. In a still further embodiment,
R.sup.2 is H; in another still further embodiment, R.sup.2 is
--CN.
[0147] An embodiment of the present invention is a compound of
Formula I wherein Y.sup.1 is O; X.sup.1 is O; each of R.sup.T1,
R.sup.T2, and R.sup.1 is H; R.sup.2 is H or --CN; one of R.sup.3
and R.sup.4 is H, and the other of R.sup.3 and R.sup.4 is H or F;
one of R.sup.5 and R.sup.6 is H or F, and the other of R.sup.5 and
R.sup.6 is selected from the group consisting of H, --CN, F,
methyl, and --OCH.sub.3; and Q.sup.1 is pyrimidinyl, pyrazinyl,
3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrazinyl, 1H-2-oxo-pyrimidinyl, or
imidazo[1,2-a]pyrazinyl, each optionally substituted with 1, 2, or
3 C.sub.1-3 alkyl. In a further embodiment, Q.sup.1 is pyrimidinyl,
pyrazinyl, 3-oxo-2H-pyridazinyl, 1H-2-oxo-pyrazinyl,
1H-2-oxo-pyrimidinyl, or imidazo[1,2-a]pyrazinyl, each optionally
substituted with 1, 2, or 3 methyl.
[0148] An embodiment of the present invention is a compound of
Formula I wherein Y.sup.1 is O; X.sup.1 is O; each of R.sup.T1,
R.sup.T2, and R.sup.1 is H; R.sup.2 is H or --CN; one of R.sup.3
and R.sup.4 is H, and the other of R.sup.3 and R.sup.4 is H or F;
one of R.sup.5 and R.sup.6 is H or F, and the other of R.sup.5 and
R.sup.6 is selected from the group consisting of H, --CN, F,
methyl, and --OCH.sub.3; and Q.sup.1 is selected from:
##STR00018##
and m is 1, 2, or 3. In a further embodiment, each R.sup.7 is
independently C.sub.1-3 alkyl optionally substituted with 1, 2, 3,
4 or 5 substituents each independently selected from the group
consisting of halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2,
--NH(C.sub.1-4 alkyl), --N(C.sub.1-4 alkyl).sub.2, pyrrolidin-1-yl,
and pyridin-1-yl. In a yet further embodiment, each R.sup.7 is
methyl. In a still further embodiment, R.sup.2 is H; in another
still further embodiment, R.sup.2 is --CN.
[0149] An embodiment of the present invention is a compound of
Formula I wherein Y.sup.1 is O; X.sup.1 is O; each of R.sup.T1,
R.sup.T2, and R.sup.1 is H; R.sup.2 is H or --CN; one of R.sup.3
and R.sup.4 is H, and the other of R.sup.3 and R.sup.4 is H or F;
one of R.sup.5 and R.sup.6 is H or F, and the other of R.sup.5 and
R.sup.6 is selected from the group consisting of H, --CN, F,
methyl, and --OCH.sub.3; and Q.sup.1 is selected from:
##STR00019##
each R.sup.7 is independently H or C.sub.1-3 alkyl (e.g. methyl or
ethyl); and each R.sup.7N is H or C.sub.1-3 alkyl, wherein the
C.sub.1-3 alkyl is optionally substituted with 1, 2, 3, 4, or 5
substituents each independently selected from halogen (e.g., F),
OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4 alkyl),
--N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl, and
pyridin-1-yl. In a further embodiment, each R.sup.7 is methyl or
ethyl and each R.sup.7N is C.sub.1-3 alkyl optionally substituted
with 1, 2, 3, 4, or 5 substituents each independently selected from
halogen (e.g., F), OH, C.sub.1-4 alkoxy, --NH.sub.2, --NH(C.sub.1-4
alkyl), --N(C.sub.1-4 alkyl).sub.2, azetidin-1-yl, pyrrolidin-1-yl,
and pyridin-1-yl. In a yet further embodiment, each R.sup.7 is
methyl and each R.sup.7N is methyl. In a still further embodiment,
R.sup.2 is H; in another still further embodiment, R.sup.2 is
--CN.
[0150] In one embodiment, the invention also provides one or more
of the compounds described as Examples 1-216 in the Examples
section of the subject application, N-oxides thereof, and
pharmaceutically acceptable salts of the compounds or the
N-oxides.
[0151] In another embodiment the invention relates to a compound of
Formula I selected from the group consisting of: [0152]
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridine;
[0153]
2-(4,6-dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)benzo-
nitrile; [0154]
5-[2-fluoro-4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-4,6-dimethylpyridazin-3-
(2H)-one; [0155]
5-[4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-4,6-dimethylpyridazin-3(2H)-one;
[0156]
(+)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimethyl-
pyridazin-3(2H)-one; [0157]
(-)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridaz-
in-3(2H)-one; [0158]
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4,6-dimethylpyridazin-3-
(2H)-one; [0159]
(+)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-
-a]pyrazine; [0160]
(-)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-
-a]pyrazine; [0161]
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-a]p-
yrazine; [0162]
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-fluorophenoxy]furo[3,2-c]pyridine;
[0163]
4-[4-(4,6-dimethylpyrimidin-5-yl)phenoxy]furo[3,2-c]pyridine;
[0164]
(-)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethyl-
pyrazin-2(1H)-one; [0165]
(+)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-
-2(1H)-one; [0166]
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrazin-2(1-
H)-one; [0167]
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimidin-2-
(1H)-one; [0168]
4-[4-(4,6-dimethylpyrimidin-5-yl)-2-fluorophenoxy]furo[3,2-c]pyridine;
[0169]
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-2,4,6-trimethylp-
yridazin-3(2H)-one; [0170]
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-4-methylpyridazin-3(2H)-
-one; [0171]
(+)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridine-
; [0172]
(-)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]-
pyridine; [0173]
4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridine;
[0174]
4-[4-(3,5-dimethyl-6-oxo-1,6-dihydropyridazin-4-yl)phenoxy]furo[3,-
2-c]pyridine-3-carbonitrile; [0175]
(-)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2-c]pyridin-
e; [0176]
(+)-4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2--
c]pyridine; [0177]
4-[4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenoxy]furo[3,2-c]pyridine;
[0178]
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyri-
midine-2,4(1H,3H)-dione; [0179]
(-)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimid-
ine-2,4(1H,3H)-dione; [0180]
(+)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimid-
ine-2,4(1H,3H)-dione; and [0181]
6-[4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H-
)-dione,
[0182] or an N-oxide thereof or a pharmaceutically acceptable salt
of the compound or the N-oxide.
[0183] The present invention also provides compositions (e.g.,
pharmaceutical compositions) comprising a compound of Formula I
(including an N-oxide thereof or a pharmaceutically acceptable salt
of the compound or the N-oxide). Accordingly, in one embodiment,
the invention provides a pharmaceutical composition comprising (a
therapeutically effective amount of) a compound of Formula I (an
N-oxide thereof or a pharmaceutically acceptable salt of the
compound or the N-oxide) and optionally comprising a
pharmaceutically acceptable carrier. In one further embodiment, the
invention provides a pharmaceutical composition comprising (a
therapeutically effective amount of) a compound of Formula I (an
N-oxide thereof or a pharmaceutically acceptable salt of the
compound or the N-oxide), optionally comprising a pharmaceutically
acceptable carrier and, optionally, at least one additional
medicinal or pharmaceutical agent (such as an antipsychotic agent
or anti-schizophrenia agent described below). In one embodiment,
the additional medicinal or pharmaceutical agent is an
anti-schizophrenia agent as described below.
[0184] The pharmaceutically acceptable carrier may comprise any
conventional pharmaceutical carrier or excipient. Suitable
pharmaceutical carriers include inert diluents or fillers, water
and various organic solvents (such as hydrates and solvates). The
pharmaceutical compositions may, if desired, contain additional
ingredients such as flavorings, binders, excipients and the like.
Thus for oral administration, tablets containing various
excipients, such as citric acid, may be employed together with
various disintegrants such as starch, alginic acid and certain
complex silicates and with binding agents such as sucrose, gelatin
and acacia. Additionally, lubricating agents such as magnesium
stearate, sodium lauryl sulfate and talc are often useful for
tableting purposes. Solid compositions of a similar type may also
be employed in soft and hard filled gelatin capsules. Non-limiting
examples of materials, therefore, include lactose or milk sugar and
high molecular weight polyethylene glycols. When aqueous
suspensions or elixirs are desired for oral administration, the
active compound therein may be combined with various sweetening or
flavoring agents, coloring matters or dyes and, if desired,
emulsifying agents or suspending agents, together with diluents
such as water, ethanol, propylene glycol, glycerin, or combinations
thereof.
[0185] The pharmaceutical composition may, for example, be in a
form suitable for oral administration as a tablet, capsule, pill,
powder, sustained release formulation, solution or suspension, for
parenteral injection as a sterile solution, suspension or emulsion,
for topical administration as an ointment or cream or for rectal
administration as a suppository.
[0186] Exemplary parenteral administration forms include solutions
or suspensions of active compounds in sterile aqueous solutions,
for example, aqueous propylene glycol or dextrose solutions. Such
dosage forms may be suitably buffered, if desired.
[0187] The pharmaceutical composition may be in unit dosage forms
suitable for single administration of precise dosages. One of
ordinary skill in the art would appreciate that the composition may
be formulated in sub-therapeutic dosage such that multiple doses
are envisioned.
[0188] In one embodiment the composition comprises a
therapeutically effective amount of a compound of Formula I (or an
N-oxide thereof or a pharmaceutically acceptable salt of the
compound or the N-oxide) and a pharmaceutically acceptable
carrier.
[0189] Compounds of Formula I (including N-oxides thereof and
pharmaceutically acceptable salts of the compounds or the N-oxides)
are D1 modulators. In some embodiments, a compound of Formula I is
a D1 agonist [i.e., binding (having affinity for) and activating D1
receptors]. In some embodiments, using dopamine as a reference full
D1 agonist, a compound of Formula I is a super agonist (i.e., a
compound that is capable of producing a greater maximal response
than the endogenous D1 agonist, dopamine, for a D1 receptor, and
thus exhibiting an efficacy of more than about 100%, for example
120%). In some embodiments, using dopamine as a reference full
agonist, a compound of Formula I is a full D1 agonist (i.e., having
an efficacy of about 100%, for example, 90%-100%, compared to that
of dopamine). In some embodiments, using dopamine as a reference
full D1 agonist, a compound of Formula I is a partial agonist
[i.e., a compound having only partial efficacy (i.e., less than
100%, for example 10%-80% or 50%-70%) at a D1 receptor relative to
the full agonist, dopamine, although it binds and activates a D1
receptor]. A D1 agonist (including superagonist, full agonist, and
partial agonist) can agonize or partially agonize an activity of
D1. In some embodiments, the EC.sub.50 of a compound of Formula I
with respect to D1 is less than about 10 .mu.M, 5 .mu.M, 2 .mu.M, 1
.mu.M, 500 nM, 200 nM, 100 nM, 50, 40, 30, 20, 10, 5, 2, or 1
nM.
[0190] As used herein, when referencing to a compound, the term "D1
modulator" or "D1 agonist" (including a super D1 agonist, a full D1
agonist, or a partial D1 agonist) refers to a compound that is a
D1-like receptor modulator or a D1-like receptor agonist
respectively (i.e., not necessarily selective between/among
subtypes of D1-like receptors). See Lewis, JPET 286:345-353, 1998.
D1Rs include, for example, D1 and D5 in humans and D1A and D1B in
rodents.
[0191] The present invention further provides a method for
modulating (such as agonizing or partially agonizing) an activity
of D1 receptor (either in vitro or in vivo), comprising contacting
(including incubating) the D1 receptor with a compound of Formula I
(such as one selected from Examples 1-216), or an N-oxide thereof
or a pharmaceutically acceptable salt of the compound or the
N-oxide.
[0192] Another embodiment of the invention includes a method for
treating a D1-mediated (or D1-associated) disorder, comprising
administering to a mammal (e.g., a human) in need thereof an amount
of a compound of Formula I (including a pharmaceutically acceptable
salt thereof or an N-oxide of the compound or salt) effective in
modulating (e.g., agonizing or partially agonizing) D1.
[0193] The compounds of Formula I used for treatment of a
D1-mediated disorder include N-oxides thereof or pharmaceutically
acceptable salts of the compounds or the N-oxides.
[0194] D1-mediated (or D1-associated) disorders include
neurological disorders [such as Tourette's syndrome; tardive
dyskinesia; Parkinson's disease; cognitive disorders {including
amnesia, senile dementia, age-related cognitive decline,
HIV-associated dementia, Alzheimer's-associated dementia,
Huntington's-associated dementia, Lewy body dementia, vascular
dementia, drug-related dementia (for example, cognitive impairment
associated with D2 antagonist therapy), delirium, and mild
cognitive impairment}; Huntington's chorea/disease], psychiatric
disorders [such as anxiety (including acute stress disorder,
generalized anxiety disorder, social anxiety disorder, panic
disorder, post-traumatic stress disorder, and obsessive-compulsive
disorder); factitious disorder (including acute hallucinatory
mania); impulse control disorders/impulsivity (including compulsive
gambling and intermittent explosive disorder); mood disorders
(including bipolar I disorder, bipolar II disorder, mania, mixed
affective state, depression including major depression, chronic
depression, seasonal depression, psychotic depression, postpartum
depression, and treatment resistant depression (TRD)); psychomotor
disorders; psychotic disorders [including schizophrenia (including,
for example, cognitive and negative symptoms in schizophrenia),
schizoaffective disorder, schizophreniform, and delusional
disorder]; substance abuse and drug dependence (including narcotic
dependence, alcoholism, amphetamine dependence, cocaine addiction,
nicotine dependence, and drug withdrawal syndrome); eating
disorders (including anorexia, bulimia, binge eating disorder,
hyperphagia, and pagophagia); autism spectrum disorder (e.g.,
autism); chronic apathy, anhedonia, chronic fatigue, seasonal
affective disorder, and pediatric psychiatric disorders (including
attention deficit disorder, attention deficit hyperactive disorder
(ADHD), conduct disorder, and autism)], endocrine disorders (such
as hyperprolactinemia), or other disorders including drowsiness,
sexual dysfunction, pain, migraine, systemic lupus erythematosus
(SLE), hyperglycemia, dislipidemia, obesity, diabetes, sepsis,
post-ischemic tubular necrosis, renal failure, resistant edema,
narcolepsy, cardiovascular disease (e.g., hypertension), congestive
heart failure, postoperative ocula hypotonia, sleep disorders,
serotonin syndrome.
[0195] Another embodiment of the invention provides a method for
treating neurological disorders [such as Tourette's syndrome;
tardive dyskinesia; Parkinson's disease; cognitive disorders
{including amnesia, senile dementia, HIV-associated dementia,
Alzheimer's-associated dementia, Huntington's-associated dementia,
Lewy body dementia, vascular dementia, drug-related dementia (for
example, cognitive impairment associated with D2 antagonist
therapy), delirium, and mild cognitive impairment)}; and
Huntington's chorea/disease], psychiatric disorders [such as
anxiety (including acute stress disorder, generalized anxiety
disorder, social anxiety disorder, panic disorder, post-traumatic
stress disorder and obsessive-compulsive disorder); factitious
disorder (including acute hallucinatory mania); impulse control
disorders/impulsivity (including compulsive gambling and
intermittent explosive disorder); mood disorders (including bipolar
I disorder, bipolar II disorder, mania, mixed affective state,
major depression, chronic depression, seasonal depression,
psychotic depression, and postpartum depression); psychomotor
disorders; psychotic disorders (including schizophrenia,
schizoaffective disorder, schizophreniform, and delusional
disorder); drug dependence (including narcotic dependence,
alcoholism, amphetamine dependence, cocaine addiction, nicotine
dependence, and drug withdrawal syndrome); eating disorders
(including anorexia, bulimia, binge eating disorder, hyperphagia,
and pagophagia); and pediatric psychiatric disorders (including
attention deficit disorder, attention deficit/hyperactive disorder,
conduct disorder, and autism)], or endocrine disorders (such as
hyperprolactinemia) in a mammal, for example a human, comprising
administering to said mammal a therapeutically effective amount of
a compound of Formula I.
[0196] Another embodiment of the invention includes a method for
treating a disorder in a mammal (e.g., a human), which method
comprises administering to said mammal a therapeutically effective
amount of a compound of Formula I, wherein the disorder is selected
from schizophrenia (e.g., cognitive and negative symptoms in
schizophrenia), cognitive impairment [e.g., cognitive impairment
associated with schizophrenia, cognitive impairment associated with
AD, cognitive impairment associated with PD, cognitive impairment
associated with pharmacotherapy therapy (e.g., D2 antagonist
therapy)], attention deficit hyperactivity disorder (ADHD),
impulsivity, compulsive gambling, overeating, autism spectrum
disorder, mild cognitive impairment (MCI), age-related cognitive
decline, dementia (e.g., senile dementia, HIV-associated dementia,
Alzheimer's dementia, Lewy body dementia, vascular dementia, or
frontotemporal dementia), restless leg syndrome (RLS), Parkinson's
disease, Huntington's chorea, anxiety, depression (e.g.,
age-related depression), major depressive disorder (MDD),
treatment-resistant depression (TRD), bipolar disorder, chronic
apathy, anhedonia, chronic fatigue, post-traumatic stress disorder,
seasonal affective disorder, social anxiety disorder, post-partum
depression, serotonin syndrome, substance abuse and drug
dependence, drug abuse relapse, Tourette's syndrome, tardive
dyskinesia, drowsiness, excessive daytime sleepiness, cachexia,
inattention, a movement disorder [e.g., dyskinesia (e.g., Chorea,
Levodopa-induced dyskinesia, or tardive dyskinesia) a Tic disorder
(e.g., Tourette's syndrome), or Tremor], a therapy-induced movement
disorder [e.g., therapy-related dyskinesia (e.g., Levodopa-induced
dyskinesia ("LID")) or therapy-related dyskinesia tremor
(SSRI-induced postural tremor.)], sexual dysfunction (e.g.,
erectile dysfunction or post-SSRI sexual dysfunction), migraine,
systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis,
dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular
necrosis, renal failure, hyponatremia, resistant edema, narcolepsy,
hypertension, congestive heart failure, postoperative ocular
hypotonia, sleep disorders, and pain.
[0197] Another embodiment of the invention includes a method for
treating a disorder in a mammal (e.g., a human), which method
comprises administering to said mammal a therapeutically effective
amount of a compound of Formula I, wherein the disorder is selected
from schizophrenia (e.g., cognitive and negative symptoms in
schizophrenia or cognitive impairment associated with
schizophrenia), cognitive impairment associated with D2 antagonist
therapy, attention deficit hyperactivity disorder (ADHD),
impulsivity, compulsive gambling, autism spectrum disorder, Mild
cognitive impairment (MCI), age-related cognitive decline,
Alzheimer's dementia, Lewy body dementia, vascular dementia,
Parkinson's disease, Huntington's chorea, depression, anxiety,
treatment resistant depression (TRD), bipolar disorder, chronic
apathy, anhedonia, chronic fatigue, post-traumatic stress disorder,
seasonal affective disorder, social anxiety disorder, post-partum
depression, serotonin syndrome, substance abuse and drug
dependence, Tourette's syndrome, tardive dyskinesia, drowsiness,
sexual dysfunction, migraine, systemic lupus erythematosus (SLE),
hyperglycemia, dislipidemia, obesity, diabetes, sepsis,
post-ischemic tubular necrosis, renal failure, resistant edema,
narcolepsy, hypertension, congestive heart failure, postoperative
ocular hypotonia, sleep disorders, and pain.
[0198] Another embodiment of the invention includes a method for
treating depression in a mammal, for example a human, comprising
administering to said mammal (e.g., a human) a therapeutically
effective amount of a compound of Formula I.
[0199] Another embodiment of the invention includes a method for
treating Parkinson's disease in a mammal, for example a human,
comprising administering to said mammal (e.g., a human) a
therapeutically effective amount of a compound of Formula I.
[0200] Another embodiment of the invention includes a method for
treating schizophrenia (e.g., cognitive and negative symptoms in
schizophrenia or cognitive impairment associated with
schizophrenia) or psychosis in a mammal, for example a human,
comprising administering to said mammal (e.g., a human) a
therapeutically effective amount of a compound of Formula I.
[0201] Another embodiment of the invention includes a method for
treating schizophrenia (e.g., cognitive and negative symptoms in
schizophrenia or cognitive impairment associated with
schizophrenia) in a mammal, for example a human, comprising
administering to said mammal a therapeutically effective amount of
a compound of Formula I.
[0202] Another embodiment of the invention includes a method for
the treatment of cognitive impairment associated with schizophrenia
in a mammal, for example a human, comprising administering to said
mammal a therapeutically effective amount of a compound of Formula
I.
[0203] The term "therapeutically effective amount" as used herein
refers to that amount of the compound (including a pharmaceutically
acceptable salt thereof or an N-oxide of the compound or salt)
being administered which will relieve to some extent one or more of
the symptoms of the disorder being treated. In reference to the
treatment of a D1-mediated disorder (e.g., schizophrenia), a
therapeutically effective amount refers to that amount which has
the effect of relieving to some extent (or, for example,
eliminating) one or more symptoms associated with a D1-mediated
disorder (e.g., schizophrenia, or cognitive and negative symptoms
in schizophrenia, or cognitive impairment associated with
schizophrenia).
[0204] The term "treating", as used herein, unless otherwise
indicated, means reversing, alleviating, inhibiting the progress
of, or preventing the disorder or condition to which such term
applies, or one or more symptoms of such disorder or condition. The
term "treatment", as used herein, unless otherwise indicated,
refers to the act of treating as "treating" is defined herein. The
term "treating" also includes adjuvant and neo-adjuvant treatment
of a subject.
[0205] Administration of the compounds of Formula I may be effected
by any method that enables delivery of the compounds to the site of
action. These methods include, for example, enteral routes (e.g.,
oral routes, buccal routes, sublabial routes, sublingual routes),
intranasal routes, inhaled routes, intraduodenal routes, parenteral
injection (including intravenous, subcutaneous, intramuscular,
intravascular or infusion), intrathecal routes, epidural routes,
intracerebral routes, intracerbroventricular routes, topical, and
rectal administration.
[0206] In one embodiment of the present invention, the compounds of
Formula I may be administered/effected by oral routes.
[0207] Dosage regimens may be adjusted to provide the optimum
desired response. For example, a single bolus may be administered,
several divided doses may be administered over time or the dose may
be proportionally reduced or increased as indicated by the
exigencies of the therapeutic situation. It may be advantageous to
formulate parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form, as used
herein, refers to physically discrete units suited as unitary
dosages for the mammalian subjects to be treated; each unit
containing a predetermined quantity of active compound calculated
to produce the desired therapeutic effect in association with the
required pharmaceutical carrier. The specifications for the dosage
unit forms of the invention are dictated by a variety of factors
such as the unique characteristics of the therapeutic agent and the
particular therapeutic or prophylactic effect to be achieved In one
embodiment of the present invention, the compounds of Formula I may
be used to treat humans.
[0208] It is to be noted that dosage values may vary with the type
and severity of the condition to be alleviated, and may include
single or multiple doses. It is to be further understood that for
any particular subject, specific dosage regimens should be adjusted
over time according to the individual need and the professional
judgment of the person administering or supervising the
administration of the compositions, and that dosage ranges set
forth herein are exemplary only and are not intended to limit the
scope or practice of the claimed composition. For example, doses
may be adjusted based on pharmacokinetic or pharmacodynamic
parameters, which may include clinical effects such as toxic
effects and/or laboratory values. Thus, the present invention
encompasses intra-patient dose-escalation as determined by the
skilled artisan. Determining appropriate dosages and regimens for
administration of the chemotherapeutic agent is well-known in the
relevant art and would be understood to be encompassed by the
skilled artisan once provided the teachings disclosed herein.
[0209] The amount of the compound of Formula I administered will be
dependent on the subject being treated, the severity of the
disorder or condition, the rate of administration, the disposition
of the compound and the discretion of the prescribing physician.
However, an effective dosage is in the range of about 0.0001 to
about 50 mg per kg body weight per day, for example about 0.01 to
about 5 mg/kg/day, in single or divided doses. For a 70 kg human,
this would amount to about 0.7 mg to about 3500 mg/day, for example
about 5 mg to about 2000 mg/day. In some instances, dosage levels
below the lower limit of the aforesaid range may be more than
adequate, while in other cases still larger doses may be employed
without causing any harmful side effect, provided that such larger
doses are first divided into several small doses for administration
throughout the day.
[0210] As used herein, the term "combination therapy" refers to the
administration of a compound of Formula I together with an at least
one additional pharmaceutical or medicinal agent (e.g., an
anti-schizophrenia agent), either sequentially or
simultaneously.
[0211] The present invention includes the use of a combination of a
compound of Formula I and one or more additional pharmaceutically
active agent(s). If a combination of active agents is administered,
then they may be administered sequentially or simultaneously, in
separate dosage forms or combined in a single dosage form.
Accordingly, the present invention also includes pharmaceutical
compositions comprising an amount of: (a) a first agent comprising
a compound of Formula I (including an N-oxide thereof or a
pharmaceutically acceptable salt of the compound or the N-oxide);
(b) a second pharmaceutically active agent; and (C) a
pharmaceutically acceptable carrier, vehicle or diluent.
[0212] Various pharmaceutically active agents may be selected for
use in conjunction with the compounds of Formula I, depending on
the disease, disorder, or condition to be treated. Pharmaceutically
active agents that may be used in combination with the compositions
of the present invention include, without limitation:
[0213] (i) acetylcholinesterase inhibitors such as donepezil
hydrochloride (ARICEPT, MEMAC); or Adenosine A.sub.2A receptor
antagonists such as Preladenant (SCH 420814) or SCH 412348;
[0214] (ii) amyloid-.beta. (or fragments thereof), such as
A.beta..sub.1-15 conjugated to pan HLA DR-binding epitope (PADRE)
and ACC-001 (Elan/Wyeth;
[0215] (iii) antibodies to amyloid-.beta. (or fragments thereof),
such as bapineuzumab (also known as AAB-001) and AAB-002
(Wyeth/Elan);
[0216] (iv) amyloid-lowering or -inhibiting agents (including those
that reduce amyloid production, accumulation and fibrillization)
such as colostrinin and bisnorcymserine (also known as BNC);
[0217] (v) alpha-adrenergic receptor agonists such as clonidine
(CATAPRES);
[0218] (vi) beta-adrenergic receptor blocking agents (beta
blockers) such as carteolol;
[0219] (vii) anticholinergics such as amitriptyline (ELAVIL,
ENDEP);
[0220] (viii) anticonvulsants such as carbamazepine (TEGRETOL,
CARBATROL);
[0221] (ix) antipsychotics, such as lurasidone (also known as
SM-13496; Dainippon Sumitomo);
[0222] (x) calcium channel blockers such as nilvadipine (ESCOR,
NIVADIL);
[0223] (xi) catechol O-methyltransferase (COMT) inhibitors such as
tolcapone (TASMAR);
[0224] (xii) central nervous system stimulants such as
caffeine;
[0225] (xiii) corticosteroids such as prednisone (STERAPRED,
DELTASONE);
[0226] (xiv) dopamine receptor agonists such as apomorphine
(APOKYN);
[0227] (xv) dopamine receptor antagonists such as tetrabenazine
(NITOMAN, XENAZINE);
[0228] (xvi) dopamine reuptake inhibitors such as nomifensine
maleate (MERITAL);
[0229] (xvii) gamma-aminobutyric acid (GABA) receptor agonists such
as baclofen (LIORESAL, KEMSTRO);
[0230] (xviii) histamine 3 (H.sub.3) antagonists such as
ciproxifan;
[0231] (xix) immunomodulators such as glatiramer acetate (also
known as copolymer-1; COPAXONE);
[0232] (xx) immunosuppressants such as methotrexate (TREXALL,
RHEUMATREX);
[0233] (xxi) interferons, including interferon beta-1a (AVONEX,
REBIF) and interferon beta-1b (BETASERON, BETAFERON);
[0234] (xxii) levodopa (or its methyl or ethyl ester), alone or in
combination with a DOPA decarboxylase inhibitor (e.g., carbidopa
(SINEMET, CARBILEV, PARCOPA));
[0235] (xxiii) N-methyl-D-aspartate (NMDA) receptor antagonists
such as memantine (NAMENDA, AXURA, EBIXA);
[0236] (xxiv) monoamine oxidase (MAO) inhibitors such as selegiline
(EMSAM);
[0237] (xxv) muscarinic receptor (particularly M1 subtype) agonists
such as bethanechol chloride (DUVOID, URECHOLINE);
[0238] (xxvi) neuroprotective drugs such as
2,3,4,9-tetrahydro-1H-carbazol-3-one oxime;
[0239] (xxvii) nicotinic receptor agonists such as epibatidine;
[0240] (xxviii) norepinephrine (noradrenaline) reuptake inhibitors
such as atomoxetine (STRATTERA);
[0241] (xxix) PDE9 inhibitors such as BAY 73-6691 (Bayer AG);
[0242] (xxx) phosphodiesterase (PDE) inhibitors including (a) PDE1
inhibitors (e.g., vinpocetine), (b) PDE2 inhibitors (e.g.,
erythro-9-(2-hydroxy-3-nonyl)adenine (ENNA)), (C) PDE4 inhibitors
(e.g., rolipram), and (d) PDE5 inhibitors (e.g., sildenafil
(VIAGRA, REVATIO));
[0243] (xxxi) quinolines such as quinine (including its
hydrochloride, dihydrochloride, sulfate, bisulfate and gluconate
salts);
[0244] (xxxii) .beta.-secretase inhibitors such as WY-25105;
[0245] (xxxiii) .gamma.-secretase inhibitors such as LY-411575
(Lilly);
[0246] (xxxiv) serotonin (5-hydroxytryptamine) 1A (5-HT.sub.1A)
receptor antagonists such as spiperone;
[0247] (xxxv) serotonin (5-hydroxytryptamine) 4 (5-HT.sub.4)
receptor agonists such as PRX-03140 (Epix);
[0248] (xxxvi) serotonin (5-hydroxytryptamine) 6 (5-HT.sub.6)
receptor antagonists such as mianserin (TORVOL, BOLVIDON,
NORVAL);
[0249] (xxxvii) serotonin (5-HT) reuptake inhibitors such as
alaproclate, citalopram (CELEXA, CIPRAMIL);
[0250] (xxxviii) trophic factors, such as nerve growth factor
(NGF), basic fibroblast growth factor (bFGF; ERSOFERMIN),
neurotrophin-3 (NT-3), cardiotrophin-1, brain-derived neurotrophic
factor (BDNF), neublastin, meteorin, and glial-derived neurotrophic
factor (GDNF), and agents that stimulate production of trophic
factors, such as propentofylline;
[0251] and the like.
[0252] The compound of Formula I is optionally used in combination
with another active agent. Such an active agent may be, for
example, an atypical antipsychotic or an anti-Parkinson's disease
agent or an anti-Alzheimer's agent. Accordingly, another embodiment
of the invention provides methods of treating a D1-mediated
disorder (e.g., a neurological and psychiatric disorder associated
with D1), comprising administering to a mammal an effective amount
of a compound of Formula I (including an N-oxide thereof or a
pharmaceutically acceptable salt of the compound or the N-oxide)
and further comprising administering another active agent.
[0253] As used herein, the term "another active agent" refers to
any therapeutic agent, other than the compound of Formula I
(including an N-oxide thereof or a pharmaceutically acceptable salt
of the compound or the N-oxide) that is useful for the treatment of
a subject disorder. Examples of additional therapeutic agents
include antidepressants, antipsychotics (such as
anti-schizophrenia), anti-pain, anti-Parkinson's disease agents,
anti-LID, anti-Alzheimer's and anti-anxiety agents. Examples of
particular classes of antidepressants that can be used in
combination with the compounds of the invention include
norepinephrine reuptake inhibitors, selective serotonin reuptake
inhibitors (SSRIs), NK-1 receptor antagonists, monoamine oxidase
inhibitors (MAOIs), reversible inhibitors of monoamine oxidase
(RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs),
corticotropin releasing factor (CRF) antagonists,
.alpha.-adrenoreceptor antagonists, and atypical antidepressants.
Suitable norepinephrine reuptake inhibitors include tertiary amine
tricyclics and secondary amine tricyclics. Examples of suitable
tertiary amine tricyclics and secondary amine tricyclics include
amitriptyline, clomipramine, doxepin, imipramine, trimipramine,
dothiepin, butriptyline, iprindole, lofepramine, nortriptyline,
protriptyline, amoxapine, desipramine and maprotiline. Examples of
suitable selective serotonin reuptake inhibitors include
fluoxetine, fluvoxamine, paroxetine, and sertraline. Examples of
monoamine oxidase inhibitors include isocarboxazid, phenelzine, and
tranylcyclopramine. Examples of suitable reversible inhibitors of
monoamine oxidase include moclobemide. Examples of suitable
serotonin and noradrenaline reuptake inhibitors of use in the
present invention include venlafaxine. Examples of suitable
atypical anti-depressants include bupropion, lithium, nefazodone,
trazodone and viloxazine. Examples of anti-Alzheimer's agents
include Dimebon, NMDA receptor antagonists such as memantine; and
cholinesterase inhibitors such as donepezil and galantamine.
Examples of suitable classes of anti-anxiety agents that can be
used in combination with the compounds of the invention include
benzodiazepines and serotonin 1A (5-HT1A) agonists or antagonists,
especially 5-HT1A partial agonists, and corticotropin releasing
factor (CRF) antagonists. Suitable benzodiazepines include
alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,
halazepam, lorazepam, oxazepam, and prazepam. Suitable 5-HT1A
receptor agonists or antagonists include buspirone, flesinoxan,
gepirone, and ipsapirone. Suitable atypical antipsychotics include
paliperidone, bifeprunox, ziprasidone, risperidone, aripiprazole,
olanzapine, and quetiapine. Suitable nicotine acetylcholine
agonists include ispronicline, varenicline and MEM 3454. Anti-pain
agents include pregabalin, gabapentin, clonidine, neostigmine,
baclofen, midazolam, ketamine and ziconotide. Examples of suitable
anti-Parkinson's disease agents include L-DOPA (or its methyl or
ethyl ester), a DOPA decarboxylase inhibitor (e.g., carbidopa
(SINEMET, CARBILEV, PARCOPA), an Adenosine A.sub.2A receptor
antagonist [e.g., Preladenant (SCH 420814) or SCH 412348],
benserazide (MADOPAR), .alpha.-methyldopa, monofluoromethyldopa,
difluoromethyldopa, brocresine, or m-hydroxybenzylhydrazine), a
dopamine agonist [such as apomorphine (APOKYN), bromocriptine
(PARLODEL), cabergoline (DOSTINEX), dihydrexidine,
dihydroergocryptine, fenoldopam (CORLOPAM), lisuride (DOPERGIN),
pergolide (PERMAX), piribedil (TRIVASTAL, TRASTAL), pramipexole
(MIRAPEX), quinpirole, ropinirole (REQUIP), rotigotine (NEUPRO),
SKF-82958 (GlaxoSmithKline), and sarizotan], a monoamine oxidase
(MAO) inhibitor [such as selegiline (EMSAM), selegiline
hydrochloride (L-deprenyl, ELDEPRYL, ZELAPAR), dimethylselegilene,
brofaromine, phenelzine (NARDIL), tranylcypromine (PARNATE),
moclobemide (AURORIX, MANERIX), befloxatone, safinamide,
isocarboxazid (MARPLAN), nialamide (NIAMID), rasagiline (AZILECT),
iproniazide (MARSILID, IPROZID, IPRONID), CHF-3381 (Chiesi
Farmaceutici), iproclozide, toloxatone (HUMORYL, PERENUM),
bifemelane, desoxypeganine, harmine (also known as telepathine or
banasterine), harmaline, linezolid (ZYVOX, ZYVOXID), and pargyline
(EUDATIN, SUPIRDYL)], a catechol O-methyltransferase (COMT)
inhibitor [such as tolcapone (TASMAR), entacapone (COMTAN), and
tropolone], an N-methyl-D-aspartate (NMDA) receptor antagonist
[such as amantadine (SYMMETREL)], anticholinergics [such as
amitriptyline (ELAVIL, ENDEP), butriptyline, benztropine mesylate
(COGENTIN), trihexyphenidyl (ARTANE), diphenhydramine (BENADRYL),
orphenadrine (NORFLEX), hyoscyamine, atropine (ATROPEN),
scopolamine (TRANSDERM-SCOP), scopolamine methylbromide (PARMINE),
dicycloverine (BENTYL, BYCLOMINE, DIBENT, DILOMINE, tolterodine
(DETROL), oxybutynin (DITROPAN, LYRINEL XL, OXYTROL), penthienate
bromide, propantheline (PRO-BANTHINE), cyclizine, imipramine
hydrochloride (TOFRANIL), imipramine maleate (SURMONTIL),
lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON),
trimipramine (SURMONTIL), and glycopyrrolate (ROBINUL)], or a
combination thereof. Examples of anti-schizophrenia agents include
ziprasidone, risperidone, olanzapine, quetiapine, aripiprazole,
asenapine, blonanserin, or iloperidone. Some additional "another
active agent" examples include rivastigmine (Exelon), Clozapine,
Levodopa, Rotigotine, Aricept, Methylphenidate, memantine.
milnacipran, guanfacine, bupropion, and atomoxetine.
[0254] As noted above, the compounds of Formula I (including
N-oxides thereof and pharmaceutically acceptable salts thereof the
compounds or salts) may be used in combination with one or more
additional anti-schizophrenia agents which are described herein.
When a combination therapy is used, the one or more additional
anti-schizophrenia agents may be administered sequentially or
simultaneously with the compound of the invention. In one
embodiment, the additional anti-schizophrenia agent is administered
to a mammal (e.g., a human) prior to administration of the compound
of the invention. In another embodiment, the additional
anti-schizophrenia agent is administered to the mammal after
administration of the compound of the invention. In another
embodiment, the additional anti-schizophrenia agent is administered
to the mammal (e.g., a human) simultaneously with the
administration of the compound of the invention (or an N-oxide
thereof or a pharmaceutically acceptable salt of the
foregoing).
[0255] The invention also provides a pharmaceutical composition for
the treatment of schizophrenia in a mammal, including a human,
which comprises an amount of a compound of Formula I (or an N-oxide
thereof or a pharmaceutically acceptable salt of the foregoing), as
defined above (including hydrates, solvates and polymorphs of said
compound or pharmaceutically acceptable salts thereof), in
combination with one or more (for example one to three)
anti-schizophrenia agents such as ziprasidone, risperidone,
olanzapine, quetiapine, aripiprazole, asenapine, blonanserin, or
iloperidone, wherein the amounts of the active agent and the
combination when taken as a whole are therapeutically effective for
treating schizophrenia.
[0256] It will be understood that the compounds of Formula I
depicted above are not limited to the particular enantiomer shown,
but also include all stereoisomers and mixtures thereof.
[0257] In a second aspect, the invention provides a D1 agonist with
reduced D1R desensitization. The D1 agonist with reduced D1R
desensitization desensitizes D1R cAMP signaling less than about 25%
relative to Control as measured by an assay similar to (or same as)
example EE as provided herein. In some embodiments, the D1 agonist
with reduced D1R desensitization desensitizes D1R cAMP signaling
less than about 20%, about 18%, about 15%, about 10%, or about 5%)
relative to Control as measured by an assay similar to (or same as)
example EE as provided herein. In a further embodiment, the D1
agonist with reduced D1R desensitization is not a catechol
derivative. In a yet further embodiment, the D1 agonist with
reduced D1R desensitization is not a dopamine derivative.
[0258] As used herein, the D1R desensitization in connection with
the D1 agonists of the present invention referred herein is
homologous desensitization.
[0259] D1R receptor homologous desensitization refers to a loss
(partial or total) of responsiveness after agonist exposure. See
JPET 286: 345-353, 1998. The D1 agonists with reduced D1R
desensitization of the present invention provide prolonged and/or
less-reduced level of potency/effects of the D1 agonists (i.e.,
drug effect) after exposure to a D1R for a certain period of time,
comparing to those D1 agonists without reduced desensitization
(e.g., catechol derivative D1 agonists such as Dopamine, SKF-38393,
Dihydrexidine, and SKF-81297). In this respect, the D1 agonist with
reduced D1R desensitization of the present invention may maintain a
therapeutic effect for a more sustained period of time and avoid
loss of efficacy caused by desensitization (known as
tachyphylaxsis), and thus may require a less amount and/or a less
frequent dosage for its therapeutic application in the treatment of
a D1-mediated/associated disorder. It may also reduce or eliminate
drug abuse/dependence.
[0260] In some embodiments, the D1 agonist with reduced D1R
desensitization is a full D1 agonist or a super D1 agonist. In a
further embodiment, the D1 agonist with reduced D1R desensitization
is a full D1 agonist.
[0261] In some embodiments, the D1 agonist with reduced D1R
desensitization is a partial D1 agonist.
[0262] As used here, a catechol derivative refers to a compound or
a salt thereof, wherein the structure of the compound includes the
following moiety DD-1:
##STR00020##
In a catechol derivative, the phenyl ring of DD-1 can be further
optionally substituted or embedded in a poly-cyclic ring (which can
also be optionally substituted). Some examples of catechol
derivative include dopamine, SKF-38393, SKF-77434, dihydrexidine,
and SKF-81297:
##STR00021##
[0263] As used here, a dopamine derivative refers to a compound or
a salt thereof, wherein the structure of the compound includes the
following moiety DD-2:
##STR00022##
In a dopamine derivative, the phenyl ring of DD-2 can be further
optionally substituted or embedded in a poly-cyclic ring (which can
also be optionally substituted), and/or each of the carbon atoms of
ethylene group and the N atom of DD-2 can be further optionally
substituted or embedded in a poly-cyclic ring (which can also be
optionally substituted). Some examples of dopamine derivative
include SKF-38393, SKF-77434, dihydrexidine, and SKF-81297.
[0264] In a third aspect, the invention provides a method for
treating a disorder in a human, which method comprises
administering to said human a therapeutically effective amount of a
compound or salt thereof wherein the compound or salt thereof is a
D1 agonist with reduced D1R desensitization in the second aspect,
and wherein the disorder is selected from schizophrenia (e.g.,
cognitive and negative symptoms in schizophrenia), cognitive
impairment [e.g., cognitive impairment associated with
schizophrenia, cognitive impairment associated with AD, cognitive
impairment associated with PD, cognitive impairment associated with
pharmacotherapy therapy (e.g., D2 antagonist therapy)], attention
deficit hyperactivity disorder (ADHD), impulsivity, compulsive
gambling, overeating, autism spectrum disorder, mild cognitive
impairment (MCI), age-related cognitive decline, dementia (e.g.,
senile dementia, HIV-associated dementia, Alzheimer's dementia,
Lewy body dementia, vascular dementia, or frontotemporal dementia),
restless leg syndrome (RLS), Parkinson's disease, Huntington's
chorea, anxiety, depression (e.g., age-related depression), major
depressive disorder (MDD), treatment-resistant depression (TRD),
bipolar disorder, chronic apathy, anhedonia, chronic fatigue,
post-traumatic stress disorder, seasonal affective disorder, social
anxiety disorder, post-partum depression, serotonin syndrome,
substance abuse and drug dependence, drug abuse relapse, Tourette's
syndrome, tardive dyskinesia, drowsiness, excessive daytime
sleepiness, cachexia, inattention, a movement disorder [e.g.,
dyskinesia (e.g., Chorea, Levodopa-induced dyskinesia, or tardive
dyskinesia) a Tic disorder (e.g., Tourette's syndrome), or Tremor],
a therapy-induced movement disorder [e.g., therapy-related
dyskinesia (e.g., LID) or therapy-related dyskinesia tremor
(SSRI-induced postural tremor.)], sexual dysfunction (e.g.,
erectile dysfunction or post-SSRI sexual dysfunction), migraine,
systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis,
dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular
necrosis, renal failure, hyponatremia, resistant edema, narcolepsy,
hypertension, congestive heart failure, postoperative ocular
hypotonia, sleep disorders, and pain.
[0265] In a fourth aspect, the invention provides a D1 agonist with
a reduced .beta.-arrestin recruitment activity relative to
Dopamine. A D1R, after binding to the D1 agonist with a reduced
.beta.-arrestin recruitment activity, recruits less than about 60%
of .beta.-arrestin relative to the D1R binding to Dopamine, as
measured by an assay similar to (or the same as) Example CC as
provided herein (either using Total Intensity/cell or Total
Area/cell). In some embodiments, a D1R, after binding to the D1
agonist with a reduced .beta.-arrestin recruitment activity,
recruits less than about 55%, about 50%, about 45%, about 40%, 35%,
or about 30% of .beta.-arrestin relative to the D1R binding to
Dopamine. In a further embodiment, the D1 agonist with a reduced
.beta.-arrestin recruitment activity is not a catechol derivative.
In a yet further embodiment, the D1 agonist with a reduced
.beta.-arrestin recruitment activity is not a dopamine
derivative.
[0266] Under the D1R homologous desensitization mechanism, a
reduced .beta.-arrestin recruitment activity leads to reduced D1R
desensitization. Accordingly, the D1 agonist with a reduced
.beta.-arrestin recruitment activity is also a D1 agonist with
reduced D1R desensitization, and thus provides prolonged and/or
less-reduced level of potency effects of the D1 agonist (i.e., drug
effect) after exposure to a D1R, for a certain period of time
comparing to those D1 agonists without reduced desensitization.
Moreover, the D1 agonist with a reduced .beta.-arrestin recruitment
activity may provide other benefits or unique properties. For
example, a .beta.-arr2/pERK signaling complex mediated by the
activation of the D1 receptor may potentially have a role in
regulating morphine-induced locomotion. See Nikhil M Urs, et. al,
"A Dopamine D1 Receptor-Dependent .beta.-Arrestin Signaling Complex
Potentially Regulates Morphine-Induced Psychomotor Activation but
not Reward in Mice," Neuropsychopharmacology (2011) 36, 551-558. A
reduced .beta.-arrestin recruitment activity of the D1 agonist of
the present invention may affect a D1 mediated "arrestinergic"
signaling (such as .beta.-arr2/pERK signaling complex mediated by
the activation of the D1 receptor) that may be utilized for further
therapeutic benefits relative to a D1 agonist that does not have
reduced .beta.-arrestin recruitment activity.
[0267] In some embodiments, the D1 agonist with a reduced
.beta.-arrestin recruitment activity desensitizes D1R cAMP
signaling less than about 25% (e.g., about 20%, about 18%, about
15%, about 10%, or about 5%) relative to Control.
[0268] In some embodiments, the D1 agonist with reduced D1R
desensitization is a full D1 agonist or a super D1 agonist. In some
further embodiment, the D1 agonist with reduced D1R desensitization
is a full D1 agonist.
[0269] In some embodiments, the D1 agonist with reduced D1R
desensitization is a partial D1 agonist.
[0270] In a fifth aspect, the invention provides a method for
treating a disorder in a human, which method comprises
administering to said human a therapeutically effective amount of a
compound or salt thereof wherein the compound or salt thereof is a
D1 agonist with a reduced .beta.-arrestin recruitment activity in
the fourth aspect, and wherein the disorder is selected from
schizophrenia (e.g., cognitive and negative symptoms in
schizophrenia), cognitive impairment [e.g., cognitive impairment
associated with schizophrenia, cognitive impairment associated with
AD, cognitive impairment associated with PD, cognitive impairment
associated with pharmacotherapy therapy (e.g., D2 antagonist
therapy)], attention deficit hyperactivity disorder (ADHD),
impulsivity, compulsive gambling, overeating, autism spectrum
disorder, mild cognitive impairment (MCI), age-related cognitive
decline, dementia (e.g., senile dementia, HIV-associated dementia,
Alzheimer's dementia, Lewy body dementia, vascular dementia, or
frontotemporal dementia), restless leg syndrome (RLS), Parkinson's
disease, Huntington's chorea, anxiety, depression (e.g.,
age-related depression), major depressive disorder (MDD),
treatment-resistant depression (TRD), bipolar disorder, chronic
apathy, anhedonia, chronic fatigue, post-traumatic stress disorder,
seasonal affective disorder, social anxiety disorder, post-partum
depression, serotonin syndrome, substance abuse and drug
dependence, drug abuse relapse, Tourette's syndrome, tardive
dyskinesia, drowsiness, excessive daytime sleepiness, cachexia,
inattention, a movement disorder [e.g., dyskinesia (e.g., Chorea,
Levodopa-induced dyskinesia, or tardive dyskinesia) a Tic disorder
(e.g., Tourette's syndrome), or Tremor], a therapy-induced movement
disorder [e.g., therapy-related dyskinesia (e.g., LID) or
therapy-related dyskinesia tremor (SSRI-induced postural tremor.)],
sexual dysfunction (e.g., erectile dysfunction or post-SSRI sexual
dysfunction), migraine, systemic lupus erythematosus (SLE),
hyperglycemia, atherosclerosis, dislipidemia, obesity, diabetes,
sepsis, post-ischemic tubular necrosis, renal failure,
hyponatremia, resistant edema, narcolepsy, hypertension, congestive
heart failure, postoperative ocular hypotonia, sleep disorders, and
pain.
[0271] In a sixth aspect, the invention provides a D1 agonist that
interacts significantly with the Ser188 of a D1R when binding to
the D1R. In a further embodiment, the D1 agonist interacting
significantly with the Ser188 of a D1R is not a catechol
derivative. In a yet further embodiment the D1 agonist interacting
significantly with the Ser188 of a D1R is not a dopamine
derivative.
[0272] As used herein, "interacting significantly with the Ser188"
refers to an EC.sub.50 fold shift being greater than about 7.0 as
measured by a S1881 mutant study similar to the one provided
herein. In some embodiments, the D1 agonist that interacts
significantly with the Ser188 of a D1R when binding to the D1R has
an EC.sub.50 fold shift greater than about 8.0 or 9.0 as measured
by a 51881 mutant study similar to the one provided herein.
[0273] In a further embodiment, the invention provides a D1 agonist
that interacts significantly with the Ser188 but not significantly
with the Ser202 of a D1R when binding to the D1R. In a further
embodiment, the D1 agonist interacting significantly with the
Ser188 but not significantly with the Ser202 of a D1R is not a
catechol derivative. In a yet further embodiment the D1 agonist
interacting significantly with the Ser188 but not significantly
with the Ser202 of a D1R is not a dopamine derivative.
[0274] As used herein, "interacting significantly with the Ser202"
refers to an EC.sub.50 fold shift being greater than about 7.0 as
measured by a S202A mutant study similar to the one provided
herein. In some embodiments, the D1 agonist that does not interact
significantly with the Ser202 of a D1R when binding to the D1R has
an EC.sub.50 fold shift less than about 7.0, 6.0, 5.0, or 4.0 as
measured by a S202A mutant study similar to the one provided
herein.
[0275] In some embodiments, the D1 agonist interacting
significantly with the Ser188 of a D1R is a full D1 agonist or a
super D1 agonist. In some embodiments, the D1 agonist interacting
significantly with the Ser188 but not significantly with the Ser202
of a D1R is a full D1 agonist or a super D1 agonist.
[0276] In some embodiments, the D1 agonist interacting
significantly with the Ser188 of a D1R is a partial D1 agonist. In
some embodiments, the D1 agonist interacting significantly with the
Ser188 but not significantly with the Ser202 of a D1R is a partial
D1 agonist.
[0277] In some embodiments, the D1 agonist interacting
significantly with the Ser188 but not significantly with the Ser202
of a D1R is also a D1 agonist with reduced D1R desensitization in
the second aspect.
[0278] In some embodiments, the D1 agonist interacting
significantly with the Ser188 but not significantly with the Ser202
of a D1R is a D1 agonist with a reduced .beta.-arrestin recruitment
activity in the fourth aspect.
[0279] In some embodiments, the D1 agonist interacting
significantly with the Ser188 but not significantly with the Ser202
of a D1R is also a D1 agonist with reduced D1R desensitization in
the second aspect and a D1 agonist with a reduced .beta.-arrestin
recruitment activity in the fourth aspect.
[0280] In some embodiments, the present invention provides a D1
agonist that interacts less strongly with the Asp103 of the D1R. In
some embodiments, the present invention provides a D1 agonist that
interacts significantly with the Ser188 but not significantly with
the Ser202 of a D1R, wherein the D1 agonist interacts less strongly
with the Asp103 of the D1R.
[0281] As used herein, "interact less strongly with the Asp103"
refers to an EC.sub.50 fold shift being less than about 100 as
measured by a D103A mutant study similar to (or same as) the one
provided herein. In some embodiments, the D1 agonist that interacts
less strongly with the Asp103 of a D1R when binding to the D1R has
an EC.sub.50 fold shift less than about 95, 90, 85, or 80 as
measured by a D103A mutant study similar to the one provided
herein.
[0282] In some embodiments, the present invention provides a full
D1 agonist or a super D1 agonist that interacts less strongly with
the Ser198 of the D1R. In some further embodiments, the present
invention provides a full D1 agonist or a super D1 agonist that
interacts less strongly with the Ser198 of the D1R and interacts
less strongly with the Asp103 of the D1R.
[0283] In some embodiments, the present invention provides a full
D1 agonist or a super D1 agonist that interacts significantly with
the Ser188 but not significantly with the Ser202 of a D1R wherein
the full D1 agonist interacts less strongly with the Ser198 of the
D1R. In a further embodiment, the full D1 agonist or a super D1
agonist interacts less strongly the Asp103 of the D1R. In a yet
further embodiment, the D1 agonist interacting significantly with
the Ser188 but not significantly with the Ser202, interacting less
strongly with the Ser198, and interacting less strongly with the
Asp103 of a D1R is also a D1 agonist with reduced D1R
desensitization in the second aspect. In another yet further
embodiment, the D1 agonist interacting significantly with the
Ser188 but not significantly with the Ser202, interacting less
strongly with the Ser198, and interacting less strongly with the
Asp103 of a D1R is a D1 agonist with a reduced .beta.-arrestin
recruitment activity in the fourth aspect.
[0284] As used herein, "interact less strongly with the Ser198"
refers to an EC.sub.50 fold shift being less than about 25 as
measured by a S198A mutant study similar to (or same as) the one
provided herein. In some embodiments, the D1 agonist that interacts
less strongly with the Ser198 of a D1R when binding to the D1R has
an EC.sub.50 fold shift less than about 22, 20, 18, or 15 as
measured by a S198A mutant study similar to (or same as) the one
provided herein.
[0285] In a seventh aspect, the invention provides a method for
treating a disorder in a human, which method comprises
administering to said human a therapeutically effective amount of a
compound or salt thereof wherein the compound or salt thereof is a
D1 agonist interacting significantly with the Ser188 (optionally
but not significantly with the Ser202) of a D1R in the sixth
aspect, and wherein the disorder is selected from schizophrenia
(e.g., cognitive and negative symptoms in schizophrenia), cognitive
impairment [e.g., cognitive impairment associated with
schizophrenia, cognitive impairment associated with AD, cognitive
impairment associated with PD, cognitive impairment associated with
pharmacotherapy therapy (e.g., D2 antagonist therapy)], attention
deficit hyperactivity disorder (ADHD), impulsivity, compulsive
gambling, overeating, autism spectrum disorder, mild cognitive
impairment (MCI), age-related cognitive decline, dementia (e.g.,
senile dementia, HIV-associated dementia, Alzheimer's dementia,
Lewy body dementia, vascular dementia, or frontotemporal dementia),
restless leg syndrome (RLS), Parkinson's disease, Huntington's
chorea, anxiety, depression (e.g., age-related depression), major
depressive disorder (MDD), treatment-resistant depression (TRD),
bipolar disorder, chronic apathy, anhedonia, chronic fatigue,
post-traumatic stress disorder, seasonal affective disorder, social
anxiety disorder, post-partum depression, serotonin syndrome,
substance abuse and drug dependence, drug abuse relapse, Tourette's
syndrome, tardive dyskinesia, drowsiness, excessive daytime
sleepiness, cachexia, inattention, a movement disorder [e.g.,
dyskinesia (e.g., Chorea, Levodopa-induced dyskinesia, or tardive
dyskinesia) a Tic disorder (e.g., Tourette's syndrome), or Tremor],
a therapy-induced movement disorder [e.g., therapy-related
dyskinesia (e.g., LID) or therapy-related dyskinesia tremor
(SSRI-induced postural tremor.)], sexual dysfunction (e.g.,
erectile dysfunction or post-SSRI sexual dysfunction), migraine,
systemic lupus erythematosus (SLE), hyperglycemia, atherosclerosis,
dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular
necrosis, renal failure, hyponatremia, resistant edema, narcolepsy,
hypertension, congestive heart failure, postoperative ocular
hypotonia, sleep disorders, and pain.
DETAILED DESCRIPTION OF THE INVENTION
[0286] Compounds of the invention, including N-oxides and salts of
the compounds or N-oxides, can be prepared using known organic
synthesis techniques and can be synthesized according to any of
numerous possible synthetic routes.
[0287] The reactions for preparing compounds of the invention can
be carried out in suitable solvents, which can be readily selected
by one of skill in the art of organic synthesis. Suitable solvents
can be substantially non-reactive with the starting materials
(reactants), the intermediates, or products at the temperatures at
which the reactions are carried out, e.g., temperatures which can
range from the solvent's freezing temperature to the solvent's
boiling temperature. A given reaction can be carried out in one
solvent or a mixture of more than one solvent. Depending on the
particular reaction step, suitable solvents for a particular
reaction step can be selected by the skilled artisan.
[0288] Preparation of compounds of the invention can involve the
protection and deprotection of various chemical groups. The need
for protection and deprotection, and the selection of appropriate
protecting groups, can be readily determined by one skilled in the
art. The chemistry of protecting groups can be found, for example,
in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3.sup.rd Ed., Wiley & Sons, Inc., New York (1999),
which is incorporated herein by reference in its entirety.
[0289] Reactions can be monitored according to any suitable method
known in the art. For example, product formation can be monitored
by spectroscopic means, such as nuclear magnetic resonance
spectroscopy (e.g., .sup.1H or .sup.13C), infrared spectroscopy,
spectrophotometry (e.g., UV-visible), mass spectrometry, or by
chromatographic methods such as high performance liquid
chromatography (HPLC) or thin layer chromatography (TLC).
[0290] Compounds of Formula I and intermediates thereof may be
prepared according to the following reaction schemes and
accompanying discussion. Unless otherwise indicated, R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.T1,
R.sup.T2, Q.sup.1, X.sup.1, and Y.sup.1, and structural Formula I
in the reaction schemes and discussion that follow are as defined
above. In general the compounds of this invention may be made by
processes which include processes analogous to those known in the
chemical arts, particularly in light of the description contained
herein. Certain processes for the manufacture of the compounds of
this invention and intermediates thereof are provided as further
features of the invention and are illustrated by the following
reaction schemes. Other processes are described in the experimental
section. The schemes and examples provided herein (including the
corresponding description) are for illustration only, and not
intended to limit the scope of the present invention.
[0291] Scheme 1 refers to preparation of compounds of Formula I.
Referring to Scheme 1, compounds of Formula 1-1 [where Lg.sup.1 is
a suitable leaving group such as triazolyl or halo (e.g., Cl or
Br)] or 1-2 [wherein Z.sup.1 is a halogen (Cl, Br, or I)] are
commercially available or can be made by methods described herein
or other methods well known to those skilled in the art. A compound
of Formula 1-3 can be prepared by coupling a compound of Formula
1-1 with a compound of Formula 1-2, for example, by heating a
mixture of a compound of Formula 1-1 with a compound of Formula 1-2
in the presence of a base, such as Cs.sub.2CO.sub.3, in an
appropriate solvent, such as DMSO at temperatures between
50.degree. C. and 120.degree. C. for about 20 minutes to 48 hours.
Alternatively, a metal-catalyzed (such as a palladium or copper
catalyst) coupling may be employed to accomplish the aforesaid
coupling. In this variant of the coupling, a mixture of a compound
of Formula 1-1 and a compound of Formula 1-2 can be heated at
temperatures ranging between 50.degree. C. and 120.degree. C. in
the presence of a base [such as Cs.sub.2CO.sub.3], a metal catalyst
[such as a palladium catalyst, e.g., Pd(OAc).sub.2], and a ligand
[such as BINAP] in an appropriate solvent, such as 1,4-dioxane, for
about 30 minutes to 48 hours. A compound of Formula 1-3 can
subsequently be reacted with a compound of Formula Q.sup.1-Z.sup.2
[wherein Z.sup.2 can be Br; B(OH).sub.2; B(OR).sub.2 wherein each R
is independently H or C.sub.1-6 alkyl, or wherein two (OR) groups,
together with the B atom to which they are attached, form a 5- to
10-membered heterocycloalkyl or heteroaryl optionally substituted
with one or more C.sub.1-6 alkyl; a trialkyltin moiety; or the
like] by a metal-catalyzed (such as palladium-) coupling reaction
to obtain a compound of Formula I. Compounds of Formula
Q.sup.1-Z.sup.2 are commercially available or can be prepared by
methods analogous to those described in the chemical art.
[0292] Alternatively, a compound of Formula 1-3 can be converted to
a compound of Formula 1-4 [wherein Z.sup.2 is defined as above].
For example, a compound of Formula 1-3 (wherein Z.sup.1 is halogen
such as Br) can be converted to a compound of Formula 1-4 [wherein
Z.sup.2 is B(OH).sub.2; B(OR).sub.2 wherein each R is independently
H or C.sub.1-6 alkyl, or wherein two (OR) groups, together with the
B atom to which they are attached, form a 5- to 10-membered
heterocycloalkyl or heteroaryl optionally substituted with one or
more C.sub.1-6 alkyl] by methods described herein or other methods
well known to those skilled in the art. In this example, the
reaction can be accomplished, for example, by reacting a compound
of Formula 1-3 (wherein Z.sup.1 is halogen such as Br) with
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane, a
suitable base [such as potassium acetate], and a palladium catalyst
[such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)] in a
suitable solvent such as 1,4-dioxane. In another example, a
compound of Formula 1-3 (wherein Z.sup.1 is halogen such as Br) can
be converted to a compound of Formula 1-4 [wherein Z.sup.2 is a
trialkyltin moiety] by alternate methods described herein or other
methods well known to those skilled in the art. In this example,
the reaction can be accomplished, for example, by reacting a
compound of Formula 1-3 (wherein Z.sup.1 is halogen such as Br)
with a hexaalkyldistannane [such as hexamethyldistannane] and a
palladium catalyst [such as
tetrakis(triphenylphosphine)palladium(0)] in a suitable solvent
such as 1,4-dioxane. A compound of Formula 1-4 can then be reacted
with a compound of Formula Q.sup.1-Z.sup.1 [wherein Z.sup.1 is
defined as above] by a metal-catalyzed (such as palladium-)
coupling reaction to obtain a compound of Formula I.
[0293] Compounds of Formula Q.sup.1-Z.sup.1 are commercially
available or can be prepared by methods analogous to those
described in the chemical art. The type of reaction employed
depends on the selection of Z.sup.1 and Z.sup.2. For example, when
Z.sup.1 is halogen or triflate and the Q.sup.1-Z.sup.2 reagent is a
boronic acid or boronic ester, a Suzuki reaction may be used [A.
Suzuki, J. Organomet. Chem. 1999, 576, 147-168; N. Miyaura and A.
Suzuki, Chem. Rev. 1995, 95, 2457-2483; A. F. Littke et al., J. Am.
Chem. Soc. 2000, 122, 4020-4028]. In some specific embodiments, an
aromatic iodide, bromide, or triflate of Formula 1-3 is combined
with 1 to 3 equivalents of an aryl or heteroaryl boronic acid or
boronic ester of Formula Q.sup.1-Z.sup.2 and a suitable base, such
as 2 to 5 equivalents of potassium phosphate, in a suitable organic
solvent such as THF. A palladium catalyst is added, such as 0.01
equivalents of S-Phos precatalyst {also known as
chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2-aminoe-
thylphenyl)]palladium(II)-tert-butyl methyl ether adduct}, and the
reaction mixture is heated to temperatures ranging from 60 to
100.degree. C. for 1 to 24 hours. Alternatively, when Z.sup.1 is
halogen or triflate and Z.sup.2 is trialkyltin, a Stille coupling
may be employed [V. Farina et al., Organic Reactions 1997, 50,
1-652]. More specifically, a compound of Formula 1-3 [wherein
Z.sup.1 is bromide, iodide, or triflate] may be combined with 1.5
to 3 equivalents of a compound of Formula Q.sup.1-Z.sup.2 [wherein
the Q.sup.1-Z.sup.2 compound is an Q.sup.1 stannane compound] in
the presence of a palladium catalyst, such as 0.05 equivalents of
dichlorobis(triphenylphosphine)palladium(II), in a suitable organic
solvent such as toluene, and the reaction may be heated to
temperatures ranging from 100.degree. C. to 130.degree. C. for 12
to 36 hours. Where Z.sup.1 is Br, I or, triflate and Z.sup.2 is Br
or I, a Negishi coupling may be used [E. Erdik, Tetrahedron 1992,
48, 9577-9648]. More specifically, a compound of Formula 1-3
[wherein Z.sup.1 is bromide, iodide, or triflate] may be
transmetallated by treatment with 1 to 1.1 equivalents of an
alkyllithium reagent followed by a solution of 1.2 to 1.4
equivalents of zinc chloride in an appropriate solvent such as
tetrahydrofuran at a temperature ranging from -80.degree. C. to
-65.degree. C. After warming to a temperature between 10.degree. C.
and 30.degree. C., the reaction mixture may be treated with a
compound of Formula Q.sup.1-Z.sup.2 (wherein Z.sup.2 is Br or I),
and heated at 50 to 70.degree. C. with addition of a catalyst such
as tetrakis(triphenylphosphine)palladium(0). The reaction may be
carried out for times ranging from 1 to 24 hours. None of these
reactions are limited to the employment of the solvent, base, or
catalyst described above, as many other conditions may be used.
##STR00023##
[0294] Scheme 2 also refers to preparation of compounds of Formula
I. Referring to Scheme 2, compounds of Formula I may be prepared
utilizing analogous chemical transformations to those described in
Scheme 1, but with a different ordering of steps. Compounds of
Formula 2-1 [wherein Pg is a suitable protecting group such as Boc
or Cbz when Y.sup.1 is NH or methyl, or Pg is benzyl when Y.sup.1
is O] are commercially available or can be made by methods
described herein or other methods well known to those skilled in
the art. A compound of Formula 2-1 can be converted to a compound
of Formula 2-2 either directly or after conversion to a compound of
Formula 2-3 using methods analogous to those described in Scheme 1.
A compound of Formula 2-2 may then be deprotected, using
appropriate conditions depending on the selection of the Pg group,
to obtain a compound of Formula 2-4, which in turn can be coupled
with a compound of Formula 1-1 in Scheme 1 to afford a compound of
Formula I. The coupling conditions employed may be analogous to
those described for the preparation of a compound of Formula 1-3 in
Scheme 1.
##STR00024##
[0295] Scheme 3 refers to a preparation of a compound of Formula
3-3 [wherein A.sup.1 is either Pg as defined above or a moiety of
Formula A.sup.1a]. When A.sup.1 is Pg, the compound of Formula 3-3
is an example of a compound of Formula 2-2. When A.sup.1 is
A.sup.1a, the compound of Formula 3-3 is an example of a compound
of Formula I. Referring to Scheme 3, compounds of Formula 3-1 are
commercially available or can be made by methods described herein
or other methods well known to those skilled in the art. A compound
of Formula 3-1 can be reacted with 4-chloro-3-nitropyridine and the
initial product can be subsequently reduced to obtain a compound of
Formula 3-2. Examples of suitable reaction conditions for the
coupling of a compound of Formula 3-1 with 4-chloro-3-nitropyridine
include mixing the two reactants with a suitable base, such as
triethylamine, in a suitable reaction solvent such as ethanol, at
temperatures typically between 0.degree. C. and 100.degree. C. for
about 20 minutes to 48 hours. The subsequent reduction of the nitro
group to afford a compound of Formula 3-2 can be achieved by, for
example, hydrogenation in the presence of a catalyst such as
palladium on carbon in a suitable solvent such as methanol under
hydrogen pressures typically between 1 atm and 4 atm. A compound of
Formula 3-2 can then be reacted with acetic anhydride and triethyl
orthoformate at temperatures between about 100.degree. C. and
150.degree. C. for about 1 hour to 48 hours to obtain a compound of
Formula 3-3.
##STR00025##
[0296] A.sup.1 is Pg or a moiety of A.sup.1a:
##STR00026##
[0297] Scheme 4 refers to a preparation of a compound of Formula
4-3 [wherein each R.sup.77 is independently H or R.sup.7 (such as
C.sub.1-3 alkyl, for example methyl)]. When A.sup.1 is Pg, the
compound of Formula 4-3 is an example of a compound of Formula 2-2.
When A.sup.1 is A.sup.1a, the compound of Formula 4-3 is an example
of a compound of Formula I. Referring to Scheme 4, compounds of
Formula 4-1 are commercially available or can be made by methods
described herein or other methods well known to those skilled in
the art. A compound of Formula 4-2 can be prepared by reacting an
aryl ketone of Formula 4-1 with N,N-dimethylformamide
dimethylacetal (DMF-DMA) in a suitable solvent such as
N,N-dimethylformamide (DMF, which is also a reagent), at
temperatures typically between 0.degree. C. and 160.degree. C., for
about 1 hour to 24 hours. A pyrazole of Formula 4-3 can be prepared
by reacting a compound of Formula 4-2 with a hydrazine of formula
R.sup.77--NH--NH.sub.2 in a suitable solvent such as DMF or
1,4-dioxane, at temperatures typically between 0.degree. C. and
100.degree. C., for about 1 hour to 24 hours.
##STR00027##
[0298] Scheme 5 refers to a preparation of a compound of Formula
5-4 or 5-5 [wherein R.sup.77 is H or R.sup.7 (such as C.sub.1-3
alkyl, for example methyl)]. When A.sup.1 is Pg, the compound of
Formula 5-4 or 5-5 is an example of a compound of Formula 2-2. When
A.sup.1 is A.sup.1a, the compound of Formula 5-4 or 5-5 is an
example of a compound of Formula I. Referring to Scheme 5,
compounds of Formula 5-1 are commercially available or can be made
by methods described herein or other methods well known to those
skilled in the art. A compound of Formula 5-2 can be prepared by
reacting an arylketone of Formula 5-1 with an alkyl nitrite (e.g.,
isoamyl nitrite) in the presence of an acid (such as hydrochloric
acid) at temperatures typically between 0.degree. C. and
100.degree. C. for about 1 hour to 24 hours. The resulting oxime of
Formula 5-2 can be converted to the diketone of Formula 5-3 upon
treatment with formaldehyde (or its equivalent such as
metaformaldehyde or polyformaldehyde) in the presence of an acid
(such as an aqueous hydrochloric acid solution) at temperatures
typically between 0.degree. C. and 50.degree. C. for about 1 hour
to 24 hours. Diketones of Formula 5-3 can be reacted with
glycinamide or a salt thereof [such as an acetic acid salt] in the
presence of a base such as sodium hydroxide to obtain pyrazinones
of Formula 5-4. Alkylation of the pyrazinone nitrogen to obtain a
compound of Formula 5-5 can be achieved by treatment of a compound
of Formula 5-4 with a base [such as LDA, LHMDS, and the like] and a
compound of the formula of R.sup.7Z.sup.3 (wherein Z.sup.3 is an
acceptable leaving group such as Cl, Br, I, methanesulfonate, and
the like), in a suitable solvent such as DMF, 1,4-dioxane, or THF,
at temperatures typically between 0.degree. C. and 50.degree. C.,
for about 1 hour to 24 hours.
##STR00028##
[0299] Scheme 6 refers to a preparation of a compound of Formula
6-5 [wherein each R.sup.77 is independently H or R.sup.7 (such as
C.sub.1-3 alkyl, for example methyl)]. When A.sup.1 is Pg, the
compound of Formula 4-3 is an example of a compound of Formula 6-5.
When A.sup.1 is A.sup.1a, the compound of Formula 6-5 is an example
of a compound of Formula I. Referring to Scheme 6, compounds of
Formula 6-1 are commercially available or can be made by methods
described herein or other methods well known to those skilled in
the art. A compound of Formula 6-3 can be prepared by coupling a
compound of Formula 6-1 with an enol triflate of Formula 6-2.
Compounds of Formula 6-2 can be prepared by methods described
herein or other methods well known to those skilled in the art. The
aforesaid coupling may be accomplished by reacting a compound of
Formula 6-1 with 1 to 3 equivalents of a triflate of Formula 6-2 in
the presence of a suitable base [such as potassium carbonate], a
suitable catalyst [such as palladium(II) acetate], a suitable
ligand [such as tricyclohexylphosphine], and optionally a suitable
phase transfer catalyst such as tetrabutylammonium chloride, in a
suitable solvent such as a polar aprotic solvent (e.g., 1,4-dioxane
or THF), at temperatures typically between 20.degree. C. and
80.degree. C., for about 1 hour to 24 hours. A compound of Formula
6-3 can be reacted with 1 to 5 equivalents of a suitable base [such
as DBU] under an oxygen atmosphere to obtain a compound of Formula
6-4, in a suitable solvent such as a polar aprotic solvent (e.g.,
DMF, 1,4-dioxane or THF), at temperatures typically between
20.degree. C. and 80.degree. C., for about 12 hours to 48 hours. A
compound of Formula 6-5 can be obtained by reacting a compound of
Formula 6-4 with hydrazine in a suitable solvent such as 1-butanol,
at temperatures typically between 20.degree. C. and 120.degree. C.,
for about 1 hour to 24 hours.
##STR00029##
[0300] Scheme 7 refers to a preparation of a compound of Formula
7-6 [wherein R.sup.77 is H or R.sup.7 (such as C.sub.1-3 alkyl,
e.g., methyl)]. When A.sup.1 is Pg, the compound of Formula 7-6 is
an example of a compound of Formula 2-2. When A.sup.1 is A.sup.1a,
the compound of Formula 7-6 is an example of a compound of Formula
I. Referring to Scheme 7, compounds of Formula 7-1 are commercially
available or can be made by methods described herein or other
methods well known to those skilled in the art. A compound of
Formula 7-3 can be prepared by coupling a compound of Formula 7-1
with a compound of Formula 7-2 [wherein Pg.sup.3 is a suitable
protecting group such as 2-tetrahydropyranyl (THP)]. A compound of
Formula 7-2 can be prepared by methods described herein or other
methods well known to those skilled in the art. The aforesaid
coupling may be accomplished by reacting a compound of Formula 7-1
with 1 to 3 equivalents of a compound of Formula 7-2 in the
presence of a suitable base [such as cesium carbonate] and a
suitable catalyst [such as
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)], in a
suitable solvent such as a polar aprotic solvent (e.g., 1,4-dioxane
or THF), at temperatures typically between 50.degree. C. and
120.degree. C., for about 1 hour to 24 hours. A compound of Formula
7-4 can be obtained by removing the protecting Pg.sup.3 group, for
example, by treating a compound of Formula 7-3 (wherein Pg.sup.3
is, for example, THP) with HCl in an alcoholic solvent [such as
2-propanol] at temperatures ranging from 20.degree. C. to
80.degree. C. Treatment of a compound of Formula 7-4 with
phosphorous oxychloride can provide a compound of Formula 7-5, at
temperatures typically between 50.degree. C. and 120.degree. C.,
for about 20 minutes to 24 hours. A compound of Formula 7-5 can be
a reactive intermediate in numerous chemical transformations to
obtain a compound of Formula 7-6. For example, a compound of
Formula 7-5 can be reacted with 1 to 3 equivalents of
trimethylaluminum and 0.05 to 0.1 equivalents of a suitable
palladium catalyst [such as
tetrakis(triphenylphosphine)palladium(0)] in 1,4-dioxane to afford
a compound of Formula 7-6 [wherein the newly introduced R.sup.7 is
methyl], at temperatures typically between 50.degree. C. and
120.degree. C., for about 30 minutes to 12 hours.
##STR00030##
[0301] Scheme 8 refers to a preparation of a compound of Formula
8-4 [wherein R.sup.77 is H or R.sup.7 (such as C.sub.1-3 alkyl,
e.g., methyl)], which is an example of a compound of Formula I.
Referring to Scheme 8, compounds of Formula 8-1 can be prepared
according to methods described in Scheme 1. A compound of Formula
8-2 can be prepared by reacting a compound of Formula 8-1 with
boron tribromide at temperatures typically between -50.degree. C.
and 50.degree. C. for about 1 hour to 24 hours. A compound of
Formula 8-3 can be obtained by treating a compound of Formula 8-2
with phosphorous oxychloride at temperatures typically from
50.degree. C. to 120.degree. C. for about 20 minutes to 24 hours. A
compound of Formula 8-3 can be reacted with 1 to 3 equivalents of a
suitable amine HNR.sup.14R.sup.15, 1 to 5 equivalents of a base
[such as triethylamine, diisopropylethylamine, and the like] and a
catalytic amount of cesium fluoride to obtain a compound of Formula
8-4 in a suitable solvent such as a polar aprotic solvent (e.g.,
1,4-dioxane, DMF, or dimethyl sulfoxide), at temperatures typically
between 50.degree. C. and 150.degree. C., for about 1 hour to 24
hours.
##STR00031##
[0302] Scheme 9 refers to a preparation of a compound of Formula
9-3 and/or 9-4, which can be used in Schemes 1 and/or 2. For
example, when A.sup.1 is Pg, the compound of Formula 9-3 or 9-4 is
an example of a compound of Formula 2-1. When A.sup.1 is A.sup.1a,
the compound of Formula 9-3 or 9-4 is an example of a compound of
Formula 1-3. Referring to Scheme 9, compounds of Formula 9-1 are
commercially available or can be made by methods described herein
or other methods well known to those skilled in the art. A compound
of Formula 9-2 can be prepared by treating a compound of Formula
9-1 with a suitable base [such as lithium diisopropylamide] and
then reacting the resulting anion with N,N-dimethylformamide in a
suitable solvent such as a polar aprotic solvent (e.g., 1,4-dioxane
or THF), at temperatures typically between -78.degree. C. and
0.degree. C. for about 1 hour to 24 hours. A compound of Formula
9-2 can be reacted with methyl hydrazine to obtain a mixture of
compounds of Formula 9-3 and Formula 9-4 in a suitable solvent such
as 1,4-dioxane at temperatures typically between 50.degree. C. and
150.degree. C., for about 1 hour to 24 hours.
##STR00032##
[0303] Scheme 10 refers to a preparation of a compound of Formula
10-3, which can be used in Schemes 1 and/or 2. For example, when
A.sup.1 is Pg, the compound of Formula 10-3 is an example of a
compound of Formula 2-1. When A.sup.1 is A.sup.1a, the compound of
Formula 10-3 is an example of a compound of Formula 1-3. Referring
to Scheme 10, compounds of Formula 10-1 are commercially available
or can be made by methods described herein or other methods well
known to those skilled in the art. A compound of Formula 10-2 can
be prepared by treating a compound of Formula 10-1 with
N-bromosuccinimide in a suitable solvent [such acetonitrile] at
temperatures typically between 0.degree. C. and 20.degree. C. for
about 30 minutes to 6 hours. A compound of Formula 10-2 can be
reacted with diiodomethane and a suitable base [such as cesium
carbonate] to obtain a compound of Formula 10-3.
##STR00033##
[0304] Scheme 11 refers to a preparation of a compound of Formula
11-2. When A.sup.1 is Pg, the compound of Formula 11-2 is an
example of a compound of Formula 2-2. When A.sup.1 is A.sup.1a, the
compound of Formula 11-2 is an example of a compound of Formula I.
Referring to Scheme 11, compounds of Formula 11-1 can be prepared
according to methods described in Scheme 5. A compound of Formula
11-1 can be reacted with 2-hydrazinyl-1H-imidazole in a suitable
solvent such as DMF to obtain a compound of Formula 11-2 at
temperatures between about 80.degree. C. and 120.degree. C.
##STR00034##
[0305] Scheme 12 refers to a preparation of a compound of Formula
12-2 [wherein each R.sup.77 is independently H or R.sup.7 (such as
C.sub.1-3 alkyl, for example methyl)], which is an example of a
compound of Formula I. Referring to Scheme 12, a compound of
Formula 12-1 can be prepared by methods described in Scheme 1. A
compound of Formula 12-1 can be reacted with chloroacetaldehyde to
obtain a compound of Formula 12-2 at temperatures typically between
80.degree. C. and 120.degree. C. for about 1 hour to 24 hours.
##STR00035##
[0306] Scheme 13 refers to a preparation of a compound of Formula
13-3 [wherein R.sup.77 is H or R.sup.7 (such as C.sub.1-3 alkyl,
for example methyl)], which is an example of a compound of Formula
I. Referring to Scheme 13, a compound of Formula 13-1 can be
prepared according to methods described in Scheme 7. A compound of
Formula 13-2 can be prepared by reacting a compound of Formula 13-1
with hydrazine in a suitable solvent such as ethanol at
temperatures typically between 60.degree. C. and 100.degree. C. for
about 12 to 24 hours. A compound of Formula 13-2 can be reacted
with 1,1'-carbonyldiimidazole in a solvent such as acetonitrile to
obtain a compound of Formula 13-3.
##STR00036##
[0307] Additionally, a compound of Formula I may also be prepared
by enzymatic modification [such as a microbial oxidation] of a
related compound of Formula I. For example, as shown in Scheme 14,
incubation of a compound of Formula I [for example, wherein Q.sup.1
is a moiety that can be oxidized such as an optionally substituted
pyridazinyl in a compound of Formula 14-1 (wherein each R.sup.77 is
independently H or R.sup.7 (such as C.sub.1-3 alkyl, for example
methyl))] with Pseudomonas putida for a reaction time between 24
and 96 hours in a suitable buffer can provide an alternate compound
of Formula I (for example, wherein Q.sup.1 is an optionally
substituted pyridazinonyl in a compound of Formula 14-2).
##STR00037##
[0308] Additional starting materials and intermediates useful for
making the compounds of the present invention can be obtained from
chemical vendors such as Sigma-Aldrich or can be made according to
methods described in the chemical art.
[0309] Those skilled in the art can recognize that in all of the
Schemes described herein, if there are functional (reactive) groups
present on a part of the compound structure such as a substituent
group, for example R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, X.sup.1, Y.sup.1, Q.sup.1, etc., further
modification can be made if appropriate and/or desired, using
methods well known to those skilled in the art. For example, a --CN
group can be hydrolyzed to afford an amide group; a carboxylic acid
can be converted to an amide; a carboxylic acid can be converted to
an ester, which in turn can be reduced to an alcohol, which in turn
can be further modified. For another example, an OH group can be
converted into a better leaving group such as a mesylate, which in
turn is suitable for nucleophilic substitution, such as by a
cyanide ion (CN.sup.-). For another example, an --S-- can be
oxidized to --S(.dbd.O)-- and/or --S(.dbd.O).sub.2--. For yet
another example, an unsaturated bond such as C.dbd.C or C.ident.C
can be reduced to a saturated bond by hydrogenation. In some
embodiments, a primary amine or a secondary amine moiety (present
on a substituent group such as R.sup.2, R.sup.5, etc.) can be
converted to an amide, sulfonamide, urea, or thiourea moiety by
reacting it with an appropriate reagent such as an acid chloride, a
sulfonyl chloride, an isocyanate, or a thioisocyanate compound. One
skilled in the art will recognize further such modifications. Thus,
a compound of Formula I having a substituent that contains a
functional group can be converted to another compound of Formula I
having a different substituent group.
[0310] Similarly, those skilled in the art can also recognize that
in all of the schemes described herein, if there are functional
(reactive) groups present on a substituent group such as R.sup.3,
R.sup.5, etc., these functional groups can be protected/deprotected
in the course of the synthetic scheme described here, if
appropriate and/or desired. For example, an OH group can be
protected by a benzyl, methyl, or acetyl group, which can be
deprotected and converted back to the OH group in a later stage of
the synthetic process. For another example, an NH.sub.2 group can
be protected by a benzyloxycarbonyl (Boc) group, which can be
deprotected and converted back to the NH.sub.2 group in a later
stage of the synthetic process.
[0311] As used herein, the term "reacting" (or "reaction" or
"reacted") refers to the bringing together of designated chemical
reactants such that a chemical transformation takes place
generating a compound different from any initially introduced into
the system. Reactions can take place in the presence or absence of
solvent.
[0312] Compounds of Formula I described herein include compounds of
Formula I, N-oxides thereof, and salts of the compounds and the
N-oxides.
[0313] Compounds of Formula I may exist as stereoisomers, such as
atropisomers, racemates, enantiomers, or diastereomers.
Conventional techniques for the preparation/isolation of individual
enantiomers include chiral synthesis from a suitable optically pure
precursor or resolution of the racemate using, for example, chiral
high pressure liquid chromatography (HPLC). Alternatively, the
racemate (or a racemic precursor) may be reacted with a suitable
optically active compound, for example, an alcohol, or, in the case
where the compound contains an acidic or basic moiety, an acid or
base such as tartaric acid or 1-phenylethylamine. The resulting
diastereomeric mixture may be separated by chromatography and/or
fractional crystallization and one or both of the diastereoisomers
converted to the corresponding pure enantiomer(s) by means well
known to one skilled in the art. Chiral compounds of Formula I (and
chiral precursors thereof) may be obtained in enantiomerically
enriched form using chromatography, typically HPLC, on an
asymmetric resin with a mobile phase consisting of a hydrocarbon,
typically heptane or hexane, containing from 0% to 50% 2-propanol,
typically from 2% to 20%, and from 0% to 5% of an alkylamine,
typically 0.1% diethylamine. Concentration of the eluate affords
the enriched mixture. Stereoisomeric conglomerates may be separated
by conventional techniques known to those skilled in the art. See,
e.g., Stereochemistry of Organic Compounds by E. L. Eliel and S. H.
Wilen (Wiley, New York, 1994), the disclosure of which is
incorporated herein by reference in its entirety. Suitable
stereoselective techniques are well-known to those of ordinary
skill in the art.
[0314] Where a compound of Formula I contains an alkenyl or
alkenylene (alkylidene) group, geometric cis/trans (or Z/E) isomers
are possible. Cis/trans isomers may be separated by conventional
techniques well known to those skilled in the art, for example,
chromatography and fractional crystallization. Salts of the present
invention can be prepared according to methods known to those of
skill in the art.
[0315] The compounds of Formula I that are basic in nature are
capable of forming a wide variety of salts with various inorganic
and organic acids. Although such salts must be pharmaceutically
acceptable for administration to animals, it is often desirable in
practice to initially isolate the compound of the present invention
from the reaction mixture as a pharmaceutically unacceptable salt
and then simply convert the latter back to the free base compound
by treatment with an alkaline reagent and subsequently convert the
latter free base to a pharmaceutically acceptable acid addition
salt. The acid addition salts of the basic compounds of this
invention can be prepared by treating the basic compound with a
substantially equivalent amount of the selected mineral or organic
acid in an aqueous solvent medium or in a suitable organic solvent,
such as methanol or ethanol. Upon evaporation of the solvent, the
desired solid salt is obtained. The desired acid salt can also be
precipitated from a solution of the free base in an organic solvent
by adding an appropriate mineral or organic acid to the
solution.
[0316] If the inventive compound is a base, the desired
pharmaceutically acceptable salt may be prepared by any suitable
method available in the art, for example, treatment of the free
base with an inorganic acid, such as hydrochloric acid, hydrobromic
acid, sulfuric acid, nitric acid, phosphoric acid and the like, or
with an organic acid, such as acetic acid, maleic acid, succinic
acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,
oxalic acid, glycolic acid, salicylic acid, isonicotinic acid,
lactic acid, pantothenic acid, bitartric acid, ascorbic acid,
2,5-dihydroxybenzoic acid, gluconic acid, saccharic acid, formic
acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic
acid, p-toluenesulfonic acid, and pamoic [i.e.,
1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] acids, a pyranosidyl
acid, such as glucuronic acid or galacturonic acid, an
alpha-hydroxy acid, such as citric acid or tartaric acid, an amino
acid, such as aspartic acid or glutamic acid, an aromatic acid,
such as benzoic acid or cinnamic acid, a sulfonic acid, such as
ethanesulfonic acid, or the like.
[0317] Those compounds of Formula I that are acidic in nature are
capable of forming base salts with various pharmacologically
acceptable cations. Examples of such salts include the alkali metal
or alkaline earth metal salts and particularly, the sodium and
potassium salts. These salts are all prepared by conventional
techniques. The chemical bases which are used as reagents to
prepare the pharmaceutically acceptable base salts of this
invention are those which form non-toxic base salts with the acidic
compounds of Formula I. These salts may be prepared by any suitable
method, for example, treatment of the free acid with an inorganic
or organic base, such as an amine (primary, secondary or tertiary),
an alkali metal hydroxide or alkaline earth metal hydroxide, or the
like. These salts can also be prepared by treating the
corresponding acidic compounds with an aqueous solution containing
the desired pharmacologically acceptable cations, and then
evaporating the resulting solution to dryness, for example under
reduced pressure. Alternatively, they may also be prepared by
mixing lower alkanolic solutions of the acidic compounds and the
desired alkali metal alkoxide together, and then evaporating the
resulting solution to dryness in the same manner as before. In
either case, stoichiometric quantities of reagents are, for
example, employed in order to ensure completeness of reaction and
maximum yields of the desired final product.
[0318] Pharmaceutically acceptable salts of compounds of Formula I
(including compounds of Formula Ia or Ib) may be prepared by one or
more of three methods:
[0319] (i) by reacting the compound of Formula I with the desired
acid or base;
[0320] (ii) by removing an acid- or base-labile protecting group
from a suitable precursor of the compound of Formula I or by
ring-opening a suitable cyclic precursor, for example, a lactone or
lactam, using the desired acid or base; or
[0321] (iii) by converting one salt of the compound of Formula I to
another by reaction with an appropriate acid or base or by means of
a suitable ion exchange column.
[0322] All three reactions are typically carried out in solution.
The resulting salt may precipitate out and be collected by
filtration or may be recovered by evaporation of the solvent. The
degree of ionization in the resulting salt may vary from completely
ionized to almost non-ionized.
[0323] Polymorphs can be prepared according to techniques
well-known to those skilled in the art, for example, by
crystallization.
[0324] When any racemate crystallizes, crystals of two different
types are possible. The first type is the racemic compound (true
racemate) referred to above wherein one homogeneous form of crystal
is produced containing both enantiomers in equimolar amounts. The
second type is the racemic mixture or conglomerate wherein two
forms of crystal are produced in equimolar amounts each comprising
a single enantiomer.
[0325] While both of the crystal forms present in a racemic mixture
have identical physical properties, they may have different
physical properties compared to the true racemate. Racemic mixtures
may be separated by conventional techniques known to those skilled
in the art--see, for example, Stereochemistry of Organic Compounds
by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).
[0326] The invention also includes isotopically labeled compounds
of Formula I wherein one or more atoms is replaced by an atom
having the same atomic number, but an atomic mass or mass number
different from the atomic mass or mass number usually found in
nature. Isotopically labeled compounds of Formula I (or
pharmaceutically acceptable salts thereof or N-oxide thereof) can
generally be prepared by conventional techniques known to those
skilled in the art or by processes analogous to those described
herein, using an appropriate isotopically labeled reagent in place
of the non-labeled reagent otherwise employed.
[0327] Prodrugs in accordance with the invention can, for example,
be produced by replacing appropriate functionalities present in the
compounds of Formula I with certain moieties known to those skilled
in the art as `pro-moieties` as described, for example, in Design
of Prodrugs by H. Bundgaard (Elsevier, 1985).
[0328] The compounds of Formula I should be assessed for their
biopharmaceutical properties, such as solubility and solution
stability (across pH), permeability, etc., in order to select the
most appropriate dosage form and route of administration for
treatment of the proposed indication.
[0329] Compounds of the invention intended for pharmaceutical use
may be administered as crystalline or amorphous products. They may
be obtained, for example, as solid plugs, powders, or films by
methods such as precipitation, crystallization, freeze drying,
spray drying, or evaporative drying. Microwave or radio frequency
drying may be used for this purpose.
[0330] They may be administered alone or in combination with one or
more other compounds of the invention or in combination with one or
more other drugs (or as any combination thereof). Generally, they
will be administered as a formulation in association with one or
more pharmaceutically acceptable excipients. The term "excipient"
is used herein to describe any ingredient other than the
compound(s) of the invention. The choice of excipient will to a
large extent depend on factors such as the particular mode of
administration, the effect of the excipient on solubility and
stability, and the nature of the dosage form.
[0331] Pharmaceutical compositions suitable for the delivery of
compounds of the present invention (or pharmaceutically acceptable
salts thereof) and methods for their preparation will be readily
apparent to those skilled in the art. Such compositions and methods
for their preparation may be found, for example, in Remington's
Pharmaceutical Sciences, 19th Edition (Mack Publishing Company,
1995).
[0332] The compounds of the invention (or pharmaceutically
acceptable salts thereof) may be administered orally. Oral
administration may involve swallowing, so that the compound enters
the gastrointestinal tract, and/or buccal, lingual, or sublingual
administration by which the compound enters the blood stream
directly from the mouth.
[0333] Formulations suitable for oral administration include solid,
semi-solid and liquid systems such as tablets; soft or hard
capsules containing multi- or nano-particulates, liquids, or
powders; lozenges (including liquid-filled); chews; gels; fast
dispersing dosage forms; films; ovules; sprays; and
buccal/mucoadhesive patches.
[0334] Liquid formulations include suspensions, solutions, syrups
and elixirs. Such formulations may be employed as fillers in soft
or hard capsules (made, for example, from gelatin or
hydroxypropylmethylcellulose) and typically comprise a carrier, for
example, water, ethanol, polyethylene glycol, propylene glycol,
methylcellulose, or a suitable oil, and one or more emulsifying
agents and/or suspending agents. Liquid formulations may also be
prepared by the reconstitution of a solid, for example, from a
sachet.
[0335] The compounds of the invention may also be used in
fast-dissolving, fast-disintegrating dosage forms such as those
described by Liang and Chen, Expert Opinion in Therapeutic Patents
2001, 11, 981-986.
[0336] For tablet dosage forms, depending on dose, the drug may
make up from 1 weight % to 80 weight % of the dosage form, more
typically from 5 weight % to 60 weight % of the dosage form. In
addition to the drug, tablets generally contain a disintegrant.
Examples of disintegrants include sodium starch glycolate, sodium
carboxymethyl cellulose, calcium carboxymethyl cellulose,
croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl
cellulose, microcrystalline cellulose, lower alkyl-substituted
hydroxypropyl cellulose, starch, pregelatinized starch and sodium
alginate. Generally, the disintegrant will comprise from 1 weight %
to 25 weight %, for example, from 5 weight % to 20 weight % of the
dosage form.
[0337] Binders are generally used to impart cohesive qualities to a
tablet formulation. Suitable binders include microcrystalline
cellulose, gelatin, sugars, polyethylene glycol, natural and
synthetic gums, polyvinylpyrrolidone, pregelatinized starch,
hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets
may also contain diluents, such as lactose (monohydrate,
spray-dried monohydrate, anhydrous and the like), mannitol,
xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose,
starch and dibasic calcium phosphate dihydrate.
[0338] Tablets may also optionally comprise surface active agents,
such as sodium lauryl sulfate and polysorbate 80, and glidants such
as silicon dioxide and talc. When present, surface active agents
may comprise from 0.2 weight % to 5 weight % of the tablet, and
glidants may comprise from 0.2 weight % to 1 weight % of the
tablet.
[0339] Tablets also generally contain lubricants such as magnesium
stearate, calcium stearate, zinc stearate, sodium stearyl fumarate,
and mixtures of magnesium stearate with sodium lauryl sulfate.
Lubricants generally comprise from 0.25 weight % to 10 weight %,
for example, from 0.5 weight % to 3 weight % of the tablet.
[0340] Other possible ingredients include anti-oxidants, colorants,
flavoring agents, preservatives and taste-masking agents.
[0341] Exemplary tablets contain up to about 80% drug, from about
10 weight % to about 90 weight % binder, from about 0 weight % to
about 85 weight % diluent, from about 2 weight % to about 10 weight
% disintegrant, and from about 0.25 weight % to about 10 weight %
lubricant.
[0342] Tablet blends may be compressed directly or by roller to
form tablets. Tablet blends or portions of blends may alternatively
be wet-, dry-, or melt-granulated, melt congealed, or extruded
before tabletting. The final formulation may comprise one or more
layers and may be coated or uncoated; it may even be
encapsulated.
[0343] The formulation of tablets is discussed in Pharmaceutical
Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman
(Marcel Dekker, New York, 1980).
[0344] Consumable oral films for human or veterinary use are
typically pliable water-soluble or water-swellable thin film dosage
forms which may be rapidly dissolving or mucoadhesive and typically
comprise a compound of Formula I, a film-forming polymer, a binder,
a solvent, a humectant, a plasticizer, a stabilizer or emulsifier,
a viscosity-modifying agent and a solvent. Some components of the
formulation may perform more than one function.
[0345] The compound of Formula I (or pharmaceutically acceptable
salts thereof or N-oxide thereof) may be water-soluble or
insoluble. A water-soluble compound typically comprises from 1
weight % to 80 weight %, more typically from 20 weight % to 50
weight %, of the solutes. Less soluble compounds may comprise a
smaller proportion of the composition, typically up to 30 weight %
of the solutes. Alternatively, the compound of Formula I may be in
the form of multiparticulate beads.
[0346] The film-forming polymer may be selected from natural
polysaccharides, proteins, or synthetic hydrocolloids and is
typically present in the range 0.01 to 99 weight %, more typically
in the range 30 to 80 weight %.
[0347] Other possible ingredients include anti-oxidants, colorants,
flavorings and flavor enhancers, preservatives, salivary
stimulating agents, cooling agents, co-solvents (including oils),
emollients, bulking agents, anti-foaming agents, surfactants and
taste-masking agents.
[0348] Films in accordance with the invention are typically
prepared by evaporative drying of thin aqueous films coated onto a
peelable backing support or paper. This may be done in a drying
oven or tunnel, typically a combined coater dryer, or by
freeze-drying or vacuuming.
[0349] Solid formulations for oral administration may be formulated
to be immediate and/or modified release. Modified release
formulations include delayed-, sustained-, pulsed-, controlled-,
targeted and programmed release.
[0350] Suitable modified release formulations for the purposes of
the invention are described in U.S. Pat. No. 6,106,864. Details of
other suitable release technologies such as high energy dispersions
and osmotic and coated particles are to be found in Verma et al.,
Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of
chewing gum to achieve controlled release is described in WO
00/35298.
[0351] The compounds of the invention (or pharmaceutically
acceptable salts thereof or N-oxide thereof) may also be
administered directly into the blood stream, into muscle, or into
an internal organ. Suitable means for parenteral administration
include intravenous, intraarterial, intraperitoneal, intrathecal,
intraventricular, intraurethral, intrasternal, intracranial,
intramuscular, intrasynovial and subcutaneous. Suitable devices for
parenteral administration include needle (including microneedle)
injectors, needle-free injectors and infusion techniques.
[0352] Parenteral formulations are typically aqueous solutions
which may contain excipients such as salts, carbohydrates and
buffering agents (for example to a pH of from 3 to 9), but, for
some applications, they may be more suitably formulated as a
sterile non-aqueous solution or as a dried form to be used in
conjunction with a suitable vehicle such as sterile, pyrogen-free
water.
[0353] The preparation of parenteral formulations under sterile
conditions, for example, by lyophilization, may readily be
accomplished using standard pharmaceutical techniques well known to
those skilled in the art.
[0354] The solubility of compounds of Formula I used in the
preparation of parenteral solutions may be increased by the use of
appropriate formulation techniques, such as the incorporation of
solubility-enhancing agents.
[0355] Formulations for parenteral administration may be formulated
to be immediate and/or modified release. Modified release
formulations include delayed-, sustained-, pulsed-, controlled-,
targeted and programmed release. Thus compounds of the invention
may be formulated as a suspension or as a solid, semi-solid, or
thixotropic liquid for administration as an implanted depot
providing modified release of the active compound. Examples of such
formulations include drug-coated stents and semi-solids and
suspensions comprising drug-loaded poly(DL-lactic-coglycolic acid)
(PLGA) microspheres.
[0356] The compounds of the invention (or pharmaceutically
acceptable salts thereof or N-oxide thereof) may also be
administered topically, (intra)dermally, or transdermally to the
skin or mucosa. Typical formulations for this purpose include gels,
hydrogels, lotions, solutions, creams, ointments, dusting powders,
dressings, foams, films, skin patches, wafers, implants, sponges,
fibers, bandages and microemulsions. Liposomes may also be used.
Typical carriers include alcohol, water, mineral oil, liquid
petrolatum, white petrolatum, glycerin, polyethylene glycol and
propylene glycol. Penetration enhancers may be incorporated--see
e.g., Finnin and Morgan, J. Pharm. Sci. 1999, 88, 955-958.
[0357] Other means of topical administration include delivery by
electroporation, iontophoresis, phonophoresis, sonophoresis and
microneedle or needle-free (e.g., Powderject.TM., Bioject.TM.,
etc.) injection.
[0358] Formulations for topical administration may be formulated to
be immediate and/or modified release. Modified release formulations
include delayed-, sustained-, pulsed-, controlled-, targeted and
programmed release.
[0359] The compounds of the invention (or pharmaceutically
acceptable salts thereof) can also be administered intranasally or
by inhalation, typically in the form of a dry powder (either alone,
as a mixture, for example, in a dry blend with lactose, or as a
mixed component particle, for example, mixed with phospholipids,
such as phosphatidylcholine) from a dry powder inhaler, as an
aerosol spray from a pressurized container, pump, spray, atomizer
(for example an atomizer using electrohydrodynamics to produce a
fine mist), or nebulizer, with or without the use of a suitable
propellant, such as 1,1,1,2-tetrafluoroethane or
1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops. For intranasal
use, the powder may comprise a bioadhesive agent, for example,
chitosan or cyclodextrin.
[0360] The pressurized container, pump, spray, atomizer, or
nebulizer contains a solution or suspension of the compound(s) of
the invention comprising, for example, ethanol, aqueous ethanol, or
a suitable alternative agent for dispersing, solubilizing, or
extending release of the active, a propellant(s) as solvent and an
optional surfactant, such as sorbitan trioleate, oleic acid, or an
oligolactic acid.
[0361] Prior to use in a dry powder or suspension formulation, the
drug product is micronized to a size suitable for delivery by
inhalation (typically less than 5 microns). This may be achieved by
any appropriate comminuting method, such as spiral jet milling,
fluid bed jet milling, supercritical fluid processing to form
nanoparticles, high pressure homogenization, or spray drying.
[0362] Capsules (made, for example, from gelatin or
hydroxypropylmethylcellulose), blisters and cartridges for use in
an inhaler or insufflator may be formulated to contain a powder mix
of the compound of the invention, a suitable powder base such as
lactose or starch and a performance modifier such as L-leucine,
mannitol, or magnesium stearate. The lactose may be anhydrous or in
the form of the monohydrate. Other suitable excipients include
dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and
trehalose.
[0363] A suitable solution formulation for use in an atomizer using
electrohydrodynamics to produce a fine mist may contain from 1
.mu.g to 20 mg of the compound of the invention per actuation and
the actuation volume may vary from 1 .mu.L to 100 .mu.L. A typical
formulation may comprise a compound of Formula I or a
pharmaceutically acceptable salt thereof, propylene glycol, sterile
water, ethanol and sodium chloride. Alternative solvents which may
be used instead of propylene glycol include glycerol and
polyethylene glycol.
[0364] Suitable flavors, such as menthol and levomenthol, or
sweeteners, such as saccharin or saccharin sodium, may be added to
those formulations of the invention intended for inhaled/intranasal
administration.
[0365] Formulations for inhaled/intranasal administration may be
formulated to be immediate and/or modified release using, for
example, PGLA. Modified release formulations include delayed-,
sustained-, pulsed-, controlled-, targeted and programmed
release.
[0366] In the case of dry powder inhalers and aerosols, the dosage
unit is determined by means of a valve which delivers a metered
amount. Units in accordance with the invention are typically
arranged to administer a metered dose or "puff" containing from
0.01 to 100 mg of the compound of Formula I. The overall daily dose
will typically be in the range 1 .mu.g to 200 mg, which may be
administered in a single dose or, more usually, as divided doses
throughout the day.
[0367] The compounds of the invention may be administered rectally
or vaginally, for example, in the form of a suppository, pessary,
or enema. Cocoa butter is a traditional suppository base, but
various alternatives may be used as appropriate.
[0368] Formulations for rectal/vaginal administration may be
formulated to be immediate and/or modified release. Modified
release formulations include delayed-, sustained-, pulsed-,
controlled-, targeted and programmed release.
[0369] The compounds of the invention may also be administered
directly to the eye or ear, typically in the form of drops of a
micronized suspension or solution in isotonic, pH-adjusted, sterile
saline. Other formulations suitable for ocular and aural
administration include ointments, gels, biodegradable (e.g.,
absorbable gel sponges, collagen) and non-biodegradable (e.g.,
silicone) implants, wafers, lenses and particulate or vesicular
systems, such as niosomes or liposomes. A polymer such as
crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid,
a cellulosic polymer, for example, hydroxypropylmethylcellulose,
hydroxyethylcellulose, or methyl cellulose, or a
heteropolysaccharide polymer, for example, gelan gum, may be
incorporated together with a preservative, such as benzalkonium
chloride. Such formulations may also be delivered by
iontophoresis.
[0370] Formulations for ocular/aural administration may be
formulated to be immediate and/or modified release. Modified
release formulations include delayed-, sustained-, pulsed-,
controlled-, targeted, or programmed release.
[0371] The compounds of the invention may be combined with soluble
macromolecular entities, such as cyclodextrin and suitable
derivatives thereof or polyethylene glycol-containing polymers, in
order to improve their solubility, dissolution rate, taste-masking,
bioavailability and/or stability for use in any of the
aforementioned modes of administration.
[0372] Drug-cyclodextrin complexes, for example, are found to be
generally useful for most dosage forms and administration routes.
Both inclusion and non-inclusion complexes may be used. As an
alternative to direct complexation with the drug, the cyclodextrin
may be used as an auxiliary additive, i.e., as a carrier, diluent,
or solubilizer. Most commonly used for these purposes are alpha-,
beta- and gamma-cyclodextrins, examples of which may be found in
International Patent Applications Nos. WO 91/11172, WO 94/02518 and
WO 98/55148.
[0373] Since the present invention has an aspect that relates to
the treatment of the disease/conditions described herein with a
combination of active ingredients which may be administered
separately, the invention also relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: a compound of Formula I a
prodrug thereof or a salt of such compound or prodrug and a second
compound as described above. The kit comprises means for containing
the separate compositions such as a container, a divided bottle or
a divided foil packet. Typically the kit comprises directions for
the administration of the separate components. The kit form is
particularly advantageous when the separate components are for
example administered in different dosage forms (e.g., oral and
parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician.
[0374] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a transparent plastic material. During the packaging process
recesses are formed in the plastic foil. The recesses have the size
and shape of the tablets or capsules to be packed. Next, the
tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic foil and the sheet. In
some embodiments, the strength of the sheet is such that the
tablets or capsules can be removed from the blister pack by
manually applying pressure on the recesses whereby an opening is
formed in the sheet at the place of the recess. The tablet or
capsule can then be removed via said opening.
[0375] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on the card,
e.g., as follows "First Week, Monday, Tuesday, etc. . . . Second
Week, Monday, Tuesday, . . . " etc. Other variations of memory aids
will be readily apparent. A "daily dose" can be a single tablet or
capsule or several pills or capsules to be taken on a given day.
Also, a daily dose of Formula I compound can consist of one tablet
or capsule while a daily dose of the second compound can consist of
several tablets or capsules and vice versa. The memory aid should
reflect this.
[0376] In another specific embodiment of the invention, a dispenser
designed to dispense the daily doses one at a time in the order of
their intended use is provided. For example, the dispenser is
equipped with a memoryaid, so as to further facilitate compliance
with the regimen. An example of such a memoryaid is a mechanical
counter which indicates the number of daily doses that has been
dispensed. Another example of such a memoryaid is a battery-powered
micro-chip memory coupled with a liquid crystal readout, or audible
reminder signal which, for example, reads out the date that the
last daily dose has been taken and/or reminds one when the next
dose is to be taken.
[0377] The invention will be described in greater detail by way of
specific examples. The following examples are offered for
illustrative purposes, and are not intended to limit the invention
in any manner. Those of skill in the art will readily recognize a
variety of non-critical parameters that can be changed or modified
to yield essentially the same results. In the following Examples
and Preparations, "DMSO" means dimethyl sulfoxide, "N" where
referring to concentration means Normal, "M" means molar, "mL"
means milliliter, "mmol" means millimoles, ".mu.mol" means
micromoles, "eq." means equivalent, ".degree. C." means degrees
Celsius, "MHz" means megahertz, "HPLC" means high-performance
liquid chromatography.
EXAMPLES
[0378] Experiments were generally carried out under inert
atmosphere (nitrogen or argon), particularly in cases where oxygen-
or moisture-sensitive reagents or intermediates were employed.
Commercial solvents and reagents were generally used without
further purification, including anhydrous solvents where
appropriate (generally Sure-Seal.TM. products from the Aldrich
Chemical Company, Milwaukee, Wis.). Products were generally dried
under vacuum before being carried on to further reactions or
submitted for biological testing. Mass spectrometry data is
reported from either liquid chromatography-mass spectrometry
(LCMS), atmospheric pressure chemical ionization (APCI) or gas
chromatography-mass spectrometry (GCMS) instrumentation. Chemical
shifts for nuclear magnetic resonance (NMR) data are expressed in
parts per million (ppm, .delta.) referenced to residual peaks from
the deuterated solvents employed. In some examples, chiral
separations were carried out to separate atropisomers (or
atropenantiomers) of certain compounds of the invention. The
optical rotation of an atropisomer was measured using a
polarimeter. According to its observed rotation data (or its
specific rotation data), an atropisomer (or atropenantiomer) with a
clockwise rotation was designated as the (+)-atropisomer [or the
(+) atropenantiomer] and an atropisomer (or atropenantiomer) with a
counter-clockwise rotation was designated as the (-)-atropisomer
[or the (-) atropenantiomer].
[0379] For syntheses referencing procedures in other Examples or
Methods, reaction conditions (length of reaction and temperature)
may vary. In general, reactions were followed by thin layer
chromatography or mass spectrometry, and subjected to work-up when
appropriate. Purifications may vary between experiments: in
general, solvents and the solvent ratios used for eluents/gradients
were chosen to provide appropriate R.sub.fs or retention times.
Example 1
4-[4-(4,6-Dimethylpyrimidin-5yl)-3-methylphenoxy]furo[3,2-c]pyridine
(1)
##STR00038##
[0380] Step 1. Synthesis of
4-(4-bromo-3-methylphenoxy)furo[3,2-c]pyridine (C1).
[0381] To a solution of 4-chlorofuro[3,2-c]pyridine (120 g, 781
mmol) in dimethyl sulfoxide (1.56 L) was added cesium carbonate
(509 g, 1.56 mol) and 4-bromo-3-methylphenol (161 g, 861 mmol), and
the reaction was heated to 125.degree. C. for 16 hours. At this
point, the reaction mixture was cooled to room temperature, poured
into water (5 L), and extracted with ethyl acetate (2.times.2.5 L).
The combined organic extracts were washed with water (2.5 L),
washed with saturated aqueous sodium chloride solution (2.5 L),
dried over anhydrous sodium sulfate, filtered and concentrated in
vacuo. Purification by chromatography on silica gel (Eluent: 2%
ethyl acetate in petroleum ether) afforded the product as a pale
yellow solid. Yield: 205 g, 674 mmol, 86%. LCMS m/z 304.0, 306.0
(M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (d, J=6.2 Hz,
1H), 7.64 (d, J=2.1 Hz, 1H), 7.55 (d, J=8.3 Hz, 1H), 7.20 (dd,
J=5.8, 0.8 Hz, 1H), 7.12 (d, J=2.9 Hz, 1H), 6.93 (dd, J=8.5, 2.7
Hz, 1H), 6.88 (dd, J=2.5, 0.8 Hz, 1H), 2.41 (s, 3H).
Step 2. Synthesis of
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2).
[0382] To a stirred solution of
4-(4-bromo-3-methylphenoxy)furo[3,2-c]pyridine (C1) (50.0 g, 164
mmol) in 1,4-dioxane (1.02 L) was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (41.76
g, 164.4 mmol), potassium acetate (64.6 g, 658 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (6.0 g,
8.2 mmol), and the reaction mixture was heated at 85.degree. C. for
16 hours. After cooling to room temperature, it was filtered
through a pad of Celite, and the pad was washed with ethyl acetate.
The combined filtrates were concentrated in vacuo and the residue
was purified by silica gel chromatography (Eluent: 2% ethyl acetate
in petroleum ether) to provide the product as a white solid. Yield:
40.0 g, 114 mmol, 70%. LCMS m/z 352.2 (M+H). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.02 (d, J=5.8 Hz, 1H), 7.84 (d, J=7.5 Hz, 1H),
7.61 (d, J=2.1 Hz, 1H), 7.19 (d, J=5.8 Hz, 1H), 7.00 (m, 2H), 6.80
(m, 1H), 2.56 (s, 3H), 1.34 (s, 12H).
Step 3. Synthesis of
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridine
(1).
[0383]
4-[3-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-
furo[3,2-c]pyridine (C2) (250 mg, 0.712 mmol),
5-bromo-4,6-dimethylpyrimidine (160 mg, 0.855 mmol),
tris(dibenzylideneacetone)dipalladium(0) (95%, 26.9 mg, 0.142
mmol), tricyclohexylphosphine (79.9 mg, 0.285 mmol) and potassium
phosphate (302 mg, 1.42 mmol) were combined in a 3:1 mixture of
1,4-dioxane and water (12 mL), and subjected to irradiation in a
microwave reactor at 120.degree. C. for 5 hours. The reaction
mixture was filtered through Celite; the filtrate was concentrated
under reduced pressure, taken up in ethyl acetate, filtered through
silica gel (1 g), and concentrated in vacuo. Purification via
silica gel chromatography (Gradient: 0% to 100% ethyl acetate in
heptane) afforded the product as a colorless oil. Yield: 123 mg,
0.371 mmol, 52%. LCMS m/z 332.1 (M+H). .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.98 (s, 1H), 8.07 (d, J=5.9 Hz, 1H), 7.67 (d,
J=2.2 Hz, 1H), 7.25-7.27 (m, 1H, assumed; partially obscured by
solvent peak), 7.24 (br d, J=2.4 Hz, 1H), 7.19 (br dd, J=8.3, 2.4
Hz, 1H), 7.08 (d, J=8.3 Hz, 1H), 6.90 (dd, J=2.2, 1.0 Hz, 1H), 2.27
(s, 6H), 2.04 (s, 3H).
Example 2
5-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methyl-[8-.sup.2H]-imi-
dazo[1,2-a]pyrazine (2)
##STR00039##
[0384] Step 1. Synthesis of
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylpyrazin-2-amine
(C3).
[0385] 6-Bromo-5-methylpyrazin-2-amine (which may be prepared
according to the method of N. Sato, J. Heterocycl. Chem. 1980, 171,
143-147) (2.40 g, 12.8 mmol),
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) (4.48 g, 12.8 mmol), and
tetrakis(triphenylphosphine)palladium(0) (95%, 466 mg, 0.383 mmol)
were combined in a pressure tube and dissolved in 1,4-dioxane (60
mL) and ethanol (20 mL). A solution of sodium carbonate (2.0 M in
water, 19.1 mL, 38.2 mmol) was added, and argon was bubbled through
the reaction mixture for 15 minutes. The tube was sealed, and then
heated at 140.degree. C. for 16 hours. The reaction mixture was
combined with a second, identical, reaction mixture for workup. The
combined reaction mixtures were filtered; solids remaining in the
reaction vessels were slurried in water and filtered, and the
filter cake was washed with ethanol. All of the organic filtrates
were passed through a pad of Celite, and the Celite pad was washed
with ethanol. These filtrates were concentrated in vacuo, and the
resulting solid was slurried in water, filtered and washed with
water. The solid was then slurried in 1:1 heptane/diethyl ether,
filtered and washed with diethyl ether to afford the product as a
light yellow solid. Yield: 6.774 g, 20.38 mmol, 80%. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. 8.14 (d, J=2.2 Hz, 1H), 8.01 (d,
J=5.7 Hz, 1H), 7.82 (s, 1H), 7.47 (dd, J=5.8, 0.9 Hz, 1H), 7.21 (d,
J=8.3 Hz, 1H), 7.15 (br d, J=2.4 Hz, 1H), 7.09 (br dd, J=8.2, 2.4
Hz, 1H), 7.06 (dd, J=2.2, 0.7 Hz, 1H), 6.18 (br s, 2H), 2.12 (s,
3H), 2.07 (br s, 3H).
Step 2. Synthesis of
3-bromo-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylpyrazin-
-2-amine (C4).
[0386] N-Bromosuccinimide (95%, 609 mg, 3.25 mmol) was added to a
solution of
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylpyrazin-2-am-
ine (C3) (900 mg, 2.71 mmol) in N,N-dimethylformamide (15 mL), and
the reaction mixture was heated to 60.degree. C. for 45 minutes.
The reaction mixture was cooled to room temperature, diluted with
ethyl acetate and quenched with a small amount of water. After
adsorption onto silica gel, the product was purified via silica gel
chromatography (Gradient: 0% to 50% ethyl acetate in heptane). The
purified material was taken up in ethyl acetate and washed with 1:1
water/saturated aqueous sodium bicarbonate solution, with water,
and with saturated aqueous sodium chloride solution to remove
residual N,N-dimethylformamide. The organic layer was dried over
sodium sulfate and concentrated in vacuo to provide the product as
a yellow solid. Yield: 700 mg, 1.71 mmol, 63%. LCMS m/z 412.9
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14 (d, J=2.2
Hz, 1H), 8.01 (d, J=5.9 Hz, 1H), 7.48 (dd, J=5.9, 1.0 Hz, 1H), 7.26
(d, J=8.2 Hz, 1H), 7.17 (br d, J=2.3 Hz, 1H), 7.11 (br dd, J=8.3,
2.4 Hz, 1H), 7.07 (dd, J=2.2, 0.9 Hz, 1H), 6.51 (br s, 2H), 2.13
(s, 3H), 2.09 (br s, 3H).
Step 3. Synthesis of
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methyl-[3-.sup.2H]-py-
razin-2-amine (C5).
[0387]
3-Bromo-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylp-
yrazin-2-amine (C4) (575 mg, 1.40 mmol) was dissolved in a mixture
of .sup.2H.sub.4-methanol and .sup.2H.sub.6-acetone under gentle
warming. The solution was allowed to stand for 10 minutes, then was
concentrated in vacuo. The residue was dissolved in 1:1
tetrahydrofuran/.sup.2H.sub.4-methanol (30 mL) and a solution of
sodium deuteroxide in .sup.2H.sub.4-methanol (3 mM, 1.5
equivalents), and hydrogenated under 5 psi .sup.2H.sub.2 for 2.5
hours at room temperature, using 10% palladium on carbon catalyst
(5% load). The reaction mixture was then filtered to remove
catalyst and concentrated under reduced pressure, to provide a
yellow solid. This solid was slurried in a small amount of ethyl
acetate, filtered and rinsed with ethyl acetate to afford the
product as a yellow solid. The filtrate was found to contain
additional product via LCMS analysis. The filtrate was concentrated
in vacuo to afford a yellow solid, which was washed with ethyl
acetate; the resulting white precipitate was removed by filtration
and discarded. The filtrate was combined with the initially
collected yellow solid, diluted with additional ethyl acetate and
washed with water, with saturated aqueous ammonium chloride
solution, with saturated aqueous sodium chloride solution, dried
over sodium sulfate and filtered. Concentration of the filtrate
under reduced pressure provided a yellow solid, which was purified
by silica gel chromatography (Gradient: 20% to 100% ethyl acetate
in heptane). A yellow solid was obtained; upon attempted
dissolution in ethyl acetate, a white solid formed, which was
filtered to provide the product as a white solid. Yield: 207 mg,
0.621 mmol, 44%. LCMS m/z 334.1 (M+H). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.14 (d, J=2.2 Hz, 1H), 8.01 (d, J=5.9 Hz,
1H), 7.47 (dd, J=5.9, 1.0 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.15 (br
d, J=2.4 Hz, 1H), 7.07-7.11 (m, 1H), 7.06 (dd, J=2.2, 1.1 Hz, 1H),
6.18 (br s, 2H), 2.11 (s, 3H), 2.07 (br s, 3H).
Step 4. Synthesis of
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methyl-[8-.sup.2H]-im-
idazo[1,2-a]pyrazine (2).
[0388] Chloroacetaldehyde (55% solution in water, 1.28 mL, 10.9
mmol) was added to a mixture of
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methyl-[3-.sup.2H-1]--
pyrazin-2-amine (C5) (182 mg, 0.546 mmol) in water (2.5 mL), and
the reaction mixture was heated to 100.degree. C. for 1 hour. After
cooling to room temperature, the reaction mixture was diluted with
water (15 mL) and ethyl acetate (15 mL), then treated with
saturated aqueous sodium bicarbonate solution (5 to 10 mL). The
aqueous layer was extracted with ethyl acetate, and the combined
organic layers were washed with water, washed with saturated
aqueous sodium chloride solution, dried over sodium sulfate,
filtered, and concentrated in vacuo. Silica gel chromatography
(Gradient: 0% to 5% methanol in dichloromethane) afforded the
product as a solid. Yield: 158 mg, 0.442 mmol, 81%. LCMS m/z 358.0
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.18 (d, J=2.2
Hz, 1H), 8.08 (d, J=5.9 Hz, 1H), 7.77 (d, J=1.0 Hz, 1H), 7.54 (dd,
J=5.8, 0.9 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.40 (br d, J=2.4 Hz,
1H), 7.30 (br dd, J=8.3, 2.4 Hz, 1H), 7.26 (d, J=1.0 Hz, 1H), 7.12
(dd, J=2.2, 1.0 Hz, 1H), 2.27 (s, 3H), 2.00 (br s, 3H).
Examples 3 and 4
(+)-5-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methyl-[8-.sup.2H]-
-imidazo[1,2-a]pyrazine (3) and
(-)-5-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methyl-[8-.sup.2H-
]-imidazo[1,2-a]pyrazine (4)
##STR00040##
[0390] Chiral separation of
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methyl-[8-.sup.2H]-im-
idazo[1,2-a]pyrazine (2) (0.158 g) was carried out using
supercritical fluid chromatography (Column: Chiralpak AD-H, 5
.mu.m; Eluent: 3:1 carbon dioxide/methanol) to afford 3
[first-eluting peak, designated as the (+)-atropisomer according to
its observed rotation data, 50 mg, 32%] and 4 [second-eluting peak,
designated as the (-)-atropisomer according to its observed
rotation data, 55 mg, 34%]. Compound 3: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.09 (d, J=5.7 Hz, 1H), 7.78-7.86 (br m, 1H),
7.71 (d, J=2.4 Hz, 1H), 7.35-7.37 (m, 1H), 7.29-7.34 (m, 3H),
7.23-7.27 (m, 1H, assumed; partially obscured by solvent peak),
6.96 (dd, J=2.2, 1.0 Hz, 1H), 2.44 (s, 3H), 2.08 (s, 3H). Compound
4: .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. 8.18 (d, J=2.3 Hz,
1H), 8.08 (d, J=5.7 Hz, 1H), 7.77 (d, J=1.0 Hz, 1H), 7.53 (dd,
J=5.8, 0.9 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.40 (d, J=2.4 Hz, 1H),
7.30 (dd, J=8.2, 2.6 Hz, 1H), 7.26 (d, J=1.0 Hz, 1H), 7.12 (dd,
J=2.2, 0.8 Hz, 1H), 2.27 (s, 3H), 2.00 (s, 3H).
Example 5
1-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-2-methyl-1H-imidazo[4,5--
c]pyridine (5)
##STR00041##
[0391] Step 1. Synthesis of
N-(4-methoxy-2-methylphenyl)-3-nitropyridin-4-amine (C6).
[0392] A solution of 4-methoxy-2-methylaniline (23.8 g, 173 mmol),
4-chloro-3-nitropyridine (25 g, 160 mmol), and triethylamine (33.0
mL, 237 mmol) in ethanol (250 mL) was stirred at room temperature
for 16 hours, then concentrated under reduced pressure. The residue
was dissolved in ethyl acetate (200 mL) and filtered through a
thick pad of silica gel (Eluent: ethyl acetate, 1 L). The filtrate
was concentrated in vacuo to provide the product as a purple oil,
which solidified on standing. This material was used without
further purification. Yield: 41 g, 160 mmol, 100%. LCMS m/z 260.1
(M+H).
Step 2. Synthesis of
N.sup.4-(4-methoxy-2-methylphenyl)pyridine-3,4-diamine (C7).
[0393] Palladium on carbon (10%, 3.times.2.12 g) was added to each
of three batches of
N-(4-methoxy-2-methylphenyl)-3-nitropyridin-4-amine (C6) (each
approximately 10 g; total 31 g, 120 mmol) in methanol (3.times.100
mL). The three suspensions were independently hydrogenated under 45
psi hydrogen at room temperature on a Parr shaker for 24 hours. The
three reaction mixtures were combined, filtered through a pad of
Celite, and concentrated in vacuo. Purification by silica gel
chromatography [Gradient: 2% to 10% (1.7 M ammonia in methanol) in
dichloromethane] afforded the product as a light brown solid.
Yield: 24.0 g, 105 mmol, 88%. LCMS m/z 230.1 (M+H). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.01 (s, 1H), 7.88 (d, J=5.5 Hz, 1H),
7.08 (d, J=8.6 Hz, 1H), 6.84 (br d, J=2.8 Hz, 1H), 6.78 (br dd,
J=8.6, 3.0 Hz, 1H), 6.34 (d, J=5.5 Hz, 1H), 5.66 (br s, 1H), 3.82
(s, 3H), 2.20 (br s, 3H).
Step 3. Synthesis of
1-(4-methoxy-2-methylphenyl)-2-methyl-1H-imidazo[4,5-c]pyridine
(C8).
[0394] A mixture of
N.sup.4-(4-methoxy-2-methylphenyl)pyridine-3,4-diamine (C7) (3.95
g, 17.2 mmol), acetic anhydride (1.96 mL, 20.7 mmol), and triethyl
orthoacetate (99%, 15.9 mL, 86.4 mmol) was heated at 145.degree. C.
for 1 hour, then at 100.degree. C. for 48 hours. After being cooled
to room temperature, the reaction mixture was diluted with ethyl
acetate (100 mL), washed with saturated aqueous sodium bicarbonate
solution (30 mL), washed with water, dried over sodium sulfate,
filtered, and concentrated under reduced pressure. Purification by
silica gel chromatography (Gradient: 2% to 5% methanol in
dichloromethane) provided the product as a light pink oil. Yield:
4.10 g, 16.2 mmol, 94%. LCMS m/z 254.1 (M+H). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 9.07 (br d, J=0.8 Hz, 1H), 8.36 (d, J=5.5 Hz,
1H), 7.15 (d, J=8.6 Hz, 1H), 6.89-6.97 (m, 3H), 3.90 (s, 3H), 2.42
(s, 3H), 1.94 (br s, 3H).
Step 4. Synthesis of
3-methyl-4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenol (C9).
[0395] Boron tribromide (1 M solution in dichloromethane, 44.1 mL,
44.1 mmol) was added drop-wise to a solution of
1-(4-methoxy-2-methylphenyl)-2-methyl-1H-imidazo[4,5-c]pyridine
(C8) (3.72 g, 14.7 mmol) in dichloromethane (150 mL) at -78.degree.
C. The reaction mixture was stirred at -78.degree. C. for 15
minutes, then the cooling bath was removed and the reaction mixture
was allowed to gradually warm to room temperature. After 20 hours
at room temperature, the reaction mixture was recooled to
-78.degree. C. and slowly quenched with methanol (20 mL). At this
point, the cooling bath was removed; the mixture was allowed to
reach ambient temperature and then stir for 15 minutes. Volatiles
were removed in vacuo, methanol (100 mL) was added, and the mixture
was heated at reflux for 30 minutes. After concentration under
reduced pressure, the resulting solid was taken directly to the
next step. LCMS m/z 240.1 (M+H).
Step 5. Synthesis of
1-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-2-methyl-1H-imidazo[4,5-
-c]pyridine (5).
[0396] A mixture of
3-methyl-4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenol (C9)
(from the preceding step, .ltoreq.14.7 mmol),
4-chlorofuro[3,2-c]pyridine (2.37 g, 15.4 mmol) and cesium
carbonate (99%, 19.3 g, 58.6 mmol) in dimethyl sulfoxide (100 mL)
was heated to 140.degree. C. for 16 hours. After cooling to room
temperature, the reaction mixture was diluted with ethyl acetate
(400 mL) and filtered through a pad of Celite. The filtrate was
washed with water, with a 1:1 mixture of water and saturated
aqueous sodium chloride solution (4.times.100 mL), dried over
sodium sulfate, filtered, and concentrated in vacuo. The residue
was purified by silica gel chromatography (Gradient: 2% to 10%
methanol in ethyl acetate) to afford a yellow solid, which was
dissolved in tert-butyl methyl ether (500 mL), treated with
activated carbon (5 g) and heated to 40.degree. C. The mixture was
filtered to provide a colorless solution, which was concentrated at
reflux until it became cloudy (.about.150 mL tert-butyl methyl
ether remaining). Upon gradual cooling to room temperature, a
precipitate formed. Filtration and washing with diethyl ether
afforded the product as a free-flowing white solid. Yield: 2.02 g,
5.67 mmol, 39% over 2 steps. LCMS m/z 357.1 (M+H). .sup.1H NMR (500
MHz, CDCl.sub.3) .delta. 9.08 (d, J=1.0 Hz, 1H), 8.39 (d, J=5.5 Hz,
1H), 8.08 (d, J=5.9 Hz, 1H), 7.71 (d, J=2.2 Hz, 1H), 7.34-7.36 (m,
1H), 7.30 (dd, J=5.9, 1.0 Hz, 1H), 7.28-7.29 (m, 2H), 7.00 (dd,
J=5.5, 1.1 Hz, 1H), 6.97 (dd, J=2.2, 1.0 Hz, 1H), 2.48 (s, 3H),
1.99 (br s, 3H).
Example 6
4-[3-Methoxy-4-(3-methylpyrazin-2-yl)phenoxy]furo[3,2-c]pyridine
(6)
##STR00042##
[0398] 2-Bromo-3-methylpyrazine (104 mg, 0.600 mmol),
tetrakis(triphenylphosphine)palladium(0) (95%, 133 mg, 0.109 mmol)
and sodium carbonate (175 mg, 1.64 mmol) were combined with
4-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[-
3,2-c]pyridine [C10, which was prepared in analogous fashion to
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) in Example 1] (200 mg, 0.545 mmol) in
1,4-dioxane (3 mL) and water (1 mL). The reaction mixture was
heated to 130.degree. C. in a microwave reactor for 1 hour. The
mixture was cooled to room temperature, and the supernatant was
decanted into another flask. The remaining solids were washed with
ethyl acetate (3.times.10 mL) and the combined organic portions
were concentrated in vacuo. Purification was carried out twice
using silica gel chromatography (First column: Eluent: 2% methanol
in dichloromethane; Second column: Gradient: 0% to 100% ethyl
acetate in heptane). The colorless fractions were combined and
concentrated under reduced pressure to provide the product as a
white solid. Yield: 85 mg, 0.25 mmol, 46%. LCMS m/z 334.0 (M+H).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.47 (AB quartet,
downfield doublet is broadened, J.sub.AB=2.5 Hz,
.DELTA..nu..sub.AB=14 Hz, 2H), 8.08 (d, J=5.9 Hz, 1H), 7.66 (d,
J=2.3 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.25-7.28 (m, 1H, assumed;
partially obscured by solvent peak), 6.90-6.96 (m, 2H), 6.88 (dd,
J=2.2, 0.8 Hz, 1H), 3.79 (s, 3H), 2.50 (s, 3H). Yellow fractions
were repurified to provide additional product: 55 mg, overall
yield: 75%.
Example 7
4-[4-(1-Methyl-1H-pyrazol-5-yl)phenoxy]thieno[3,2-c]pyridine
(7)
##STR00043##
[0399] Step 1. Synthesis of
5-[4-(benzyloxy)phenyl]-1-methyl-1H-pyrazole (C11).
[0400] N,N-Dimethylformamide dimethyl acetal (94%, 19.0 mL, 134
mmol) was added to a solution of 1-[4-(benzyloxy)phenyl]ethanone
(15.32 g, 67.71 mmol) in N,N-dimethylformamide (30 mL) and the
reaction mixture was heated at reflux for 18 hours. At this point,
the reflux condenser was replaced with a distillation head, and
distillation was carried out until the temperature of the
distillate reached 140.degree. C. The material in the reaction pot
was cooled to room temperature, treated with methylhydrazine (98%,
7.4 mL, 136 mmol) and heated at 75.degree. C. for 3 hours. The
reaction mixture was cooled, diluted with ethyl acetate, washed
four times with aqueous 5% sodium chloride solution, dried over
magnesium sulfate, filtered, and concentrated in vacuo.
Purification via silica gel chromatography (Gradient: 2% to 10%
ethyl acetate in dichloromethane) afforded the product as a light
yellow solid. Yield: 13.79 g, 52.17 mmol, 77%. LCMS m/z 265.1
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) characteristic peaks,
.delta. 3.81 (s, 3H), 5.17 (s, 2H), 6.31 (d, J=1.5 Hz, 1H), 7.12
(d, J=8.8 Hz, 2H).
Step 2. Synthesis of 4-(1-methyl-1H-pyrazol-5-yl)phenol (C12).
[0401] 5-[4-(Benzyloxy)phenyl]-1-methyl-1H-pyrazole (C11) (13.49 g,
51.04 mmol) was mixed with 10% palladium on carbon (.about.50% in
water, 1.46 g) and dissolved in ethanol (125 mL). The reaction
mixture was hydrogenated at room temperature and 1 atmosphere
hydrogen for 18 hours, then filtered and concentrated in vacuo. The
residue was triturated with heptane to afford the product as a
colorless solid. Yield: 8.74 g, 50.2 mmol, 98%. LCMS m/z 175.1
(M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.73 (br s, 1H),
7.40 (d, J=1.9 Hz, 1H), 7.31 (br d, J=8.7 Hz, 2H), 6.86 (br d,
J=8.7 Hz, 2H), 6.26 (d, J=1.9 Hz, 1H), 3.79 (s, 3H).
Step 3. Synthesis of
4-[4-(1-methyl-1H-pyrazol-5-yl)phenoxy]thieno[3,2-c]pyridine
(7).
[0402] 4-(1-Methyl-1H-pyrazol-5-yl)phenol (C12) (123 mg, 0.706
mmol) and 4-chlorothieno[3,2-c]pyridine (100 mg, 0.590 mmol) were
combined in 1-methylpyrrolidin-2-one (2 mL). Cesium carbonate (99%,
388 mg, 1.18 mmol) was added and the reaction mixture was heated to
135.degree. C. for 24 hours. After addition of water (30 mL), the
layers were separated and the aqueous layer was extracted with 1:1
diethyl ether/hexanes (4.times.30 mL). The combined organic layers
were washed with aqueous sodium hydroxide solution (1 N, 2.times.20
mL) and with saturated aqueous sodium chloride solution (20 mL),
then dried over sodium sulfate. After filtration and concentration
under reduced pressure, purification using silica gel
chromatography (Eluent: 30% ethyl acetate in heptane) provided the
product as a white solid. Yield: 78 mg, 0.25 mmol, 42%. LCMS m/z
308.3 (M+H). .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. 7.90 (d,
J=5.6 Hz, 1H), 7.74 (d, J=5.5 Hz, 1H), 7.69 (dd, J=5.7, 0.7 Hz,
1H), 7.65 (dd, J=5.5, 0.8 Hz, 1H), 7.55 (br d, J=8.7 Hz, 2H), 7.51
(d, J=2.0 Hz, 1H), 7.32 (br d, J=8.7 Hz, 2H), 6.39 (d, J=2.0 Hz,
1H), 3.91 (s, 3H).
Example 8
4-{[4-(1-Methyl-1H-pyrazol-5-yl)phenyl]sulfanyl}furo[3,2-c]pyridine,
trifluoroacetate salt (8)
##STR00044##
[0403] Step 1. Synthesis of
4-[(4-bromophenyl)sulfanyl]furo[3,2-c]pyridine (C13).
[0404] Cesium carbonate (99%, 522 mg, 1.59 mmol) was added to a
mixture of 4-chlorofuro[3,2-c]pyridine (146 mg, 0.951 mmol) and
4-bromobenzenethiol (150 mg, 0.793 mmol) in dimethyl sulfoxide (3
mL); the reaction mixture was degassed, and then heated at
80.degree. C. for 16 hours. Water (30 mL) was added and extraction
was carried out with 1:1 ethyl acetate/hexanes (4.times.30 mL). The
combined organic layers were dried over sodium sulfate, filtered,
and concentrated in vacuo. Purification via silica gel
chromatography (Gradient: 5% to 10% ethyl acetate in heptane)
provided a colorless oil (220 mg); this was dissolved in diethyl
ether (20 mL) and washed with aqueous sodium hydroxide solution (1
N, 3.times.15 mL). The organic layer was concentrated under reduced
pressure to provide the product, determined by .sup.1H NMR analysis
to be contaminated with extraneous furo[3,2-c]pyridyl activity.
This was taken to the following step without further purification.
LCMS m/z 308.3 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) product
peaks only, .delta. 8.32 (d, J=5.7 Hz, 1H), 7.60 (d, J=2.2 Hz, 1H),
7.47 (br AB quartet, J.sub.AB=8.7 Hz, .DELTA..nu..sub.AB=31.2 Hz,
4H), 7.29 (dd, J=5.8, 1.0 Hz, 1H), 6.58 (dd, J=2.3, 1.0 Hz,
1H).
Step 2. Synthesis of
4-{[4-(1-methyl-1H-pyrazol-5-yl)phenyl]sulfanyl}furo[3,2-c]pyridine,
trifluoroacetate salt (8).
[0405] 4-[(4-Bromophenyl)sulfanyl]furo[3,2-c]pyridine (C13) (210 mg
from the previous step), (1-methyl-1H-pyrazol-5-yl)boronic acid
(104 mg, 0.826 mmol), triphenylphosphine (21.5 mg, 0.0819 mmol) and
potassium carbonate (190 mg, 1.37 mmol) were combined in
N,N-dimethylformamide (6 mL) and water (2 mL), and the mixture was
degassed with nitrogen for 20 minutes. Palladium(II) acetate (98%,
4.8 mg, 0.021 mmol) was added, and the reaction mixture was heated
at 80.degree. C. for 18 hours. After cooling to room temperature,
the reaction mixture was diluted with water (15 mL) and extracted
with 1:1 ethyl acetate/hexanes (3.times.15 mL). The combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Purification was effected first via silica
gel chromatography (Eluent: 80% ethyl acetate in heptane), followed
by HPLC (Column: Waters XBridge C18, 5 .mu.m; Mobile phase A: water
with trifluoroacetic acid modifier; Mobile phase B: acetonitrile
with trifluoroacetic acid modifier; Gradient: 40% to 100% B), to
afford the product as a white solid. Yield: 30 mg, 0.071 mmol, 9%
over two steps. LCMS m/z 308.0 (M+H). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.29 (d, J=5.8 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H),
7.61 (br d, J=8.6 Hz, 2H), 7.53 (br d, J=8.7 Hz, 2H), 7.51 (d,
J=2.1 Hz, 1H), 7.49 (dd, J=5.8, 1.0 Hz, 1H), 6.66 (dd, J=2.3, 1.1
Hz, 1H), 6.42 (d, J=2.0 Hz, 1H), 3.90 (s, 3H).
Example 9
2-(4,6-Dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)benzonitrile
(9)
##STR00045##
[0406] Step 1. Synthesis of
2-bromo-5-{[tert-butyl(dimethyl)silyl]oxy}benzonitrile (C14).
[0407] 1H-Imidazole (2.14 g, 31.4 mmol) was added portion-wise to a
0.degree. C. solution of 2-bromo-5-hydroxybenzonitrile (5.65 g,
28.5 mmol) and tert-butyldimethylsilyl chloride (4.52 g, 30.0 mmol)
in tetrahydrofuran (56.5 mL). The reaction mixture was allowed to
stir at room temperature for 2 hours, and was then filtered. The
filtrate was washed with water and with saturated aqueous sodium
chloride solution. The aqueous layer was extracted with diethyl
ether, and the combined organic layers were concentrated in vacuo
to afford the product as an orange oil. Yield: 8.87 g, 28.4 mmol,
99.6%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (d, J=8.8 Hz,
1H), 7.08-7.12 (m, 1H), 6.90-6.95 (m, 1H), 0.98 (s, 9H), 0.22 (s,
6H).
Step 2. Synthesis of
5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)benzonitrile (C15).
[0408] 2-Bromo-5-{[tert-butyl(dimethyl)silyl]oxy}benzonitrile (C14)
(8.00 g, 25.6 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (6.83 g,
26.9 mmol) and potassium acetate (10.06 g, 102.5 mmol) were
combined in degassed 1,4-dioxane (160 mL). After addition of
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.05
g, 1.28 mmol), the reaction mixture was heated to 80.degree. C. for
4 hours. After cooling, it was filtered through Celite, and the
filter pad was rinsed with ethyl acetate. The filtrate was
concentrated in vacuo and purified via silica gel chromatography
(Gradient: 20% to 50% ethyl acetate in heptane) to provide the
product as a colorless, viscous oil. Yield: 5.60 g, 15.6 mmol, 61%.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.76 (br d, J=8.3 Hz,
1H), 7.15 (dd, J=2.4, 0.3 Hz, 1H), 7.02 (dd, J=8.3, 2.3 Hz, 1H),
1.38 (s, 12H), 0.98 (s, 9H), 0.22 (s, 6H).
Step 3. Synthesis of
2-(4,6-dimethylpyrimidin-5-yl)-5-hydroxybenzonitrile (C16).
[0409]
5-{[tert-Butyl(dimethyl)silyl]oxy}-2-(4,4,5,5-tetramethyl-1,3,2-dio-
xaborolan-2-yl)benzonitrile (C15) (4.05 g, 11.3 mmol) was combined
with 5-bromo-4,6-dimethylpyrimidine hydrobromide (7.16 g, 26.7
mmol) and potassium phosphate (7.03 g, 33.1 mmol) in
2-methyltetrahydrofuran (20.2 mL) and water (16.2 mL).
[2'-(Azanidyl-.kappa.N)biphenyl-2-yl-.kappa.C.sub.2](chloro)[dicyclohexyl-
(2',6'-dimethoxybiphenyl-2-yl)-.lamda..sup.5-phosphanyl]palladium
(prepared from biphenyl-2-amine and
dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphane (S-Phos)
according to the procedure of S. L. Buchwald et al., J. Am. Chem.
Soc. 2010, 132, 14073-14075) (0.20 g, 0.28 mmol) was added, and the
reaction mixture was heated to reflux for 18 hours. It was then
cooled to room temperature, and the organic layer was extracted
with aqueous hydrochloric acid (2 N, 2.times.20 mL). The combined
extracts were adjusted to a pH of roughly 6-7 with 2 M aqueous
sodium hydroxide solution, and then extracted with ethyl acetate.
These combined organic layers were dried over magnesium sulfate,
filtered, and concentrated in vacuo. The resulting solids were
triturated with hot heptane to afford the product as a tan solid.
Yield: 1.86 g, 8.26 mmol, 73%. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.48 (s, 1H), 8.94 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 7.31
(d, J=2.5 Hz, 1H), 7.23 (dd, J=8.5, 2.6 Hz, 1H), 2.18 (s, 6H).
Step 4. Synthesis of
2-(4,6-dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)benzonitrile
(9).
[0410] 2-(4,6-Dimethylpyrimidin-5-yl)-5-hydroxybenzonitrile (C16)
(1.00 g, 4.44 mmol), 4-chlorofuro[3,2-c]pyridine (750 mg, 4.88
mmol), palladium(II) acetate (49.8 mg, 0.222 mmol),
1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) (96%, 288 mg,
0.444 mmol) and cesium carbonate (99%, 2.92 g, 8.87 mmol) were
combined in 1,4-dioxane (25 mL) and nitrogen was bubbled through
the mixture for 15 minutes. The reaction mixture was then heated at
100.degree. C. for 18 hours, cooled to room temperature and
filtered through Celite. The filtrate was partitioned between ethyl
acetate and water, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate,
filtered, and concentrated in vacuo. Purification using silica gel
chromatography (Gradient: 75% to 100% ethyl acetate in heptane)
provided the product as a viscous yellow oil, which slowly
solidified on standing. Further purification was effected using
supercritical fluid chromatography (Column: Princeton
2-ethylpyridine, 5 .mu.m; Eluent: 4:1 carbon dioxide/methanol).
Yield: 1.5 g, 4.4 mmol, 99%. LCMS m/z 343.1 (M+H). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.04 (s, 1H), 8.06 (d, J=5.9 Hz, 1H), 7.78
(br d, J=2.5 Hz, 1H), 7.72 (d, J=2.2 Hz, 1H), 7.66 (dd, J=8.4, 2.5
Hz, 1H), 7.36 (dd, J=8.4, 0.4 Hz, 1H), 7.33 (dd, J=5.7, 1.0 Hz, 1H)
6.97 (dd, J=2.2, 1.0 Hz, 1H), 2.36 (s, 6H).
Example 10
4-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylpyridazin-3(2H)--
one, bis-hydrochloride salt (10)
##STR00046## ##STR00047##
[0411] Step 1. Synthesis of
4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
(C17).
[0412] A mixture of 4,5-dichloropyridazin-3-ol (42 g, 250 mmol),
3,4-dihydro-2H-pyran (168 g, 2.00 mol) and para-toluenesulfonic
acid (8.8 g, 51 mmol) in tetrahydrofuran (2 L) was refluxed for 2
days. After cooling to room temperature, the mixture was
concentrated under reduced pressure. The residue was purified by
chromatography on silica gel (Gradient: 3% to 5% ethyl acetate in
petroleum ether) to afford the product as a white solid. Yield: 42
g, 170 mmol, 68%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.84
(s, 1H), 6.01 (br d, J=11 Hz, 1H), 4.10-4.16 (m, 1H), 3.70-3.79 (m,
1H), 1.99-2.19 (m, 2H), 1.50-1.80 (m, 4H).
Step 2. Synthesis of
4-chloro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
(C18) and
5-chloro-4-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
(C19).
[0413] To a mixture of
4,5-dichloro-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (C17)
(40 g, 0.16 mol), methylboronic acid (9.6 g, 0.16 mol) and cesium
carbonate (155 g, 0.476 mol) in a mixture of 1,4-dioxane (500 mL)
and water (50 mL) was added
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5 g, 7
mmol). The reaction mixture was stirred at 110.degree. C. for 2
hours, then concentrated under reduced pressure. Purification by
silica gel chromatography (Gradient: 3% to 5% ethyl acetate in
petroleum ether) provided product C18 as a pale yellow solid
(Yield: 9 g, 40 mmol, 25%) and product C19, also as a pale yellow
solid (Yield: 9.3 g, 41 mmol, 26%). C18: LCMS m/z 250.8
(M+Na.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71 (s,
1H), 6.07 (dd, J=10.7, 2.1 Hz, 1H), 4.10-4.18 (m, 1H), 3.71-3.81
(m, 1H), 2.30 (s, 3H), 1.98-2.19 (m, 2H), 1.53-1.81 (m, 4H). C19:
LCMS m/z 250.7 (M+Na.sup.+). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.77 (s, 1H), 6.02 (dd, J=10.7, 2.1 Hz, 1H), 4.10-4.17 (m,
1H), 3.71-3.79 (m, 1H), 2.27 (s, 3H), 1.99-2.22 (m, 2H), 1.51-1.79
(m, 4H).
Step 3. Synthesis of
4-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methyl-2-(tetrahydro--
2H-pyran-2-yl)pyridazin-3(2H)-one (C20).
[0414] A mixture of
4-chloro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
(C18) (457 mg, 2.00 mmol),
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) (702 mg, 2.00 mmol) and
[2'-(azanidyl-.kappa.N)biphenyl-2-yl-.kappa.C.sub.2](chloro)[dicyclohexyl-
(2',6'-dimethoxybiphenyl-2-yl)-.lamda..sup.5-phosphanyl]palladium
(29 mg, 0.040 mmol) was subjected to three rounds of vacuum
evacuation followed by introduction of nitrogen. Degassed
tetrahydrofuran (4 mL) was added, followed by degassed aqueous
potassium phosphate solution (0.5 M, 8.0 mL, 4.0 mmol), and the
reaction mixture was allowed to stir at room temperature for 23
hours. The reaction mixture was then partitioned between ethyl
acetate (20 mL) and water (8 mL); the organic layer was dried over
sodium sulfate, filtered, and concentrated in vacuo. Purification
via silica gel chromatography (Gradient: 20% to 70% ethyl acetate
in heptane) afforded the product as a white solid. By NMR, this was
determined to consist of a diastereomeric mixture due to the
tetrahydropyranyl group. Yield: 588 mg, 1.41 mmol, 70%. LCMS m/z
418.0 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.06 (d,
J=5.9 Hz, 1H), 7.82 (d, J=2.8 Hz, 1H), 7.63 (d, J=2.3 Hz, 1H),
7.23-7.25 (m, 1H), 7.16-7.17 (m, 1H), 7.06-7.13 (m, 2H), 6.79-6.81
(m, 1H), 6.10 (dd, J=10.6, 2.2 Hz, 1H), 4.14-4.20 (m, 1H),
3.72-3.80 (m, 1H), 2.15-2.25 (m, 1H, assumed; partially obscured by
methyl group), 2.14 and 2.15 (2 s, total 3H), 2.01-2.08 (m, 1H,
assumed; partially obscured by methyl group), 2.03 and 2.04 (2 s,
total 3H), 1.71-1.82 (m, 3H), 1.55-1.63 (m, 1H).
Step 4. Synthesis of
4-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylpyridazin-3(2H)-
-one, bis-hydrochloride salt (10).
[0415]
4-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methyl-2-(tetra-
hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (C20) (580 mg, 1.39 mmol)
was dissolved in methanol (3 mL), treated with a solution of
hydrogen chloride in 1,4-dioxane (4 M, 5.0 mL, 20 mmol) and allowed
to stir at room temperature for 3 hours. Removal of solvent under
reduced pressure provided the product as a pale yellow solid,
presumed to be the bis-hydrochloride salt. Yield: 550 mg, 1.35
mmol, 97%. LCMS m/z 334.0 (M+H). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 13.01 (br s, 1H), 8.15 (d, J=2.3 Hz, 1H),
8.02 (d, J=5.8 Hz, 1H), 7.89 (s, 1H), 7.48 (dd, J=5.8, 1.1 Hz, 1H),
7.16-7.18 (m, 1H), 7.08-7.12 (m, 3H), 2.06 (br s, 3H), 1.95 (s,
3H).
Example 11
[0416]
4-[4-(3-Chloro-5-methylpyridazin-4yl)-3-methylphenoxy]furo[3,2-c]py-
ridine (11)
##STR00048##
[0417]
4-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylpyridazin-
-3(2H)-one, bis-hydrochloride salt (10) (550 mg, 1.35 mmol) was
suspended in phosphorus oxychloride (6.0 mL, 64 mmol), and the
reaction mixture was heated at 90.degree. C. for 2 hours. After
removal of phosphorus oxychloride under reduced pressure, the
residue was partitioned between dichloromethane (35 mL), water (10
mL), and saturated aqueous sodium bicarbonate solution (10 mL). The
organic layer was dried over sodium sulfate, filtered, and
concentrated in vacuo to afford the product as a foamy, pale amber
solid. Yield: 465 mg, 1.32 mmol, 98%. LCMS m/z 352.0 (M+H). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 9.07 (s, 1H), 8.11 (d, J=5.8 Hz,
1H), 7.69 (d, J=2.3 Hz, 1H), 7.31 (dd, J=5.9, 0.9 Hz, 1H),
7.25-7.28 (m, 1H, assumed; partially obscured by solvent peak),
7.21-7.24 (m, 1H), 7.09 (d, J=8.2 Hz, 1H), 6.84 (dd, J=2.2, 0.8 Hz,
1H), 2.19 (s, 3H), 2.08 (br s, 3H).
Example 12
4-[4-(3,5-Dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridine
(12)
##STR00049##
[0419] Nitrogen was bubbled into a mixture of
tetrakis(triphenylphosphine)palladium(0) (31.0 mg, 0.027 mmol) and
4-[4-(3-chloro-5-methylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridin-
e (11) (427 mg, 1.21 mmol) in 1,4-dioxane (12 mL) for 10 minutes. A
solution of trimethylaluminum in toluene (2 M, 1.2 mL, 2.4 mmol)
was added, and the reaction mixture was heated to 95.degree. C. for
90 minutes, then cooled in an ice bath and treated drop-wise with
methanol (12 mL) {Caution: gas evolution!}. The mixture was
filtered through Celite and the filter cake was rinsed with
additional methanol (35 mL); the filtrate was concentrated in vacuo
and purified using silica gel chromatography (Eluent: 2.5% methanol
in ethyl acetate) to provide the product as a solid. Yield: 320 mg,
0.966 mmol, 80%. LCMS m/z 332.1 (M+H). .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 9.05 (s, 1H), 7.99 (d, J=6.0 Hz, 1H), 7.90 (d,
J=2.2 Hz, 1H), 7.39 (dd, J=5.9, 0.9 Hz, 1H), 7.26-7.27 (m, 1H),
7.19 (br dd, half of ABX pattern, J=8.3, 2.1 Hz, 1H), 7.15 (d, half
of AB pattern, J=8.3 Hz, 1H), 6.94 (dd, J=2.2, 1.0 Hz, 1H), 2.42
(s, 3H), 2.16 (s, 3H), 2.03 (s, 3H).
Examples 13 and 14
(+)-4-[4-(3,5-Dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridine
(13) and
H-4-[4-(3,5-Dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]p-
yridine (14)
##STR00050##
[0421] Example 12
(4-[4-(3,5-dimethylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyridine)
(316 mg) was separated into its component atropenantiomers using
supercritical fluid chromatography (Column: Chiralpak AS-H, 5
.mu.m; Eluent: 7:3 carbon dioxide/ethanol). Both were obtained as
solids. First-eluting atropenantiomer: 13 [designated as the (+)
atropenantiomer according to its observed rotation data], yield:
137 mg, 43%. LCMS m/z 332.3 (M+H). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 9.03 (s, 1H), 7.99 (d, J=5.8 Hz, 1H), 7.89 (d,
J=2.2 Hz, 1H), 7.38 (br d, J=5.8 Hz, 1H), 7.24-7.27 (m, 1H), 7.19
(br dd, half of ABX pattern, J=8.3, 2.0 Hz, 1H), 7.14 (d, half of
AB quartet, J=8.2 Hz, 1H), 6.91-6.94 (m, 1H), 2.41 (s, 3H), 2.14
(s, 3H), 2.02 (s, 3H). Second-eluting atropenantiomer: 14
[designated as the (-)-atropenantiomer according to its observed
rotation data], yield: 132 mg, 42%. LCMS m/z 332.3 (M+H). .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 9.04 (s, 1H), 7.99 (d, J=6.0 Hz,
1H), 7.89 (d, J=2.2 Hz, 1H), 7.38 (dd, J=6.0, 1.0 Hz, 1H),
7.25-7.27 (m, 1H), 7.19 (br dd, half of ABX pattern, J=8.3, 2.2 Hz,
1H), 7.15 (d, half of AB quartet, J=8.2 Hz, 1H), 6.93 (dd, J=2.2,
1.0 Hz, 1H), 2.41 (s, 3H), 2.15 (s, 3H), 2.02 (s, 3H).
Example 15
4-[4-(1-tert-Butyl-4-methyl-1H-pyrazol-5yl)-3-methylphenoxy]furo[3,2-c]pyr-
idine (15)
##STR00051##
[0422] Step 1. Synthesis of
1-(4-methoxy-2-methylphenyl)propan-1-one (C21).
[0423] To a mixture of 1-methoxy-3-methylbenzene (12.2 g, 100 mmol)
and propanoyl chloride (18.5 g, 200 mmol) in dichloromethane (200
mL) was added aluminum chloride (26.5 g, 199 mmol) in one portion,
and the reaction mixture was stirred at room temperature for 4
hours. The reaction was quenched with aqueous hydrochloric acid (1
N, 100 mL), and the organic layer was dried over magnesium sulfate,
filtered, and concentrated in vacuo. The residue was purified by
silica gel chromatography to afford the product as a yellow solid.
Yield: 3.87 g, 21.7 mmol, 22%.
Step 2. Synthesis of 1-(4-hydroxy-2-methylphenyl)propan-1-one
(C22).
[0424] Boron tribromide (5.57 g, 22.2 mmol) was added to a solution
of 1-(4-methoxy-2-methylphenyl)propan-1-one (C21) (3.87 g, 21.7
mmol) in dichloromethane (50 mL), and the reaction mixture was
stirred at room temperature for 4 hours. Water (20 mL) was added,
and the organic layer was separated, dried over magnesium sulfate,
and concentrated under reduced pressure to provide the product as a
yellow solid, which was used without further purification. Yield:
3.77 g, >100%.
Step 3. Synthesis of
1-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]propan-1-one
(C23).
[0425] A mixture of 1-(4-hydroxy-2-methylphenyl)propan-1-one (C22)
(1.64 g, <10.0 mmol), 4-chlorofuro[3,2-c]pyridine (1.53 g, 9.96
mmol), and potassium carbonate (2.76 g, 20.0 mmol) in
N,N-dimethylformamide (50 mL) was heated to reflux for 8 hours. The
reaction mixture was partitioned between water (50 mL) and ethyl
acetate (150 mL); the organic layer was dried over magnesium
sulfate and concentrated in vacuo to afford the product as a yellow
oil, which was used without additional purification. Yield: 2.97 g,
>100%.
Step 4. Synthesis of
3-(dimethylamino)-1-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-2-met-
hylprop-2-en-1-one (C24).
[0426]
1-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]propan-1-one (C23)
(2.87 g, <10.7 mmol) in a mixture of N,N-dimethylformamide
dimethyl acetal (10 mL) and N,N-dimethylformamide (10 mL) was
heated to reflux for 30 minutes. After removal of solvent under
reduced pressure, the residue was washed with ethyl acetate to
provide the product as a yellow solid. Yield: 1.76 g, 5.23 mmol,
>49%. LCMS m/z 337.1 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 7.94 (d, J=6.1 Hz, 1H), 7.87 (d, J=2.2 Hz, 1H), 7.35 (dd,
J=5.9, 1.0 Hz, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.04-7.07 (m, 2H), 7.00
(br dd, J=8.1, 2.4 Hz, 1H), 6.90 (dd, J=2.3, 1.0 Hz, 1H), 3.15 (s,
6H), 2.24 (s, 3H), 2.14 (s, 3H).
Step 5. Synthesis of
4-[4-(1-tert-butyl-4-methyl-1H-pyrazol-5-yl)-3-methylphenoxy]furo[3,2-c]p-
yridine (15).
[0427] A solution of
3-(dimethylamino)-1-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-2-met-
hylprop-2-en-1-one (C24) in ethanol (0.125 M, 0.600 mL, 0.075 mmol)
was combined with a solution of tert-butylhydrazine in 0.2 M
aqueous hydrochloric acid (0.128 M, 0.700 mL, 0.090 mmol). Acetic
acid (0.05 mL, 0.9 mmol) was added, and the reaction mixture was
shaken at 100.degree. C. for 3 hours. Solvents were removed in
vacuo, and the residue was purified by HPLC (Column: Phenomenex
Gemini C18, 5 .mu.m; Mobile phase A: aqueous ammonium hydroxide, pH
10; Mobile phase B: acetonitrile; Gradient: 70% to 90% B) to afford
the product. LCMS m/z 362 (M+H). Retention time: 3.056 min (Column:
Welch XB-C18, 2.1.times.50 mm, 5 .mu.m; Mobile phase A: 0.0375%
trifluoroacetic acid in water; Mobile phase B: 0.01875%
trifluoroacetic acid in acetonitrile; Gradient: 25% B for 0.50
minutes, 25% to 100% B over 3.0 minutes; Flow rate: 0.8
mL/minute).
Example 16
5-(Furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridin-5-yl)aniline
(16)
##STR00052##
[0428] Step 1. Synthesis of
2-bromo-5-(furo[3,2-c]pyridin-4-yloxy)aniline (C25).
[0429] This reaction was carried out in two identical batches. A
mixture of 3-amino-4-bromophenol (13 g, 69 mmol), cesium carbonate
(45 g, 140 mmol) and 4-chlorofuro[3,2-c]pyridine (7.0 g, 46 mmol)
in dimethyl sulfoxide (200 mL) was heated to 130.degree. C. for 18
hours. The two batches were cooled to room temperature and
combined, and the mixture was poured into ice water (800 mL) and
extracted with ethyl acetate (5.times.1200 mL). The combined
organic layers were washed with saturated aqueous sodium chloride
solution (500 mL), dried over anhydrous sodium sulfate, filtered,
and concentrated under reduced pressure. Purification using silica
gel chromatography (Gradient: 17% to 25% ethyl acetate in petroleum
ether) provided the product as a white solid. Yield: 25 g, 82 mmol,
89%.
Step 2. Synthesis of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)aniline (C26).
[0430] This reaction was carried out in two identical batches. To a
solution of 2-bromo-5-(furo[3,2-c]pyridin-4-yloxy)aniline (C25)
(10.9 g, 35.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (3.3
g, 3.6 mmol), and biphenyl-2-yl(dicyclohexyl)phosphane (1.3 g, 3.7
mmol) in toluene (250 mL) was added triethylamine (10.9 g, 108
mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.8 g, 108
mmol), and the reaction mixture was heated to reflux for 18 hours.
The two batches were cooled to room temperature and combined, then
filtered and evaporated to dryness. The residue was dissolved in
methanol, filtered and concentrated in vacuo. Purification via
silica gel chromatography (Gradient: 9% to 25% ethyl acetate in
petroleum ether) afforded the product as a yellow solid. Yield:
13.5 g, 38.3 mmol, 54%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.10 (d, J=2.0 Hz, 1H), 8.00 (d, J=5.9 Hz, 1H), 7.47 (dd, J=5.9,
0.8 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 6.96 (dd, J=2.4, 0.8 Hz, 1H),
6.36 (d, J=2.0 Hz, 1H), 6.28 (dd, J=8.2, 2.4 Hz, 1H), 5.65 (br s,
2H), 1.29 (s, 12H).
Step 3. Synthesis of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridin-5-yl)aniline
(16).
[0431] This reaction was carried out in two identical batches. A
mixture of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)aniline (C26) (4.5 g, 13 mmol), potassium phosphate
trihydrate (9.6 g, 36 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.1 g,
1.3 mmol) and 5-bromoimidazo[1,2-a]pyridine (3.8 g, 19 mmol) in
2-methyltetrahydrofuran (50 mL) and water (10 mL) was heated to
75.degree. C. for 18 hours. The two batches were cooled to room
temperature and combined. After filtration, the filter cake was
washed with water, and the combined filtrates were extracted with
ethyl acetate (4.times.100 mL). The combined organic layers were
washed with saturated aqueous sodium chloride solution, dried over
sodium sulfate, filtered, and concentrated in vacuo. The residue
was combined with the filter cake and purified by silica gel
chromatography (Gradient: 2% to 5% methanol in dichloromethane) to
provide the product as a yellow solid. Yield: 4.2 g, 12 mmol, 46%.
LCMS m/z 342.9 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
8.14 (d, J=2.2 Hz, 1H), 8.06 (d, J=5.9 Hz, 1H), 7.60 (br d, J=9.0
Hz, 1H), 7.58 (d, J=1.0 Hz, 1H), 7.50 (dd, J=5.9, 0.8 Hz, 1H), 7.33
(dd, J=9.0, 6.8 Hz, 1H), 7.32 (br s, 1H), 7.19 (d, J=8.2 Hz, 1H),
7.07 (dd, J=2.2, 0.9 Hz, 1H), 6.89 (br dd, J=6.8, 0.7 Hz, 1H), 6.65
(d, J=2.4 Hz, 1H), 6.50 (dd, J=8.4, 2.4 Hz, 1H), 5.17 (br s,
2H).
Example 17
N-[4-(Imidazo[1,2-a]pyridin-5-yl)-3-methylphenyl]furo[3,2-c]pyridin-4-amin-
e (17)
##STR00053##
[0432] Step 1. Synthesis of
5-(2-methyl-4-nitrophenyl)imidazo[1,2-a]pyridine (C27).
[0433] A mixture of
4,4,5,5-tetramethyl-2-(2-methyl-4-nitrophenyl)-1,3,2-dioxaborolane
(390 mg, 1.48 mmol), 5-bromoimidazo[1,2-a]pyridine (243 mg, 1.23
mmol), potassium carbonate (683 mg, 4.94 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (90 mg,
0.12 mmol) in N,N-dimethylformamide (10 mL) was stirred at
120.degree. C. for 1 hour. The reaction mixture was filtered and
the filtrate was concentrated in vacuo. Purification via silica gel
chromatography (Eluent: 2% methanol in dichloromethane) afforded
the product as a yellow oil. Yield: 320 mg, 1.26 mmol, 100%.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.27 (br s, 1H), 8.22 (br
d, J=8.5 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.66 (br s, 1H), 7.56 (d,
J=8.0 Hz, 1H), 7.31 (dd, J=9.0, 7.0 Hz, 1H), 7.05 (s, 1H), 6.75 (d,
J=6.5 Hz, 1H), 2.23 (s, 3H).
Step 2. Synthesis of 4-(imidazo[1,2-a]pyridin-5-yl)-3-methylaniline
(C28).
[0434] A mixture of
5-(2-methyl-4-nitrophenyl)imidazo[1,2-a]pyridine (C27) (300 mg,
1.18 mmol), iron (199 mg, 3.56 mmol) and ammonium chloride (253 mg,
4.73 mmol) in ethanol (9 mL) and water (3 mL) was heated at reflux
for 1 hour. The mixture was filtered and the filtrate was
concentrated in vacuo; purification via silica gel chromatography
(Eluent: 5% methanol in dichloromethane) provided the product as a
solid. Yield: 224 mg, 1.00 mmol, 85%. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.72 (br d, J=9 Hz, 1H), 7.61 (br s, 1H),
7.29-7.36 (m, 1H), 7.19 (br s, 1H), 7.12 (d, J=8.3 Hz, 1H), 6.74
(br d, J=6.5 Hz, 1H), 6.67-6.69 (m, 1H), 6.64 (dd, J=8, 2 Hz, 1H),
2.01 (s, 3H).
Step 3. Synthesis of
N-[4-(imidazo[1,2-a]pyridin-5-yl)-3-methylphenyl]furo[3,2-c]pyridin-4-ami-
ne (17).
[0435] A mixture of 4-(imidazo[1,2-a]pyridin-5-yl)-3-methylaniline
(C28) (185 mg, 0.828 mmol), 4-chlorofuro[3,2-c]pyridine (127 mg,
0.827 mmol), cesium carbonate (810 mg, 2.49 mmol), palladium(II)
acetate (28 mg, 0.12 mmol) and
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 72 mg,
0.12 mmol) in 1,4-dioxane (8 mL) was stirred at 120.degree. C. for
2 hours. After the reaction mixture was filtered, the filtrate was
diluted with ethyl acetate (100 mL), washed with saturated aqueous
sodium chloride solution, and concentrated in vacuo. The residue
was purified via preparative thin layer chromatography (Eluent: 5%
methanol in dichloromethane) to afford the product as a yellow
solid. Yield: 157 mg, 0.461 mmol, 56%. LCMS m/z 341.3 (M+H).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.16 (d, J=6.0 Hz, 1H),
7.58-7.67 (m, 4H), 7.29 (d, J=8.0 Hz, 1H), 7.25-7.36 (br m, 1H,
assumed; partially obscured by solvent peak), 7.21 (br s, 1H), 7.09
(br d, J=6 Hz, 1H), 6.92-7.03 (br m, 1H), 6.72-6.80 (br m, 2H),
2.11 (s, 3H).
Example 18
4-[4-(4-Chloro-6-methylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridine
(18)
##STR00054##
[0436] Step 1. Synthesis of
4-[4-(4-methoxy-6-methylpyrimidin-5yl)-3-methylphenoxy]furo[3,2-c]pyridin-
e (C29).
[0437] A mixture of
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) (4.0 g, 11 mmol),
5-bromo-4-methoxy-6-methylpyrimidine (Z. Wang et al., Synthesis
2011, 1529-1531) (2.0 g, 10 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.1 g,
1.4 mmol) and potassium carbonate (4.0 g, 29 mmol) in 1,4-dioxane
(30 mL) containing 5 drops of water was heated at 120.degree. C.
for 2 hours. After filtration and concentration of the filtrate
under reduced pressure, the residue was purified by silica gel
chromatography (Eluent: 33% ethyl acetate in petroleum ether) to
give the product as a yellow solid. Yield: 1.8 g, 5.2 mmol, 52%.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.72 (s, 1H), 8.07 (d,
J=6.0 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H), 7.25 (dd, J=5.9, 0.9 Hz,
1H), 7.19-7.21 (m, 1H), 7.09-7.16 (m, 2H), 6.88 (dd, J=2.3, 0.8 Hz,
1H), 3.95 (s, 3H), 2.29 (s, 3H), 2.07 (s, 3H).
Step 2. Synthesis of
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylpyrimidin-4-ol
(C30).
[0438] Boron tribromide (20 g, 80 mmol) was slowly added to a
solution of
4-[4-(4-methoxy-6-methylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridi-
ne (C29) (1.8 g, 5.2 mmol) in dichloromethane (150 mL) at
-60.degree. C. The reaction mixture was allowed to warm to room
temperature and stirred for 18 hours. Methanol (150 mL) was then
added, and the pH was adjusted to 6 via addition of solid sodium
bicarbonate. The mixture was filtered and the filtrate was
concentrated in vacuo. This residue was mixed with acetone and
filtered again; concentration of the filtrate afforded the product
as a yellow solid. Yield: 1.5 g, 4.5 mmol, 87%.
Step 3. Synthesis of
4-[4-(4-chloro-6-methylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridin-
e (18).
[0439] A mixture of
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylpyrimidin-4-ol
(C30) (1.5 g, 4.5 mmol) and phosphorus oxychloride (100 g, 65 mmol)
was heated at reflux for 2 hours. After concentration under reduced
pressure, the residue was slowly treated with saturated aqueous
sodium bicarbonate solution (200 mL). The resulting mixture was
extracted with ethyl acetate (4.times.100 mL) and the combined
organic layers were dried, filtered and concentrated in vacuo.
Purification via silica gel chromatography (Eluent: 50% ethyl
acetate in petroleum ether) provided the product as a yellow solid.
Yield: 750 mg, 2.13 mmol, 47%. LCMS m/z 352.1 (M+H). .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 8.86 (s, 1H), 7.99 (br d, J=5.9 Hz,
1H), 7.88 (d, J=2.3 Hz, 1H), 7.38 (dd, J=5.9, 0.9 Hz, 1H),
7.22-7.25 (m, 1H), 7.20 (d, half of AB quartet, J=8.2 Hz, 1H), 7.16
(br dd, half of ABX pattern, J=8.3, 2.2 Hz, 1H), 6.88 (dd, J=2.3,
1.0 Hz, 1H), 2.35 (s, 3H), 2.08 (br s, 3H).
Example 19
5-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-a]py-
razin-8-ol (19)
##STR00055##
[0441] To a mixture of
3-bromo-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylpyrazin-
-2-amine (C4) (1.5 g, 3.6 mmol) in water (30 mL) was added
chloroacetaldehyde (0.57 g, 7.3 mmol), and the reaction mixture was
heated at reflux for 18 hours. After basification to pH 8 with
solid sodium bicarbonate, the mixture was concentrated in vacuo.
Purification via silica gel chromatography (Gradient: 2% to 5%
methanol in dichloromethane) provided the product as a yellow
solid. Yield: 255 mg, 0.685 mmol, 19%. LCMS m/z 372.8 (M+H).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.98 (d, J=5.8 Hz, 1H),
7.93 (d, J=2.3 Hz, 1H), 7.46-7.48 (m, 1H), 7.43 (d, J=8.3 Hz, 1H),
7.40 (br d, J=5.8 Hz, 1H), 7.31 (d, J=2.3 Hz, 1H), 7.22 (dd, J=8.3,
2.5 Hz, 1H), 7.17-7.18 (m, 1H), 7.01-7.03 (m, 1H), 2.16 (s, 3H),
2.07 (s, 3H).
Example 20
[2-(4,6-Dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)phenyl]metha-
nol (20)
##STR00056##
[0442] Step 1. Synthesis of
4-[4-bromo-3-(bromomethyl)phenoxy]furo[3,2-c]pyridine (C31).
[0443] To a solution of
4-(4-bromo-3-methylphenoxy)furo[3,2-c]pyridine (C1) (4.00 g, 13.2
mmol) in carbon tetrachloride (80 mL) was added N-bromosuccinimide
(2.34 g, 13.2 mmol) and 2,2'-azobisisobutyronitrile (AIBN, 108 mg,
0.658 mmol) at room temperature. The reaction mixture was heated to
reflux for 3 hours, cooled to room temperature, and treated with
water (150 mL). The mixture was extracted with dichloromethane
(3.times.50 mL), and the combined organic layers were dried over
sodium sulfate and concentrated in vacuo to give the crude product.
Yield: 5.04 g, 13.2 mmol, 100%. LCMS m/z 383.7 (M+H).
Step 2. Synthesis of
[2-bromo-5-(furo[3,2-c]pyridin-4-yloxy)phenyl]methanol (C32).
[0444] To a solution of
4-[4-bromo-3-(bromomethyl)phenoxy]furo[3,2-c]pyridine (C31) (5.04
g, 13.2 mmol) in N,N-dimethylformamide (60 mL) was added sodium
acetate (5.40 g, 65.8 mmol) at room temperature. The reaction
mixture was heated to 80.degree. C. for 3 hours, then cooled and
partitioned between water (150 mL) and dichloromethane (200 mL).
The aqueous layer was separated and extracted with dichloromethane
(3.times.50 mL). The combined organic layers were dried over sodium
sulfate and concentrated in vacuo; the resulting residue was
dissolved in methanol (40 mL) and treated with aqueous sodium
hydroxide solution (1 N, 13.1 mL, 13.1 mmol). After stirring for 1
hour at room temperature, the reaction mixture was partitioned
between water (100 mL) and dichloromethane (100 mL). The aqueous
layer was separated and extracted with dichloromethane (3.times.50
mL). The combined organic layers were dried over sodium sulfate and
concentrated under reduced pressure to afford the crude product.
Yield: 4.2 g, 13.1 mmol, 99%. LCMS m/z 321.7 (M+H).
Step 3. Synthesis of 2-bromo-5-(furo[3,2-c]pyridin-4-yloxy)benzyl
acetate (C33).
[2-Bromo-5-(furo[3,2-c]pyridin-4-yloxy)phenyl]methanol (C32) (230
mg, 0.718 mmol), pyridine (170 mg, 2.15 mmol), and acetyl chloride
(113 mg, 1.44 mmol) were combined in tetrahydrofuran (5 mL) at room
temperature. The reaction mixture was subjected to microwave
irradiation at 60.degree. C. for 40 minutes, then poured into
saturated aqueous sodium bicarbonate solution (30 mL). After
extraction with dichloromethane (3.times.20 mL), the combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo to afford the product. Yield: 260 mg, 0.718
mmol, 100%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (d,
J=5.8 Hz, 1H), 7.67 (d, J=2.0 Hz, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.32
(d, J=2.5 Hz, 1H), 7.23 (d, J=6.0 Hz, 1H), 7.10 (dd, J=8.6, 2.6 Hz,
1H), 6.90-6.93 (m, 1H), 5.20 (s, 2H), 2.14 (s, 3H). Step 4.
Synthesis of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)benzyl acetate (C34).
[0445] To 2-bromo-5-(furo[3,2-c]pyridin-4-yloxy)benzyl acetate
(C33) (260 mg, 0.718 mmol) in 1,4-dioxane (6 mL) were added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (237 mg,
0.933 mmol), potassium acetate (211 mg, 2.15 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (157
mg, 0.215 mmol) at room temperature. The mixture was heated to
80.degree. C. and stirred for 3 hours, then cooled and filtered.
The filtrate was concentrated in vacuo and purified by silica gel
chromatography to provide the product. Yield: 164 mg, 0.401 mmol,
56%. .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.97 (d, J=6.0 Hz,
1H), 7.85-7.89 (m, 2H), 7.39 (d, J=6.0 Hz, 1H), 7.20-7.23 (m, 1H),
7.11-7.15 (m, 1H), 6.82-6.84 (m, 1H), 5.36 (s, 2H), 2.1 (s, 3H),
1.36 (s, 12H).
Step 5. Synthesis of
2-(4,6-dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)benzyl
acetate (C35).
[0446] To a solution of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan--
2-yl)benzyl acetate (C34) (82 mg, 0.20 mmol) in 1,4-dioxane (10 mL)
were added 5-bromo-4,6-dimethylpyrimidine (41 mg, 0.22 mmol),
potassium carbonate (83 mg, 0.6 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg,
0.060 mmol) and water (5 drops) at room temperature. The reaction
mixture was degassed with nitrogen for 5 minutes, then subjected to
microwave irradiation at 120.degree. C. for 50 minutes. After
filtration of the reaction mixture, the filtrate was concentrated
in vacuo; purification was carried out by preparative thin layer
chromatography to give the product. Yield: 28 mg, 0.072 mmol, 36%.
LCMS m/z 389.9 (M+H).
Step 6. Synthesis of
[2-(4,6-dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)phenyl]meth-
anol (20).
[0447] Aqueous sodium hydroxide solution (1 N, 0.36 mL, 0.36 mmol)
was added to a solution of
2-(4,6-dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)benzyl
acetate (C35) (28 mg, 0.072 mmol) in tetrahydrofuran (2 mL), and
the reaction mixture was stirred at room temperature for 18 hours.
Saturated aqueous sodium chloride solution was added, and the
mixture was extracted with tetrahydrofuran (3.times.10 mL). The
combined organic layers were concentrated in vacuo and purified by
preparative thin layer chromatography on silica gel to give the
product. Yield: 19 mg, 0.055 mmol, 76%. LCMS m/z 347.9 (M+H).
.sup.1H NMR (400 MHz, CDCl.sub.3), characteristic peaks: .delta.
8.96 (s, 1H), 8.03 (d, J=5.5 Hz, 1H), 7.67 (br s, 1H), 7.53 (br s,
1H), 7.21-7.34 (m, 2H, assumed; partially obscured by solvent
peak), 7.10 (d, J=8.0 Hz, 1H), 6.90 (br s, 1H), 4.33 (s, 2H), 2.26
(s, 6H).
Example 21
4-[4-(4,6-Dimethylpyrimidin-5-yl)-3-(fluoromethyl)phenoxy]furo[3,2-c]pyrid-
ine (21)
##STR00057##
[0449] (Diethylamino)sulfur trifluoride (37 mg, 0.23 mmol) was
added to a solution of
[2-(4,6-dimethylpyrimidin-5-yl)-5-(furo[3,2-c]pyridin-4-yloxy)phenyl]meth-
anol (20) (20 mg, 0.058 mmol) in dichloromethane (2 mL) at
0.degree. C. The reaction mixture was stirred for 30 minutes at
40.degree. C., then concentrated in vacuo. Purification by
preparative thin layer chromatography on silica gel afforded the
product. Yield: 10 mg, 0.029 mmol, 50%. LCMS m/z 350.0 (M+H).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.01 (s, 1H), 8.07 (d,
J=5.8 Hz, 1H), 7.69 (d, J=2.3 Hz, 1H), 7.49-7.52 (m, 1H), 7.39-7.43
(m, 1H), 7.29 (dd, J=5.9, 0.6 Hz, 1H), 7.18 (br d, J=8.0 Hz, 1H),
6.94 (dd, J=2.0, 0.7 Hz, 1H), 5.04 (d, J.sub.HF=47.4 Hz, 2H), 2.28
(s, 6H).
Example 22
4-[4-(4,6-Dimethylpyrimidin-5-yl)-3-methylphenoxy]-3-methylfuro[3,2-c]pyri-
dine (22)
##STR00058##
[0450] Step 1. Synthesis of
2-(4-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(C36).
[0451] Compound C36 was prepared from
1-bromo-4-methoxy-2-methylbenzene according to the general
procedure for the synthesis of
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) in Example 1. The product was obtained as a
solid. Yield: 15 g, 60 mmol, 80%.
Step 2. Synthesis of
5-(4-methoxy-2-methylphenyl)-4,6-dimethylpyrimidine (C37).
[0452] The product was prepared from
2-(4-methoxy-2-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(C36) and 5-bromo-4,6-dimethylpyrimidine according to the general
procedure described in step 3 of Example 1. The product was
obtained as a solid. Yield: 3.5 g, 15 mmol, 75%.
Step 3. Synthesis of 4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenol
(C38).
[0453] Boron tribromide (3.8 mL, 40 mmol) was added drop-wise to a
solution of 5-(4-methoxy-2-methylphenyl)-4,6-dimethylpyrimidine
(C37) (3.0 g, 13 mmol) in dichloromethane (150 mL) at -70.degree.
C. The reaction mixture was stirred at room temperature for 16
hours, then adjusted to pH 8 with saturated aqueous sodium
bicarbonate solution. The aqueous layer was extracted with
dichloromethane (3.times.200 mL), and the combined organic layers
were dried over sodium sulfate, filtered, and concentrated in
vacuo. Silica gel chromatography (Gradient: 60% to 90% ethyl
acetate in petroleum ether) afforded the product as a yellow solid.
Yield: 1.2 g, 5.6 mmol, 43%. LCMS m/z 215.0 (M+H). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.98 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.86
(d, J=2.3 Hz, 1H), 6.80 (dd, J=8.3, 2.5 Hz, 1H), 2.24 (s, 6H), 1.96
(s, 3H).
Step 4. Synthesis of
3-bromo-4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyri-
dine (C40). 3-Bromo-4-chlorofuro[3,2-c]pyridine (C39, prepared
according to the method of Y. Miyazaki et al., Bioorg. Med. Chem.
Lett. 2007, 17, 250-254; 430 mg, 1.85 mmol),
4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenol (C38) (396 mg, 1.85
mmol) and cesium carbonate (1.21 g, 3.71 mmol) were combined in
dimethyl sulfoxide (8.0 mL) and heated at 120.degree. C. for 3
hours. The reaction mixture was filtered through Celite, the Celite
pad was rinsed thoroughly with ethyl acetate, and the combined
filtrates were washed twice with a 1:1 mixture of water and
saturated aqueous sodium chloride solution, then washed twice with
1 N aqueous sodium hydroxide solution. The organic layer was dried
over sodium sulfate, filtered, and concentrated in vacuo. Silica
gel chromatographic purification (Gradient: 50% to 90% ethyl
acetate in heptane) afforded the product as a white solid. Yield:
404 mg, 0.985 mmol, 53%. LCMS m/z 412.0 (M+H). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.98 (s, 1H), 8.07 (d, J=5.9 Hz, 1H), 7.69
(s, 1H), 7.26-7.28 (m, 1H, assumed; partially obscured by solvent
peak), 7.25 (d, J=5.9 Hz, 1H), 7.21-7.25 (m, 1H), 7.09 (br d, J=8.2
Hz, 1H), 2.28 (s, 6H), 2.05 (br s, 3H). Step 5. Synthesis of
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]-3-methylfuro[3,2-c]pyr-
idine (22).
[0454]
3-Bromo-4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2--
c]pyridine (C40) (89.0 mg, 0.217 mmol), methylboronic acid (98%, 27
mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg,
0.013 mmol) were combined in a mixture of 1,4-dioxane (2.4 mL) and
ethanol (0.78 mL), and the mixture was deoxygenated by bubbling
nitrogen through it. Aqueous sodium carbonate solution (2 M, 0.34
mL, 0.68 mmol) was added, and the reaction mixture was subjected to
microwave irradiation at 120.degree. C. for 2 hours. As starting
material was observed at this point by GCMS, additional
methylboronic acid (2 equivalents) and
tetrakis(triphenylphosphine)palladium(0) (0.06 equivalents) were
added, the reaction mixture was again purged with nitrogen, and
then subjected to microwave conditions for an additional 12 hours
at 120.degree. C. The mixture was filtered through a 0.45 .mu.m
filter, which was then rinsed with ethyl acetate; the combined
filtrates were concentrated in vacuo and purified by HPLC (Column:
Phenomenex Lux Cellulose-2, 5 .mu.m; Mobile phase A: heptane;
Mobile phase B: ethanol; Gradient: 5% to 100% B). The product was
obtained as a yellow-orange solid. Yield: 10.1 mg, 0.0292 mmol,
13%. LCMS m/z 345.9 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 8.98 (s, 1H), 8.01 (d, J=5.9 Hz, 1H), 7.42-7.43 (m, 1H),
7.23 (br d, J=2.1 Hz, 1H), 7.18 (d, J=5.9 Hz, 1H), 7.17-7.20 (m,
1H), 7.08 (d, J=8.2 Hz, 1H), 2.44 (d, J=1.3 Hz, 3H), 2.28 (s, 6H),
2.04 (s, 3H).
Example 23
4-{[4-(4,6-Dimethylpyrimidin-5-yl)-1H-indol-7-yl]oxy}furo[3,2-c]pyridine
(23)
##STR00059##
[0455] Step 1. Synthesis of
7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
(C41).
[0456] Compound C41 was prepared from 4-bromo-7-methoxy-1H-indole
according to the general procedure for the synthesis of
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) in Example 1, except that the reaction solvent
employed was 6% water in 1,4-dioxane. Purification in this case was
carried out via silica gel chromatography (Gradient: 90% to 100%
dichloromethane in heptane), to afford the product as a dark yellow
solid. Yield: 371 mg, 1.36 mmol, 62%. GCMS m/z 273 (M.sup.+).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.70 (d, J=8.0 Hz, 1H),
7.55 (d, J=3.7 Hz, 1H), 7.10 (d, J=3.5 Hz, 1H), 6.81 (d, J=8.0 Hz,
1H), 3.97 (s, 3H), 1.37 (s, 12H).
Step 2. Synthesis of
4-(4,6-dimethylpyrimidin-5-yl)-7-methoxy-1H-indole (C42).
[0457] Compound C42 was prepared from
7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole
(C41) according to the general procedure for the synthesis of
4-[4-(4,6-dimethylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridine
(1) in Example 1, to provide the product as a yellow oil. Yield: 70
mg, 0.28 mmol, 24%. GCMS m/z 253 (M.sup.+). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.99 (s, 1H), 7.54 (d, J=3.7 Hz, 1H), 6.94 (AB
quartet, J.sub.AB=8.1 Hz, .DELTA..nu..sub.AB=24.6 Hz, 2H), 6.01 (d,
J=3.7 Hz, 1H), 4.02 (s, 3H), 2.23 (s, 6H).
Step 3. Synthesis of 4-(4,6-dimethylpyrimidin-5-yl)-1H-indol-7-ol
(C43).
[0458] Compound C43 was prepared from
4-(4,6-dimethylpyrimidin-5-yl)-7-methoxy-1H-indole (C42) according
to the general procedure for the synthesis of
3-methyl-4-(2-methyl-1H-imidazo[4,5-c]pyridin-1-yl)phenol (C9) in
Example 5. The crude product was triturated with ethyl acetate to
afford a mustard-yellow solid containing some impurities. Yield: 53
mg, <0.22 mmol, <88%. LCMS m/z 240.1 (M+H). .sup.1H NMR (400
MHz, CD.sub.3OD), product peaks only: .delta. 9.29 (s, 1H), 7.29
(d, J=3.1 Hz, 1H), 6.75 (AB quartet, J.sub.AB=7.8 Hz,
.DELTA..nu..sub.AB=38.4 Hz, 2H), 6.04 (d, J=3.1 Hz, 1H), 2.49 (s,
6H).
Step 4. Synthesis of
4-{[4-(4,6-dimethylpyrimidin-5-yl)-1H-indol-7-yl]oxy}furo[3,2-c]pyridine
(23).
[0459] 4-(4,6-Dimethylpyrimidin-5-yl)-1H-indol-7-ol (C43) (50 mg,
0.21 mmol), 4-chlorofuro[3,2-c]pyridine (32 mg, 0.21 mmol) and
cesium carbonate (136 mg, 0.417 mmol) were combined in dimethyl
sulfoxide (1 mL), and the reaction mixture was heated to
120.degree. C. for 19 hours. After cooling to room temperature, the
mixture was filtered through Celite, the filter pad was rinsed with
ethyl acetate, and the combined filtrates were washed twice with a
1:1 mixture of water and saturated aqueous sodium chloride
solution, then washed twice with aqueous 1 N sodium hydroxide
solution. The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo. Purification via silica gel
chromatography (Gradient: 50% to 100% ethyl acetate in heptane)
provided the product as an off-white solid. Yield: 3 mg, 0.008
mmol, 4%. LCMS m/z 357.2 (M+H). .sup.1H NMR (500 MHz, CDCl.sub.3)
.delta. 9.01 (s, 1H), 8.67 (br s, 1H), 8.07 (d, J=5.9 Hz, 1H), 7.68
(d, J=2.2 Hz, 1H), 7.29 (br d, J=5.7 Hz, 1H), 7.22 (dd, J=2.9, 2.7
Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.86-6.87
(m, 1H), 6.12 (dd, J=2.9, 2.2 Hz, 1H), 2.31 (s, 6H).
Example 24
4-[4-(4-Ethoxy-6-methylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridine
(24)
##STR00060##
[0460] Step 1. Synthesis of potassium
trifluoro[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]borate
(C44).
[0461] A solution of potassium hydrogen difluoride (124 mg, 1.59
mmol) in water (0.50 mL) was added to a mixture of
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) (186 mg, 0.530 mmol) in methanol (0.50 mL) and
acetone (0.30 mL). After 1 hour, the volume of the reaction mixture
was reduced in vacuo, and the resulting solid was isolated via
filtration and rinsed with a small amount of methanol. The product
was obtained as a white solid. Yield: 110 mg, 0.332 mmol, 63%.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.13 (d, J=2.4 Hz, 1H),
7.97 (d, J=5.9 Hz, 1H), 7.68 (d, J=8.2 Hz, 1H), 7.47 (dd, J=5.9,
1.0 Hz, 1H), 7.04 (dd, J=2.2, 1.0 Hz, 1H), 7.03 (br d, J=2.4 Hz,
1H), 6.98 (br dd, J=8.0, 2.4 Hz, 1H), 2.47 (s, 3H).
Step 2. Synthesis of
4-[4-(4-ethoxy-6-methylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridin-
e (24).
[0462] 5-Bromo-4-chloro-6-methylpyrimidine (65 mg, 0.31 mmol),
potassium
trifluoro[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]borate
(C44) (110 mg, 0.332 mmol), potassium carbonate (130 mg, 0.941
mmol), palladium(II) acetate (0.40 mg, 0.0018 mmol) and
dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphane (1.20 mg,
0.0029 mmol) were dissolved in nitrogen-purged ethanol, and the
reaction mixture was heated to 85.degree. C. for 66 hours. After
cooling to room temperature, the reaction mixture was diluted with
methanol and ethyl acetate, filtered through Celite, and
concentrated under reduced pressure. Purification via silica gel
chromatography (Gradient: 0% to 70% ethyl acetate in heptane)
afforded the product as a colorless oil. Yield: 24 mg, 0.066 mmol,
21%. LCMS m/z 362.4 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.67 (s, 1H), 8.06 (d, J=5.9 Hz, 1H), 7.63 (d, J=2.0 Hz,
1H), 7.23 (d, J=5.9 Hz, 1H), 7.16-7.19 (m, 1H), 7.13 (dd, half of
ABX pattern, J=8.2, 2.0 Hz, 1H), 7.09 (d, half of AB pattern, J=8.2
Hz, 1H), 6.80-6.84 (m, 1H), 4.32-4.52 (m, 2H), 2.25 (s, 3H), 2.06
(s, 3H), 1.28 (t, J=7.0 Hz, 3H).
Example 25 and Example 26
(+)-5-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2--
a]pyrazine (25) and
(-)-5-[4-(Furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-
-a]pyrazine (26)
##STR00061##
[0463] Step 1. Synthesis of
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-a]p-
yrazine (C46).
[0464] To a solution of
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) (13.5 g, 38.4 mmol) in 1,4-dioxane (200 mL) and
water (10 mL) were added 5-bromo-6-methylimidazo[1,2-a]pyrazine
(C45, see A. R. Harris et al., Tetrahedron 2011, 67, 9063-9066)
(8.15 g, 38.4 mmol), potassium carbonate (15.9 g, 115 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.8 g,
3.8 mmol) at room temperature. The reaction mixture was degassed
with nitrogen for 5 minutes, then stirred for 10 hours at reflux.
The mixture was cooled to room temperature and filtered; the
filtrate was concentrated in vacuo and purified via chromatography
on silica gel (Gradient: 0% to 50% ethyl acetate in petroleum
ether) to afford the product as a yellow solid. Yield: 12.4 g, 34.8
mmol, 91%. LCMS m/z 357.0 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 9.02 (s, 1H), 8.00 (d, J=6.0 Hz, 1H), 7.93 (d, J=2.0 Hz,
1H), 7.79-7.80 (m, 1H), 7.48-7.51 (m, 1H), 7.44 (d, J=8.5 Hz, 1H),
7.41 (dd, J=6.0, 1.0 Hz, 1H), 7.36 (br d, J=2.0 Hz, 1H), 7.28 (br
dd, J=8, 2 Hz, 1H), 7.02-7.05 (m, 1H), 2.38 (s, 3H), 2.07 (s,
3H).
Step 2. Synthesis of
(+)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-
-a]pyrazine (25) and
(-)-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo[1,2-
-a]pyrazine (26)
[0465]
5-[4-(Furo[3,2-c]pyridine-4-yloxy)-2-methylphenyl]-6-methylimidazo[-
1,2-a]pyrazine (C46) was separated into its atropenantiomers using
supercritical fluid chromatography (Column: Chiralpak AD-H, 5
.mu.m; Eluent: 3:1 carbon dioxide/methanol). Example 25 [designated
the (+)-atropenantiomer according to its observed rotation data]
was the first-eluting isomer, followed by Example 26. Example 26
[designated the (-)-atropenantiomer according to its observed
rotation data] was examined by vibrational circular dichroism (VCD)
spectroscopy [Chiral/R.TM. VCD spectrometer (BioTools, Inc.)], and
on the basis of this work, the absolute configuration of Example 26
was assigned as (R).
Example 25
[0466] LCMS m/z 357.1 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.10 (s, 1H), 8.08 (d, J=5.8 Hz, 1H), 7.73 (d, J=1.0 Hz,
1H), 7.70 (d, J=2.2 Hz, 1H), 7.31-7.34 (m, 2H), 7.26-7.30 (m, 2H,
assumed; partially obscured by solvent peak), 7.16-7.18 (m, 1H),
6.95 (dd, J=2.2, 1.0 Hz, 1H), 2.38 (s, 3H), 2.07 (br s, 3H).
Example 26
[0467] LCMS m/z 357.1 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 9.10 (s, 1H), 8.09 (d, J=5.8 Hz, 1H), 7.73 (d, J=1.0 Hz,
1H), 7.70 (d, J=2.3 Hz, 1H), 7.31-7.35 (m, 2H), 7.26-7.31 (m, 2H,
assumed; partially obscured by solvent peak), 7.16-7.18 (m, 1H),
6.95 (dd, J=2.2, 0.9 Hz, 1H), 2.38 (s, 3H), 2.07 (br s, 3H).
Example 27
5-[2-Fluoro-4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-4,6-dimethylpyridazin-3(-
2H)-one (27)
##STR00062##
[0468] Step 1. Synthesis of 4-hydroxy-3,5-dimethylfuran-2(5H)-one
(C47).
[0469] Methylation of ethyl 3-oxopentanoate (according to the
method of D. Kalaitzakis et al., Tetrahedron: Asymmetry 2007, 18,
2418-2426) afforded ethyl 2-methyl-3-oxopentanoate; subsequent
treatment with one equivalent of bromine in chloroform provided
ethyl 4-bromo-2-methyl-3-oxopentanoate. This crude material (139 g,
586 mmol) was slowly added to a 0.degree. C. solution of potassium
hydroxide (98.7 g, 1.76 mol) in water (700 mL); the internal
reaction temperature rose to 30.degree. C. during the addition. The
reaction mixture was subjected to vigorous stirring for 4 hours in
an ice bath, at which point it was acidified via slow addition of
concentrated hydrochloric acid. After extraction with ethyl
acetate, the aqueous layer was saturated with solid sodium chloride
and extracted three additional times with ethyl acetate. The
combined organic layers were washed with saturated aqueous sodium
chloride solution, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure to afford a mixture of oil and
solid (81.3 g). This material was suspended in chloroform (200 mL);
solids were filtered, then washed with chloroform (2.times.50 mL).
The combined filtrates were concentrated in vacuo and treated with
a 3:1 mixture of heptane and diethyl ether (300 mL). The mixture
was vigorously swirled until some of the oil began to solidify,
then concentrated under reduced pressure to afford an oily solid
(60.2 g). After addition of a 3:1 mixture of heptane and diethyl
ether (300 mL) and vigorous stirring for 10 minutes, filtration
afforded the product as an off-white solid. Yield: 28.0 g, 219
mmol, 37%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 4.84 (br q,
J=6.8 Hz, 1H), 1.74 (br s, 3H), 1.50 (d, J=6.8 Hz, 3H).
Step 2. Synthesis of 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl
trifluoromethanesulfonate (C48).
[0470] Trifluoromethanesulfonic anhydride (23.7 mL, 140 mmol) was
added portion-wise to a solution of
4-hydroxy-3,5-dimethylfuran-2(5H)-one (C47) (15.0 g, 117 mmol) and
N,N-diisopropylethylamine (99%, 24.8 mL, 140 mmol) in
dichloromethane (500 mL) at -20.degree. C., at a rate that
maintained the internal reaction temperature below -10.degree. C.
The reaction mixture was stirred at -20.degree. C., then allowed to
warm gradually to 0.degree. C. over 5 hours. The reaction mixture
was passed through a plug of silica gel, dried over magnesium
sulfate, and concentrated in vacuo. The residue was suspended in
diethyl ether and filtered; the filtrate was concentrated under
reduced pressure. Purification using silica gel chromatography
(Gradient: 0% to 17% ethyl acetate in heptane) afforded the product
as a pale yellow oil. Yield: 21.06 g, 80.94 mmol, 69%. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 5.09-5.16 (m, 1H), 1.94-1.96 (m, 3H),
1.56 (d, J=6.6 Hz, 3H).
Synthesis of
4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C49)
[0471] Compound C49 was synthesized using the method described for
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) in Example 1, except that 4-bromo-3-fluorophenol
was used in place of 4-bromo-3-methylphenol. The product was
obtained as an off-white solid. Yield: 22.5 g, 63.3 mmol, 39% over
2 steps. LCMS m/z 356.1 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.04 (d, J=5.9 Hz, 1H), 7.80 (dd, J=8.2, 6.9 Hz, 1H), 7.65
(d, J=2.3 Hz, 1H), 7.25 (dd, J=5.8, 0.9 Hz, 1H), 7.02 (dd, J=8.3,
2.1 Hz, 1H), 6.94 (dd, J=10.2, 2.1 Hz, 1H), 6.85 (dd, J=2.3, 1.0
Hz, 1H), 1.37 (s, 12H).
Step 3. Synthesis of
4-[2-fluoro-4-(furo[3,2-c]pyridine-4-yloxy)phenyl]-3,5-dimethylfuran-2(5H-
)-one (C50).
[0472] A solution of
4-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C49) (3.20 g, 9.01 mmol) and
2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate
(C48) (2.46 g, 9.45 mmol) in 1,4-dioxane (80 mL) was purged with
nitrogen for 5 minutes. A mixture of tetrabutylammonium chloride
(99%, 127 mg, 0.452 mmol), tricyclohexylphosphine (99%, 128 mg,
0.452 mmol) and palladium(II) acetate (101 mg, 0.450 mmol) was
added, followed by an aqueous solution of potassium carbonate (3 M,
9.0 mL, 27.0 mmol), and the reaction mixture was heated at
50.degree. C. for 18 hours. After cooling to room temperature, the
reaction mixture was diluted with ethyl acetate, washed three times
with water, washed once with saturated aqueous sodium chloride
solution, and dried over magnesium sulfate. Filtration and removal
of solvent under reduced pressure was followed by chromatographic
purification on silica gel (Gradient: 15% to 50% ethyl acetate in
heptane), affording the product as a tan oil that slowly solidified
upon standing. Yield: 1.55 g, 4.57 mmol, 51%. LCMS m/z 340.3 (M+H).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.06 (d, J=5.9 Hz, 1H),
7.70 (d, J=2.2 Hz, 1H), 7.33-7.38 (m, 1H), 7.31 (dd, J=5.9, 1.0 Hz,
1H), 7.13-7.20 (m, 2H), 6.94 (dd, J=2.2, 0.9 Hz, 1H), 5.43-5.51 (m,
1H), 1.99-2.01 (m, 3H), 1.38 (d, J=6.6 Hz, 3H).
Step 4. Synthesis of
4-[2-fluoro-4-(furo[3,2-c]pyridine-4-yloxy)phenyl]-5-hydroxy-3,5-dimethyl-
furan-2(5H)-one (C51).
[0473] A solution of
4-[2-fluoro-4-(furo[3,2-c]pyridine-4-yloxy)phenyl]-3,5-dimethylfuran-2(5H-
)-one (C50) (5.0 g, 15 mmol) in tetrahydrofuran (200 mL) and
N,N-dimethylformamide (100 mL) was treated with
1,8-diazabicyclo[5.4.0]undec-7-ene (6.61 mL, 44.2 mmol) and purged
with oxygen for 10 minutes. A slight positive pressure of oxygen
was introduced into the flask and the reaction mixture was heated
at 50.degree. C. with vigorous stirring for 5 hours. Upon heating,
a slight additional pressure build-up was noted within the flask
via examination of the rubber septum. LCMS analysis indicated
approximately 6% of the starting material remaining; the flask was
cooled to room temperature, recharged with oxygen, and heated at
50.degree. C. for an additional 18 hours. The reaction was cooled
to room temperature, diluted with ethyl acetate (300 mL) and washed
sequentially with aqueous hydrochloric acid (0.25 M, 175 mL) and
water (150 mL). The pH of the combined aqueous layers was adjusted
from pH 3 to roughly pH 4-5, and the aqueous layer was extracted
with ethyl acetate (300 mL). The combined organic layers were
washed with saturated aqueous sodium chloride solution, dried over
magnesium sulfate, filtered, and concentrated in vacuo.
Purification via silica gel chromatography (Gradient: 0% to 40%
ethyl acetate in heptane) afforded the product as a white foam.
Yield: 4.20 g, 11.8 mmol, 79%. LCMS m/z 356.4 (M+H). .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.07 (d, J=5.8 Hz, 1H), 7.66-7.71 (m,
2H), 7.31 (br d, J=5.8 Hz, 1H), 7.11-7.17 (m, 2H), 6.93-6.94 (m,
1H), 3.95 (br s, 1H), 1.86-1.88 (m, 3H), 1.64 (s, 3H).
Step 5. Synthesis of
5-[2-fluoro-4-(furo[3,2-c]pyridine-4-yloxy)phenyl]-4,6-dimethylpyridazin--
3(2H)-one (27).
[0474] Anhydrous hydrazine (98.5%, 1.88 mL, 59.0 mmol) was added to
a solution of
4-[2-fluoro-4-(furo[3,2-c]pyridine-4-yloxy)phenyl]-5-hydroxy-3,5-dimethyl-
furan-2(5H)-one (C51) (4.20 g, 11.8 mmol) in 1-butanol (75 mL), and
the reaction mixture was heated at 110.degree. C. for 2 hours.
After cooling to room temperature and stirring at this temperature
for 18 hours, the reaction mixture was stored in a refrigerator for
66 hours. The resulting suspension was filtered to afford a gray
solid, which was dissolved in hot ethanol (150-175 mL) and filtered
through a nylon syringe filter. The filtrate was concentrated in
vacuo to provide the product as a white solid. Yield: 1.30 g, 3.70
mmol, 31%. LCMS m/z 352.2 (M+H). .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 12.89 (br s, 1H), 8.17 (d, J=2.2 Hz, 1H),
8.06 (d, J=5.8 Hz, 1H), 7.54 (br d, J=5.8 Hz, 1H), 7.38-7.46 (m,
2H), 7.25 (br dd, J=8.4, 2.2 Hz, 1H), 7.12-7.14 (m, 1H), 1.99 (s,
3H), 1.85 (s, 3H).
Example 28
5-[4-(Furo[3,2-c]pyridin-4-yloxy)phenyl]-4,6-dimethylpyridazin-3(2H)-one
(28)
##STR00063##
[0475] Step 1. Synthesis of
4-[4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-3,5-dimethylfuran-2(5H)-one
(C53).
[0476] The product was prepared as an off-white solid, via reaction
of 2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl
trifluoromethanesulfonate (C48) with
4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3,2-c-
]pyridine (C52) [this may be prepared in a similar manner to
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) in Example 1] as described for synthesis of
4-[2-fluoro-4-(furo[3,2-c]pyridine-4-yloxy)phenyl]-3,5-dimethylfuran-2(5H-
)-one (C50) in Example 27. Yield: 760 mg, 2.36 mmol, 80%. LCMS m/z
322.2 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.04 (d,
J=5.9 Hz, 1H), 7.69 (d, J=2.2 Hz, 1H), 7.40 (br AB quartet,
J.sub.AB=8.8 Hz, .DELTA..nu..sub.AB=27.3 Hz, 4H), 7.26-7.29 (m, 1H,
assumed; partially obscured by solvent peak), 6.93 (dd, J=2.2, 1.0
Hz, 1H), 5.43 (qq, J=6.7, 1.8 Hz, 1H), 2.09 (d, J=1.8 Hz, 3H), 1.43
(d, J=6.6 Hz, 3H).
Step 2. Synthesis of
5-[4-(furo[3,2-c]pyridine-4-yloxy)phenyl]-4,6-dimethylpyridazin-3(2H)-one
(28).
[0477]
4-[4-(Furo[3,2-c]pyridin-4-yloxy)phenyl]-3,5-dimethylfuran-2(5H)-on-
e (C53) was converted to the product in a similar manner to that
described for synthesis of
5-[2-fluoro-4-(furo[3,2-c]pyridine-4-yloxy)phenyl]-4,6-dimethylpyridazin--
3(2H)-one (27) in Example 27. The crude product was subjected to
silica gel chromatography (Eluent: 40% ethyl acetate in
dichloromethane), then recrystallized from ethanol to afford the
title product as a white solid. Yield: 270 mg, 0.810 mmol, 35% over
2 steps. LCMS m/z 334.0 (M+H). .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.79 (br s, 1H), 8.15 (d, J=2.4 Hz, 1H), 8.03 (d, J=5.9
Hz, 1H), 7.50 (dd, J=5.9, 1.0 Hz, 1H), 7.31-7.38 (m, 4H), 7.09 (dd,
J=2.2, 1.0 Hz, 1H), 1.97 (s, 3H), 1.83 (s, 3H).
Example 29
4-[3,5-Dimethyl-4-(3-methylpyridin-4-yl)phenoxy]furo[3,2-c]pyridine
(29)
##STR00064##
[0479] The product was prepared from
4-(4-bromo-3,5-dimethylphenoxy)furo[3,2-c]pyridine [synthesized via
reaction of 4-bromo-3,5-dimethylphenol with
4-chlorofuro[3,2-c]pyridine] and (3-methylpyridin-4-yl)boronic
acid, according to the general procedure for the synthesis of
5-(2-chloro-4-methoxyphenyl)-4,6-dimethylpyrimidine (C64) in
Preparation P7. LCMS m/z 331.1 (M+H). .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.57 (br s, 1H), 8.49 (br d, J=4.8 Hz, 1H),
8.13 (d, J=2.2 Hz, 1H), 8.02 (d, J=5.9 Hz, 1H), 7.47 (dd, J=5.8,
1.0 Hz, 1H), 7.10 (br d, J=4.8 Hz, 1H), 7.05 (dd, J=2.2, 0.9 Hz,
1H), 7.02-7.04 (m, 2H), 1.97 (s, 3H), 1.89 (s, 6H).
Example 30
4-{[4-(Imidazo[1,2-a]pyridin-5-yl)naphthalen-1-yl]oxy}furo[3,2-c]pyridine,
trifluoroacetate salt (30)
##STR00065##
[0481] Potassium hydroxide (112 mg, 1.99 mmol) and
1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6; 13.3 mg, 0.050
mmol) were added to a solution of
4-(imidazo[1,2-a]pyridin-5-yl)naphthalen-1-ol (C54) [prepared via
Suzuki reaction between (4-methoxynaphthalen-1-yl)boronic acid and
5-bromoimidazo[1,2-a]pyridine as described in Example 8, followed
by boron tribromide-mediated methyl ether cleavage] (85 mg, 0.25
mmol) and 4-chlorofuro[3,2-c]pyridine (57.3 mg, 0.373 mmol) in
xylene (3 mL), and the reaction mixture was heated to 140.degree.
C. for 24 hours. Solvent was removed in vacuo, and the crude
material was combined with crude product from a similar reaction
carried out on 30 mg of C54. After the reaction was partitioned
between ethyl acetate (25 mL) and water (25 mL), the aqueous layer
was extracted with ethyl acetate (3.times.30 mL), and the combined
organic layers were dried over sodium sulfate. Purification was
first effected via silica gel chromatography (Eluent: ethyl
acetate), followed by HPLC (Column: XBridge C18, 5 .mu.m, Mobile
phase A: water with trifluoroacetic acid modifier; Mobile phase B:
acetonitrile with trifluoroacetic acid modifier; Gradient: 30% to
50% B). The product was obtained as a colorless gum. Yield: 20 mg,
0.041 mmol, 12%. LCMS m/z 378.1 (M+H). .sup.1H NMR (500 MHz,
CD.sub.3OD) .delta. 8.17 (dd, half of ABX pattern, J=9.0, 7.1 Hz,
1H), 8.15 (br d, J=8.0 Hz, 1H), 8.10 (br d, half of AB pattern, J=9
Hz, 1H), 7.99-8.01 (m, 2H), 7.89 (d, J=5.9 Hz, 1H), 7.83 (d, J=7.8
Hz, 1H), 7.70 (br d, J=2 Hz, 1H), 7.67 (dd, J=7.1, 1.0 Hz, 1H),
7.61 (ddd, J=8.3, 6.8, 1.2 Hz, 1H), 7.56 (ddd, J=8.3, 6.8, 1.2 Hz,
1H), 7.54 (d, J=7.6 Hz, 1H), 7.41-7.44 (m, 2H), 7.20 (dd, J=2.2,
1.0 Hz, 1H).
PREPARATIONS
[0482] Preparations P1-P15 describe preparations of some starting
materials or intermediates used for preparation of certain
compounds of the invention.
Preparation P1
5-(Furo[3,2-c]pyridin-4-yloxy)-2-(3-methylpyrazin-2-yl)phenol
(P1)
##STR00066##
[0484] Boron tribromide (1.9 g, 7.6 mmol) was slowly added to a
solution of
4-[3-methoxy-4-(3-methylpyrazin-2-yl)phenoxy]furo[3,2-c]pyridine
(6) (2.3 g, 6.9 mmol) in dichloromethane (100 mL) at 0.degree. C.
The reaction mixture was stirred at 0.degree. C. for 1 hour, then
quenched with water, stirred and filtered. The filtrate was
adjusted to neutral pH with saturated aqueous sodium bicarbonate
solution and extracted with dichloromethane (3.times.50 mL). The
combined organic layers were dried, filtered, and concentrated in
vacuo. Silica gel chromatography (Gradient: 0% to 2% methanol in
dichloromethane) afforded the product. Yield: 1.2 g, 3.8 mmol, 55%.
LCMS m/z 320.1 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
11.83 (s, 1H), 8.48 (d, J=2.5 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H), 8.08
(d, J=5.8 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.66 (d, J=2.3 Hz, 1H),
7.25-7.28 (m, 1H, assumed; partially obscured by solvent peak),
6.95 (d, J=2.5 Hz, 1H), 6.90 (dd, J=2.3, 1.0 Hz, 1H), 6.86 (dd,
J=8.8, 2.5 Hz, 1H), 2.87 (s, 3H).
Preparation P2
4-(6-Methylimidazo[1,2-a]pyridin-5-yl)phenol, hydrobromide salt
(P2)
##STR00067##
[0485] Step 1. Synthesis of
5-(4-methoxyphenyl)-6-methylimidazo[1,2-a]pyridine (C56).
[0486] The product was prepared from C55 (a 1:1 mixture of
5-bromo-6-methylimidazo[1,2-a]pyridine and
5-chloro-6-methylimidazo[1,2-a]pyridine, see A. R. Harris et al.,
Tetrahedron 2011, 67, 9063-9066) (210 mg, 1.00 mmol) and
(4-methoxyphenyl)boronic acid (116 mg, 0.765 mmol) using the method
of Example 6. Silica gel chromatography (Gradient: 0% to 40% [20%
methanol in dichloromethane] in dichloromethane) afforded the
product. Yield: 159 mg, 0.667 mmol, 87%. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 7.55 (d, J=9.3 Hz, 1H), 7.50 (s, 1H), 7.30 (d,
J=8.5 Hz, 2H), 7.14 (d, J=9.3 Hz, 1H), 7.12 (s, 1H), 7.07 (d, J=8.5
Hz, 2H), 3.89 (s, 3H), 2.13 (s, 3H).
Step 2. Synthesis of 4-(6-methylimidazo[1,2-a]pyridin-5-yl)phenol,
hydrobromide salt (P2).
[0487] The product was prepared from
5-(4-methoxyphenyl)-6-methylimidazo[1,2-a]pyridine (C56) (159 mg,
0.667 mmol) as described for the synthesis of
6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (P8) in
Preparation P8. In this case, after the second addition of
methanol, the mixture was concentrated in vacuo, then azeotroped
with heptane to provide the product as a brown solid. Yield: 193
mg, 0.63 mmol, 95%. LCMS m/z 225.0 (M+H). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.97 (d, J=9.2 Hz, 1H), 7.91 (d, J=2.2 Hz, 1H),
7.83 (br d, J=9.4 Hz, 1H), 7.54 (dd, J=2.2, 0.7 Hz, 1H), 7.36 (br
d, J=8.6 Hz, 2H), 7.08 (br d, J=8.8 Hz, 2H), 2.31 (s, 3H).
Preparation P3
7-Chloro-6-methyl[1,2,4]triazolo[1,5-a]pyrimidine (P3)
##STR00068##
[0488] Step 1. Synthesis of methyl 3-hydroxy-2-methylprop-2-enoate
(C57).
[0489] Methyl propanoate (44 g, 0.50 mol) was reacted with methyl
formate (55.5 g, 0.75 mol) according to the method of F. Kido et
al., Tetrahedron 1987, 43, 5467-5474. Purification by distillation
(70-104.degree. C.) gave compound C57 as a colorless liquid. Yield:
23 g, 0.20 mol, 40%. .sup.1H NMR (400 MHz, CDCl.sub.3), roughly 1:1
mixture of aldehyde and enol forms: .delta. 11.24 (d, J=11.5 Hz,
1H), 9.78 (s, 1H), 6.99 (d, J=10.5 Hz, 1H), 3.79 (s, 6H), 3.41 (q,
J=7 Hz, 1H), 1.68 (s, 3H), 1.36 (d, J=7 Hz, 3H).
Step 2. Synthesis of 6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-ol
(C58).
[0490] A solution of methyl 3-hydroxy-2-methylprop-2-enoate (C57)
(95 g, 0.82 mol) and 1H-1,2,4-triazol-5-amine (100 g, 1.19 mol) in
a mixture of ethanol (300 mL) and acetic acid (150 mL) was heated
to reflux for 12 hours. The reaction mixture was allowed to cool to
ambient temperature and solids were filtered to afford the product
as a white solid. Yield: 41 g, 27 mmol, 33%. .sup.1H NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.18 (s, 1H), 7.91 (s, 1H), 2.00 (s, 3H).
Step 3. Synthesis of
7-chloro-6-methyl[1,2,4]triazolo[1,5-a]pyrimidine (P3).
[0491] To a stirred suspension of
6-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-ol (C58) (105 g, 0.699
mol) in phosphorus oxychloride (500 mL) at room temperature was
added drop-wise N,N-diisopropylethylamine (100 mL) and the reaction
mixture was heated to reflux for 110 minutes. After the mixture
cooled to ambient temperature, it was concentrated to near dryness
in vacuo, poured into ice water, and adjusted to pH 9 by addition
of potassium carbonate. The resulting solution was extracted three
times with dichloromethane (800 mL) and the combined organic phases
were washed with saturated aqueous sodium chloride solution, dried
over sodium sulfate, and concentrated under reduced pressure.
Silica gel chromatography (Gradient: 17% to 33% ethyl acetate in
petroleum ether) provided the product as a white solid. Yield: 55
g, 330 mmol, 47%. LCMS m/z 169.2 (M+H). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.70 (s, 1H), 8.52 (s, 1H), 2.54 (s, 3H).
Preparation P4
3-Bromo-2-methylimidazo[1,2-a]pyrazine (P4)
##STR00069##
[0492] Step 1. Synthesis of 2-methylimidazo[1,2-a]pyrazine (C59).
Pyrazin-2-amine (1 g, 10 mmol) was dissolved in ethanol (15 mL) and
1-chloropropan-2-one (1.2 mL, 14 mmol) was added. The resulting
solution was stirred at reflux for 2 hours, cooled to room
temperature, and concentrated in vacuo. Saturated aqueous sodium
bicarbonate solution (50 mL) was added, and the mixture was
extracted three times with chloroform (20 mL); the combined organic
layers were dried over sodium sulfate, filtered, and concentrated.
Silica gel chromatography (Gradient: 0% to 50% methanol in ethyl
acetate) gave C59 as an orange solid. Yield: 122 mg, 0.916 mmol,
9%. LCMS m/z 133.9 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.98 (br s, 1H), 7.99 (dd, J=4.6, 1.5 Hz, 1H), 7.83 (br d, J=4.5
Hz, 1H), 7.46 (br s, 1H), 2.53 (s, 3H). Step 2. Synthesis of
3-bromo-2-methylimidazo[1,2-a]pyrazine (P4).
[0493] 2-Methylimidazo[1,2-a]pyrazine (C59) (122 mg, 0.916 mmol)
was dissolved in chloroform (2 mL) and treated with
N-bromosuccinimide (189 mg, 1.1 mmol). The resulting mixture was
stirred at ambient temperature for 1.5 hours and then concentrated
in vacuo. Silica gel chromatography (Gradient: 33% to 100% ethyl
acetate in heptane) afforded the product, still containing some
succinimide. This material was dissolved in dichloromethane (25 mL)
and washed with aqueous sodium hydroxide solution (0.5 M,
3.times.10 mL). The organic layer was dried over sodium sulfate,
filtered, and concentrated in vacuo to afford the product as an
off-white solid. Yield: 125 mg, 0.59 mmol, 64%. LCMS m/z 213.9
(M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.93 (s, 1H), 7.96
(br s, 2H), 2.51 (s, 3H).
Preparation P5
4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)phen-
oxy]furo[3,2-c]pyridine (P5)
##STR00070##
[0495] 4-[4-Bromo-3-(trifluoromethyl)phenoxy]furo[3,2-c]pyridine
(3.58 g, 10.0 mmol) was reacted with
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (99%,
3.33 g, 13.0 mmol), potassium acetate (95%, 4.13 g, 40.0 mmol) and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (732
mg, 1.00 mmol) in analogous fashion to the synthesis of
4-[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine (C2) in Example 1. Silica gel chromatography
(Gradient: 0% to 20% ethyl acetate in heptane) provided the product
as a white solid. Yield: 2.035 g, 5.022 mmol, 50%. LCMS m/z 406.2
(M+H). .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.00 (d, J=5.9 Hz,
1H), 7.84 (br d, J=8.0 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.55 (br d,
J=2.2 Hz, 1H), 7.39 (br dd, J=8.2, 2.3 Hz, 1H), 7.25 (dd, J=5.9,
1.0 Hz, 1H), 6.87 (dd, J=2.2, 1.0 Hz, 1H), 1.38 (s, 12H).
Preparation P6
2,5-Dimethyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenol (P6)
##STR00071##
[0496] Step 1. Synthesis of
6-(4-methoxy-2,5-dimethylphenyl)-5-methylpyrazin-2-amine (C61).
[0497] 6-Bromo-5-methylpyrazin-2-amine (C60, see A. R. Harris et
al., Tetrahedron 2011, 67, 9063-9066; 111 mg, 0.590 mmol),
(4-methoxy-2,5-dimethylphenyl)boronic acid (127 mg, 0.708 mmol) and
tetrakis(triphenylphosphine)palladium(0) (95%, 40 mg, 0.033 mmol)
were combined in a pressure tube and dissolved in 1,4-dioxane (2
mL) and water (0.6 mL). An aqueous solution of sodium carbonate
(2.0 M, 0.885 mL, 1.77 mmol) was added, and the reaction was
conducted in analogous fashion to the synthesis of
6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methylpyrazin-2-amine
(C3) in Example 2. Silica gel chromatography (Gradient: 0% to 75%
ethyl acetate in heptane) afforded the product. Yield: 116 mg,
0.477 mmol, 81%. LCMS m/z 244.1 (M+H). .sup.1H NMR (400 MHz,
CD.sub.3CN) .delta. 7.83 (s, 1H), 6.90 (s, 1H), 6.82 (s, 1H), 4.93
(br s, 2H), 3.83 (s, 3H), 2.15 (br s, 3H), 2.11 (s, 3H), 2.05 (br
s, 3H).
Step 2. Synthesis of
5-(4-methoxy-2,5-dimethylphenyl)-6-methylimidazo[1,2-a]pyrazine
(C62).
[0498] Chloroacetaldehyde (55% solution in water, 0.28 mL, 2.38
mmol) was added to a mixture of
6-(4-methoxy-2,5-dimethylphenyl)-5-methylpyrazin-2-amine (C61) (116
mg, 0.477 mmol) in water (3.6 mL). The reaction mixture was heated
to 115.degree. C. for 2 hours in a microwave reactor and then
cooled to room temperature, whereupon the solvent was removed in
vacuo. Silica gel chromatography (Gradient: 0% to 10% methanol in
dichloromethane) afforded the product. Yield: 115 mg, 0.43 mmol,
90%. LCMS m/z 268.1 (M+H). .sup.1H NMR (400 MHz, CD.sub.3CN)
.delta. 9.45 (s, 1H), 7.99 (br s, 1H), 7.37 (br s, 1H), 7.08 (s,
1H), 7.04 (s, 1H), 3.91 (s, 3H), 2.41 (s, 3H), 2.20 (br s, 3H),
2.03 (br s, 3H).
Step 3. Synthesis of
2,5-dimethyl-4-(6-methylimidazo[1,2-a]pyrazin-5-yl)phenol (P6).
[0499]
5-(4-Methoxy-2,5-dimethylphenyl)-6-methylimidazo[1,2-a]pyrazine
(C62) (115 mg, 0.43 mmol) was dissolved in dichloromethane (5 mL)
and the reaction mixture was cooled to -78.degree. C. A solution of
boron tribromide (1 M in dichloromethane, 2.58 mL, 2.58 mmol) was
added slowly drop-wise, and the resulting mixture was stirred for
15 minutes; the cooling bath was then removed and the reaction
mixture was stirred at room temperature for 18 hours. Methanol (5
mL) was added and the resulting mixture was heated to a gentle
reflux for 30 minutes. The solvent was removed in vacuo and the
resulting yellow residue was triturated three times with ethyl
acetate (10 mL) to afford the product. Yield: 104 mg, 0.410 mmol,
95%. LCMS m/z 254.1 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 9.40 (s, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.60-7.62 (m, 1H),
7.11 (s, 1H), 6.91 (s, 1H), 2.46 (s, 3H), 2.23 (br s, 3H), 1.98 (br
s, 3H).
Preparation P7
3-Chloro-4-(4,6-dimethylpyrimidin-5-yl)phenol (P7)
##STR00072##
[0500] Step 1. Synthesis of
5-(2-chloro-4-methoxyphenyl)-4,6-dimethylpyrimidine (C64).
[0501]
4,6-Dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimid-
ine (C63, prepared from 5-bromo-4,6-dimethylpyrimidine using the
method of Example 1, step 2) (750 mg, 3.2 mmol) and
1-bromo-2-chloro-4-methoxybenzene (1.46 g, 6.41 mmol) were
dissolved in tetrahydrofuran (10 mL), and aqueous potassium
phosphate solution (0.5 M, 12.8 mL) was added. Nitrogen was bubbled
through the reaction mixture for 10 minutes.
[2'-(Azanidyl-.kappa.N)biphenyl-2-yl-.kappa.C.sub.2](Chloro)[dicyclohexyl-
(2',6'-dimethoxybiphenyl-2-yl)-.lamda..sup.5-phosphanyl]palladium
(116 mg, 0.161 mmol) was added, and then nitrogen bubbling was
continued for a few minutes. The reaction vessel was sealed and
stirred at 70.degree. C. for 18 hours. The reaction mixture was
cooled to room temperature, diluted with ethyl acetate, washed with
water and with saturated aqueous sodium chloride solution, dried
over magnesium sulfate, filtered, and concentrated under reduced
pressure. The crude material was purified by chromatography on
silica gel (Eluent: 25% ethyl acetate in heptane) to afford the
product as a light yellow oil, which solidified on standing. Yield:
320 mg, 1.29 mmol, 40%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
8.93 (s, 1H), 7.05 (d, J=2.5 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 6.90
(dd, J=8.6, 2.5 Hz, 1H), 3.84 (s, 3H), 2.21 (s, 6H).
Step 2. Synthesis of 3-chloro-4-(4,6-dimethylpyrimidin-5-yl)phenol
(P7).
[0502] 5-(2-Chloro-4-methoxyphenyl)-4,6-dimethylpyrimidine (C64)
(310 mg, 1.25 mmol) was converted to the product according to the
general procedure for the synthesis of
5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylpyrimidin-4-ol
(C30) in Example 18. The product was obtained as an orange solid.
Yield: 280 mg, 1.19 mmol, 95%. .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.82 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.98 (d, J=2.3 Hz,
1H), 6.85 (dd, J=8.4, 2.3 Hz, 1H), 2.20 (s, 6H).
Preparation P8
6-(4-Hydroxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (P8)
##STR00073##
[0503] Step 1. Synthesis of
1-(4-methoxy-2-methylphenyl)propan-1-one (C65).
[0504] A mixture of 1-methoxy-3-methylbenzene (85.5 g, 0.700 mol)
and aluminum chloride (138.6 g, 1.04 mol) in dichloromethane (2.5
L) was cooled in an ice bath; propanoyl chloride (97.1 g, 1.05 mol)
was added drop-wise over a period of 30 minutes. The ice bath was
removed, and the resulting mixture was stirred at room temperature
for 20 minutes, then re-cooled in an ice bath. Water (150 mL) was
added drop-wise followed by addition of more water (500 mL). The
organic phase was separated and concentrated in vacuo. Silica gel
chromatography (3% ethyl acetate in petroleum ether) gave the
product as a colorless oil, which became a white solid upon
standing at room temperature. By NMR, the product was contaminated
with a small amount of another isomer. Yield: 100 g, 0.56 mol, 80%.
.sup.1H NMR (400 MHz, CDCl.sub.3), product peaks: .delta. 7.73 (d,
J=9.5 Hz, 1H), 6.73-6.78 (m, 2H), 3.84 (s, 3H), 2.91 (q, J=7.3 Hz,
2H), 2.55 (s, 3H), 1.19 (t, J=7.3 Hz, 3H).
Step 2. Synthesis of
2-(hydroxyimino)-1-(4-methoxy-2-methylphenyl)propan-1-one
(C66).
[0505] To a mixture of 1-(4-methoxy-2-methylphenyl)propan-1-one
(C65) (100 g, 0.56 mol) in tetrahydrofuran (2.5 L) was slowly added
isoamyl nitrite (131 g, 1.12 mol) and hydrogen chloride (4 N in
1,4-dioxane, 200 mL). The mixture was stirred at room temperature
for 24 hours, then concentrated in vacuo. Silica gel chromatography
(Gradient: 3% to 10% ethyl acetate in petroleum ether) gave crude
product (120 g), which was further purified by slurrying in a
mixture of petroleum ether (1 L) and ethyl acetate (100 mL) at room
temperature for 30 minutes. The mixture was filtered to yield the
product as a solid. Yield: 75 g, 0.36 mol, 64%. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.98-8.12 (br m, 1H), 7.46 (d, J=8.3 Hz,
1H), 6.72-6.79 (m, 2H), 3.84 (s, 3H), 2.40 (s, 3H), 2.16 (s,
3H).
Step 3. Synthesis of 1-(4-methoxy-2-methylphenyl)propane-1,2-dione
(C67).
[0506] To a mixture of
2-(hydroxyimino)-1-(4-methoxy-2-methylphenyl)propan-1-one (C66)
(37.5 g, 181 mmol) in water (720 mL) was slowly added formaldehyde
solution (450 mL) and concentrated hydrochloric acid (270 mL). A
second batch of the reaction was prepared in the same manner. Both
mixtures were stirred at room temperature for 18 hours. The two
batches were combined and extracted with ethyl acetate (3.times.2
L); the combined organic extracts were concentrated. Silica gel
chromatography (5% ethyl acetate in petroleum ether) gave the
product as a yellow oil. Yield: 60 g, 310 mmol, 86%. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.66 (d, J=8.5 Hz, 1H), 6.75-6.83 (m,
2H), 3.87 (s, 3H), 2.60 (s, 3H), 2.51 (s, 3H).
Step 4. Synthesis of
6-(4-methoxy-2-methylphenyl)-5-methylpyrazin-2(1H)-one (C68).
[0507] 1-(4-Methoxy-2-methylphenyl)propane-1,2-dione (C67) (4.0 g,
21 mmol) and glycinamide acetate (2.79 g, 20.8 mmol) were dissolved
in methanol (40 mL) and cooled to -10.degree. C. Aqueous sodium
hydroxide solution (12 N, 3.5 mL, 42 mmol) was added, and the
resulting mixture was slowly warmed to room temperature. After
stirring for 3 days, the reaction mixture was concentrated in
vacuo. The residue was diluted with water, and 1 N aqueous
hydrochloric acid was added until the pH was approximately 7. The
aqueous phase was extracted several times with ethyl acetate, and
the combined organic extracts were washed with saturated aqueous
sodium chloride solution, dried over magnesium sulfate, filtered,
and concentrated under reduced pressure. The resulting residue was
slurried with 3:1 ethyl acetate/heptane, stirred for 5 minutes, and
then filtered. The filtrate was concentrated under reduced
pressure. Silica gel chromatography (Eluent: ethyl acetate) gave
the product as a tan solid that contained 15% of an undesired
regioisomer; this material was used without further purification.
Yield: 2.0 g, 8.7 mmol, <41%. LCMS m/z 231.1 (M+H). .sup.1H NMR
(400 MHz, CDCl.sub.3), product peaks: .delta. 8.09 (s, 1H), 7.14
(d, J=8.2 Hz, 1H), 6.82-6.87 (m, 2H), 3.86 (s, 3H), 2.20 (s, 3H),
2.11 (s, 3H).
Step 5. Synthesis of
6-(4-methoxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one
(C69).
[0508] 6-(4-Methoxy-2-methylphenyl)-5-methylpyrazin-2(1H)-one (C68)
(from the previous step, 1.9 g, <8.2 mmol) was dissolved in
N,N-dimethylformamide (40 mL). Lithium bromide (0.86 g, 9.9 mmol)
and sodium bis(trimethylsilyl)amide (95%, 1.91 g, 9.89 mmol) were
added and the reaction mixture was stirred for 30 minutes. Methyl
iodide (0.635 mL, 10.2 mmol) was added and the resulting solution
was stirred at room temperature for 18 hours. The reaction mixture
was diluted with water and brought to a pH of approximately 7 by
slow portion-wise addition of 1 N aqueous hydrochloric acid. The
aqueous layer was extracted with ethyl acetate and the combined
ethyl acetate layers were washed several times with water, dried
over magnesium sulfate, filtered, and concentrated. Silica gel
chromatography (Gradient: 75% to 100% ethyl acetate in heptane)
gave the product as a viscous orange oil. Yield: 1.67 g, 6.84 mmol,
33% over two steps. LCMS m/z 245.1 (M+H). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.17 (s, 1H), 7.03 (br d, J=8 Hz, 1H),
6.85-6.90 (m, 2H), 3.86 (s, 3H), 3.18 (s, 3H), 2.08 (br s, 3H),
2.00 (s, 3H).
Step 6. Synthesis of
6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one
(P8).
[0509] To a cooled (-78.degree. C.) solution of
6-(4-methoxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one (C69)
(1.8 g, 7.37 mmol) in dichloromethane was added a solution of boron
tribromide in dichloromethane (1 M, 22 mL, 22 mmol). The cooling
bath was removed after 30 minutes, and the reaction mixture was
allowed to warm to room temperature and stir for 18 hours. The
reaction was cooled to -78.degree. C., and methanol (10 mL) was
slowly added; the resulting mixture was slowly warmed to room
temperature. The reaction mixture was concentrated in vacuo,
methanol (20 mL) was added, and the mixture was again concentrated
under reduced pressure. The residue was diluted with ethyl acetate
(300 mL) and water (200 mL) and the resulting aqueous layer was
brought to pH 7 via the portion-wise addition of saturated aqueous
sodium carbonate solution. The mixture was extracted with ethyl
acetate (3.times.200 mL). The combined organic extracts were washed
with water and with saturated aqueous sodium chloride solution,
dried over magnesium sulfate, filtered, and concentrated in vacuo
to afford the product as a light tan solid. Yield: 1.4 g, 6.0 mmol,
81%. LCMS m/z 231.1 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 8.21 (s, 1H), 6.98 (d, J=8.2 Hz, 1H), 6.87-6.89 (m, 1H),
6.85 (br dd, J=8.2, 2.5 Hz, 1H), 3.22 (s, 3H), 2.06 (br s, 3H),
2.03 (s, 3H).
Preparation P9
3-Methyl-4-(3-methylimidazo[2,1-c][1,2,4]triazin-4-yl)phenol
(P9)
##STR00074##
[0510] Step 1. Synthesis of
4-(4-methoxy-2-methylphenyl)-3-methylimidazo[2,1-c][1,2,4]triazine
(C70).
[0511] A mixture of 1-(4-methoxy-2-methylphenyl)propane-1,2-dione
(C67) (1.0 g, 5.2 mmol) and 2-hydrazinyl-1H-imidazole hydrochloride
(1.05 g, 7.8 mmol) in N,N-dimethylformamide (8 mL) was heated to
100.degree. C. in a microwave reactor for 20 minutes. After the
progress of the reaction had been assessed by thin layer
chromatography, the mixture was heated to 120.degree. C. for 20
minutes. The solvent was removed in vacuo and the residue was taken
up in ethyl acetate (30 mL) and water (10 mL). Saturated aqueous
sodium bicarbonate solution was added to adjust the pH to roughly
8. The aqueous layer was extracted with additional ethyl acetate
(30 mL) and the combined organic extracts were dried over magnesium
sulfate, filtered, and concentrated in vacuo. Silica gel
chromatography (Gradient: 50% to 100% ethyl acetate in heptane)
afforded the product as a light yellow solid. Yield: 587 mg, 2.31
mmol, 44%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.06 (d, J=0.9
Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.15 (d, J=1.1 Hz, 1H), 6.95-7.00
(m, 2H), 3.91 (s, 3H), 2.63 (s, 3H), 2.03 (br s, 3H).
Step 2. Synthesis of
3-methyl-4-(3-methylimidazo[2,1-c][1,2,4]triazin-4-yl)phenol
(P9).
[0512]
4-(4-Methoxy-2-methylphenyl)-3-methylimidazo[2,1-c][1,2,4]triazine
(C70) (587 mg, 2.31 mmol) in dichloromethane (5 mL) was reacted
with boron tribromide (1 M in dichloromethane, 13.1 mL, 13.1 mmol)
as described in Preparation P8. The product was obtained as a tan
solid. Yield: 543 mg, 2.25 mmol, 97%. LCMS m/z 241.1 (M+H). .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 9.99 (s, 1H), 8.09 (d, J=1.0
Hz, 1H), 7.43 (d, J=1.2 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 6.89 (br
d, J=2.2 Hz, 1H), 6.83 (br dd, J=8.3, 2.4 Hz, 1H), 2.49 (s, 3H),
1.91 (br s, 3H).
Preparation P10
7-(4,6-Dimethylpyrimidin-5-yl)-2-methyl-2H-indazol-4-ol (P10)
##STR00075## ##STR00076##
[0513] Step 1. Synthesis of
4-[(benzyloxy)methoxy]-1-bromo-2-fluorobenzene (C71).
[0514] A solution of 4-bromo-3-fluorophenol (1.22 g, 6.39 mmol),
benzyl chloromethyl ether (60%, 2.22 mL, 9.58 mmol) and
diisopropylethylamine (2.23 mL, 12.8 mmol) in dichloromethane was
heated at reflux for two hours. The reaction mixture was then
concentrated in vacuo and purified by silica gel chromatography
(Gradient: 15% to 40% ethyl acetate in heptane) to afford the
product as a colorless oil. Yield: 2.35 g, >100%. .sup.1H NMR
(400 MHz, CD.sub.3OD), characteristic peaks: .delta. 7.48 (dd,
J=8.9, 8.1 Hz, 1H), 6.95 (dd, J=10.6, 2.7 Hz, 1H), 6.84 (ddd,
J=8.9, 2.8, 1.1 Hz, 1H), 5.31 (s, 2H), 4.70 (s, 2H).
Step 2. Synthesis of
6-[(benzyloxy)methoxy]-3-bromo-2-fluorobenzaldehyde (C72).
[0515] A solution of 4-[(benzyloxy)methoxy]-1-bromo-2-fluorobenzene
(C71) (from the previous step, 525 mg, <1.69 mmol) in
tetrahydrofuran (20 mL) was cooled to -78.degree. C. for 15
minutes. Lithium diisopropylamide (1.60 M, 1.58 mL, 2.53 mmol) was
then added drop-wise over 15 minutes. After one hour at -78.degree.
C., N,N-dimethylformamide (0.197 mL, 2.53 mmol) in tetrahydrofuran
(5 mL) was added. The reaction mixture was stirred at -78.degree.
C. for 30 minutes, quenched with 50% saturated aqueous sodium
chloride solution (30 mL) and then allowed to reach room
temperature. The reaction mixture was extracted with ethyl acetate
(3.times.30 mL). The combined organic layers were dried over sodium
sulfate, filtered, concentrated in vacuo and purified by silica gel
chromatography (Gradient: 15% to 40% ethyl acetate in heptane) to
afford the product as a light yellow oil. Yield: 397 mg, 1.17 mmol,
82% over two steps. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.36
(d, J=1.4 Hz, 1H), 7.66 (dd, J=9.2, 7.6 Hz, 1H), 7.29-7.38 (m, 5H),
7.04 (dd, J=9.1, 1.5 Hz, 1H), 5.42 (s, 2H), 4.75 (s, 2H).
Step 3. Synthesis of
4-[(benzyloxy)methoxy]-7-bromo-1-methyl-1H-indazole (C73) and
4-[(benzyloxy)methoxy]-7-bromo-2-methyl-2H-indazole (C74).
[0516] A mixture of
6-[(benzyloxy)methoxy]-3-bromo-2-fluorobenzaldehyde (C72) (1.40 g,
4.13 mmol) and methylhydrazine (8.69 mL, 165 mmol) was dissolved in
1,4-dioxane (8 mL) in a pressure vessel and heated at 110.degree.
C. for 4 hours, then at 120.degree. C. for 16 hours. The mixture
was submitted to microwave irradiation at 150.degree. C. for 90
minutes. The reaction mixture was concentrated in vacuo and
purified by silica gel chromatography (Gradient: 15% to 40% ethyl
acetate in heptane) to provide C73 as a colorless oil and C74 as a
yellow oil. Yield: C73, 801 mg, 2.31 mmol, 56%; C74, 296 mg, 0.852
mmol, 21%. C73: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05 (s,
1H), 7.41 (d, J=8.2 Hz, 1H), 7.28-7.38 (m, 5H), 6.67 (d, J=8.2 Hz,
1H), 5.44 (s, 2H), 4.76 (s, 2H), 4.41 (s, 3H). C74: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 8.06 (br s, 1H), 7.38 (d, J=7.9 Hz,
1H), 7.28-7.38 (m, 5H), 6.59 (d, J=8.0 Hz, 1H), 5.42 (s, 2H), 4.76
(s, 2H), 4.26 (br s, 3H).
Step 4. Synthesis of
4-[(benzyloxy)methoxy]-7-(4,6-dimethylpyrimidin-5-yl)-2-methyl-2H-indazol-
e (C75).
[0517] A mixture of
4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine
(C63) (152 mg, 0.649 mmol),
4-[(benzyloxy)methoxy]-7-bromo-2-methyl-2H-indazole (C74) (150 mg,
0.432 mmol), tetrahydrofuran (5 mL), and aqueous potassium
phosphate solution (0.5 M, 2.59 mL, 1.30 mmol) was purged with
nitrogen for two minutes before adding
[2'-(azanidyl-.kappa.N)biphenyl-2-yl-.kappa.C.sub.2](Chloro)[dicyclohexyl-
(2',6'-dimethoxybiphenyl-2-yl)-.lamda..sup.5-phosphanyl]palladium
(31 mg, 0.043 mmol). The reaction mixture was heated at 70.degree.
C. for 40 hours, then filtered through a thin layer of Celite. The
filtrate was concentrated in vacuo and purified by silica gel
chromatography (Gradient: 5% to 10% methanol in dichloromethane) to
give the product as a dark oil. Yield: 63 mg, 0.17 mmol, 39%. LCMS
m/z 375.2 (M+H). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.98 (s,
1H), 8.06 (s, 1H), 7.29-7.41 (m, 5H), 6.96 (d, J=7.6 Hz, 1H), 6.76
(d, J=7.6 Hz, 1H), 5.50 (s, 2H), 4.83 (s, 2H), 4.17 (s, 3H), 2.31
(s, 6H).
Step 5. Synthesis of
7-(4,6-dimethylpyrimidin-5-yl)-2-methyl-2H-indazol-4-ol (P10).
[0518] To a solution of acetyl chloride (98%, 0.122 mL, 1.68 mmol)
in methanol (2 mL) was added a solution of
4-[(benzyloxy)methoxy]-7-(4,6-dimethylpyrimidin-5-yl)-2-methyl-2H-indazol-
e (C75) (63 mg, 0.17 mmol) in methanol (2 mL). After 16 hours, the
reaction mixture was concentrated in vacuo and purified by silica
gel chromatography (Gradient: 5% to 10% methanol in
dichloromethane) to afford the product as a glassy solid. Yield: 37
mg, 0.14 mmol, 82%. LCMS m/z 255.2 (M+H). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.87 (s, 1H), 8.28 (s, 1H), 6.97 (d, J=7.6 Hz,
1H), 6.47 (d, J=7.6 Hz, 1H), 4.13 (s, 3H), 2.25 (s, 6H).
Preparation P11
7-(4,6-Dimethylpyrimidin-5-yl)-1-methyl-1H-indazol-4-ol (P11)
##STR00077##
[0520] Compound P11 was prepared from
4-[(benzyloxy)methoxy]-7-bromo-1-methyl-1H-indazole (C73) according
to steps 4 and 5 of the synthesis of
7-(4,6-dimethylpyrimidin-5-yl)-2-methyl-2H-indazol-4-ol (P10) in
Preparation P10, to provide the product as an off-white solid.
Yield: 36 mg, 0.14 mmol, 64%. LCMS m/z 255.2 (M+H). .sup.1H NMR
(400 MHz, DMSO-d.sub.6) .delta. 10.40 (br s, 1H), 8.95 (s, 1H),
8.09 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 6.53 (d, J=7.8 Hz, 1H), 3.38
(s, 3H), 2.15 (s, 6H).
Preparation P12
5-(Furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridin-5-yl)benzoic
acid (P12)
##STR00078##
[0521] Step 1. Synthesis of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(trimethylstannanyl)benzonitrile
(C76).
[0522] To a solution of
2-bromo-5-(furo[3,2-c]pyridin-4-yloxy)benzonitrile (prepared from
2-bromo-5-hydroxybenzonitrile and 4-iodofuro[3,2-c]pyridine by the
method of Step 3 in Example 7; 4-iodofuro[3,2-c]pyridine was
synthesized from 4-chlorofuro[3,2-c]pyridine with acetyl chloride
and sodium iodide in acetonitrile) (7.0 g, 22 mmol) in 1,4-dioxane
(70 mL) was added hexamethyldistannane (21.8 g, 66.6 mmol) and
tetrakis(triphenylphosphine)palladium(0) (1.28 g, 1.11 mmol). The
resulting mixture was heated at 120.degree. C. for 18 hours. The
reaction mixture was filtered and the filtrate was concentrated to
give a crude residue, which was purified by silica gel
chromatography (Eluent: 400:1 petroleum ether/ethyl acetate) to
provide the product as a white solid. Yield: 6.0 g, 15 mmol, 67%.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01 (d, J=5.9 Hz, 1H),
7.68 (d, J=2.2 Hz, 1H), 7.62 (d, J=8.1 Hz, 1H), 7.55-7.58 (m, 1H),
7.42 (dd, J=8.0, 2.4 Hz, 1H), 7.26 (dd, J=5.8, 0.9 Hz, 1H), 6.93
(dd, J=2.2, 0.9 Hz, 1H), 0.47 (s, 9H).
Step 2. Synthesis of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridin-5-yl)benzonitrile
(C77).
[0523] To a solution of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(trimethylstannyl)benzonitrile
(C76) (8.3 g, 21 mmol) in tetrahydrofuran (160 mL) was added
5-bromoimidazo[1,2-a]pyridine (3.9 g, 20 mmol), lithium chloride
(0.67 g, 15.8 mmol), copper(I) bromide (0.57 g, 4.0 mmol) and
tetrakis(triphenylphosphine)palladium(0) (2.27 g, 2.0 mmol). The
mixture was heated to reflux for 48 hours. The reaction mixture was
filtered and the filtrate was concentrated to give crude product,
which was purified by silica gel chromatography (Gradient: 7% to
20% ethyl acetate in petroleum ether) to give the product as a
brown solid. Yield: 5 g, 13 mmol, 68%. LCMS m/z 353.0 (M+H).
.sup.1H NMR (400 MHz, CD.sub.3OD, concentrated HCl), characteristic
peaks: .delta. 8.23-8.26 (m, 1H), 8.12 (br d, half of AB quartet,
J=8 Hz, 1H), 8.06 (br d, half of AB quartet, J=8 Hz, 1H), 7.93 (br
d, J=6 Hz, 1H), 7.77-7.81 (m, 1H).
Step 3. Synthesis of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridin-5-yl)benzoic
acid (P12).
[0524] To an aqueous solution of sodium hydroxide (15% w/v, 25 mL)
was added
5-(furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridine-5-yl)benzo-
nitrile (C77) (4.35 g, 12.3 mmol) and ethanol (25 mL), and the
reaction mixture was heated to reflux for 18 hours. The mixture was
cooled to room temperature and extracted with dichloromethane. The
aqueous layer was adjusted to pH 7 with 3 N aqueous hydrochloric
acid; the resulting mixture was filtered, and the filter cake was
washed with ethyl acetate and dichloromethane, then dried under
vacuum to give the product as a yellow solid. Yield: 1.9 g, 5.1
mmol, 42%. LCMS m/z 371.9 (M+H). .sup.1H NMR (400 MHz,
DMSO-d.sub.6), characteristic peaks: .delta. 8.17 (d, J=2.4 Hz,
1H), 8.04 (d, J=5.9 Hz, 1H), 7.52 (d, J=5.9 Hz, 1H), 6.72 (br d,
J=6.7 Hz, 1H).
Preparation P13
4-{[7-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzodioxol-4-yl]o-
xy}furo[3,2-c]pyridine (P13)
##STR00079##
[0525] Step 1. Synthesis of 3-bromo-6-methoxybenzene-1,2-diol
(C78).
[0526] To a mixture of 3-methoxybenzene-1,2-diol (578 mg, 4.12
mmol) in acetonitrile (10 mL) at 0.degree. C. was slowly added
N-bromosuccinimide (95%, 811 mg, 4.33 mmol) in acetonitrile (5 mL).
After two hours at 0.degree. C., aqueous sodium thiosulfate
solution (1 M, 2 mL) was added. After ten minutes, the reaction
mixture was concentrated in vacuo and purified by silica gel
chromatography (Gradient: 20% to 40% ethyl acetate in heptane) to
give the product as a white solid. Yield: 858 mg, 0.3.92 mmol, 95%.
LCMS m/z 216.8 (M-H). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.00 (d, J=9.0 Hz, 1H), 6.43 (d, J=9.0 Hz, 1H), 5.54 (s, 1H), 5.48
(s, 1H), 3.89 (s, 3H).
Step 2. Synthesis of 4-bromo-7-methoxy-1,3-benzodioxole (C79).
[0527] To a solution of 3-bromo-6-methoxybenzene-1,2-diol (C78)
(420 mg, 1.92 mmol) in N,N-dimethylformamide (5 mL) were added
diiodomethane (0.170 mL, 2.11 mmol) and cesium carbonate (690 mg,
2.1 mmol). The reaction mixture was stirred at 100.degree. C. for
one hour, then cooled to room temperature and diluted with ethyl
acetate (20 mL). The solid was removed by filtration and washed
with ethyl acetate (30 mL). The filtrate was washed with 50%
saturated aqueous sodium chloride solution (4.times.20 mL), dried
over sodium sulfate, filtered, concentrated in vacuo, and purified
by silica gel chromatography (Gradient: 20% to 40% ethyl acetate in
heptane) to give the product as a white solid. Yield: 335 mg, 1.45
mmol, 76%. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 6.92 (d, J=9.0
Hz, 1H), 6.46 (d, J=9.1 Hz, 1H), 6.05 (s, 2H), 3.90 (s, 3H).
Step 3. Synthesis of 7-bromo-1,3-benzodioxol-4-ol (C80).
[0528] To a solution of 4-bromo-7-methoxy-1,3-benzodioxole (C79)
(186 mg, 0.805 mmol) in acetonitrile (5 mL) was added
trimethylsilyl iodide (0.343 mL, 2.42 mmol). The reaction mixture
was heated at 85.degree. C. for 18 hours and purified by silica gel
chromatography (Gradient: 30% to 40% ethyl acetate in heptane) to
give the product as an oil. Yield: 59 mg, 0.27 mmol, 34%. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 6.86 (d, J=9.0 Hz, 1H), 6.44 (d,
J=9.0 Hz, 1H), 6.05 (s, 2H).
Step 4. Synthesis of
4-[(7-bromo-1,3-benzodioxol-4-yl)oxy]furo[3,2-c]pyridine (C81).
[0529] A mixture of 7-bromo-1,3-benzodioxol-4-ol (C80) (59 mg, 0.27
mmol), 4-chlorofuro[3,2-c]pyridine (62.7 mg, 0.408 mmol) and cesium
carbonate (224 mg, 0.687 mmol) in dimethyl sulfoxide (2 mL) was
heated at 140.degree. C. for 4 hours. The reaction mixture was
cooled to room temperature and combined with a similar reaction
carried out on 16 mg of C80. Ethyl acetate was added and the solid
was removed by filtration. The filtrate was washed with 50%
saturated aqueous sodium chloride solution (3.times.15 mL),
concentrated in vacuo and purified by silica gel chromatography
(Gradient: 10% to 30% ethyl acetate in heptane) to afford the
product as an oil. Yield: 61 mg, 0.182 mmol, 53%. LCMS m/z 335.9
(M+H).
Step 5. Synthesis of
4-{[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzodioxol-4-yl]-
oxy}furo[3,2-c]pyridine (P13).
[0530] A mixture of
4-[(7-bromo-1,3-benzodioxol-4-yl)oxy]furo[3,2-c]pyridine (C81) (61
mg, 0.18 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (99%,
70.3 mg, 0.274 mmol),
1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50%,
26.3 mg, 0.018 mmol) and potassium acetate (55 mg, 0.55 mmol) were
combined in acetonitrile (3 mL). After bubbling nitrogen through
the reaction mixture for five minutes, it was heated at 80.degree.
C. for 18 hours. The reaction mixture was then filtered through a
thin layer of Celite, washing with ethyl acetate (20 mL). The
filtrate was concentrated in vacuo and the residue was partitioned
between water (15 mL) and ethyl acetate (20 mL). The aqueous layer
was extracted with ethyl acetate (3.times.10 mL); the combined
organic layers were dried over sodium sulfate, filtered, and
concentrated in vacuo. Purification by silica gel chromatography
(Gradient: 15% to 50% ethyl acetate in heptane) provided the
product as a light yellow gum. Yield: 25 mg, 0.066 mmol, 37%.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.00 (d, J=5.8 Hz, 1H),
7.64 (d, J=2.2 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.21 (dd, J=5.8,
1.0 Hz, 1H), 6.92 (dd, J=2.2, 0.9 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H),
6.03 (s, 2H), 1.37 (s, 12H).
Preparation P14
8-(4,6-Dimethylpyrimidin-5-yl)isoquinolin-5-ol (P14)
##STR00080##
[0531] Step 1. Synthesis of 8-bromo-5-methoxyisoquinoline
(C82).
[0532] To a solution of 5-methoxyisoquinoline (1.48 g, 9.30 mmol)
in acetic acid (15 mL) was added a solution of bromine (2.1 g, 13
mmol) in acetic acid (5 mL). After three days at room temperature,
the reaction mixture was cooled to 0.degree. C., quenched with
saturated aqueous sodium bicarbonate solution and extracted with
dichloromethane (3.times.50 mL). The combined organic layers were
dried over sodium sulfate, filtered, concentrated in vacuo and
purified by silica gel chromatography (Gradient: 5% to 33% ethyl
acetate in petroleum ether) to give the product as a solid. Yield:
1.72 g, 7.22 mmol, 78%. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.40 (s, 1H), 8.64 (d, J=6.0 Hz, 1H), 7.99 (d, J=5.5 Hz, 1H), 7.90
(d, J=8.5 Hz, 1H), 7.18 (d, J=8.5 Hz, 1H), 4.00 (s, 3H).
Step 2. Synthesis of
8-(4,6-dimethylpyrimidin-5-yl)-5-methoxyisoquinoline (C83).
[0533] To a solution of 8-bromo-5-methoxyisoquinoline (C82) (1.72
g, 7.22 mmol) in 1,4-dioxane (75 mL) and water (5 mL) were added
4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine
(C63) (2.20 g, 9.40 mmol), tris(dibenzylideneacetone)dipalladium(0)
(659 mg, 0.72 mmol), tricyclohexylphosphine (403 mg, 1.44 mmol) and
potassium phosphate (3.07 g, 14.46 mmol). The reaction mixture was
degassed with nitrogen for five minutes, then stirred for 6 hours
at 120.degree. C. More
4,6-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidi-
ne (C63) (1.1 g, 4.7 mmol) was added. The reaction mixture was
stirred for 7 hours at 120.degree. C. and then filtered. The
filtrate was concentrated in vacuo and purified by silica gel
chromatography (Gradient: 0.5% to 2.5% methanol in dichloromethane)
to provide the product as a solid. Yield: 1.0 g, 3.8 mmol, 53%.
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.00 (s, 1H), 8.56-8.60
(m, 2H), 8.07 (dd, J=5.8, 0.8 Hz, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.36
(d, J=8.0 Hz, 1H), 4.07 (s, 3H), 2.08 (s, 6H).
Step 3. Synthesis of 8-(4,6-dimethylpyrimidin-5-yl)isoquinolin-5-ol
(P14).
[0534] To a solution of
8-(4,6-dimethylpyrimidin-5-yl)-5-methoxyisoquinoline (C83) (1.0 g,
3.8 mmol) in dichloromethane (60 mL) was slowly added boron
tribromide (4.7 g, 19 mmol) at -78.degree. C. The mixture was
allowed to warm to room temperature and stirred overnight before
being quenched at -20.degree. C. with methanol. The reaction
mixture was washed with saturated aqueous sodium bicarbonate
solution; the aqueous layer was extracted with dichloromethane
(5.times.50 mL) and ethyl acetate (5.times.50 mL). The combined
organic layers were dried over sodium sulfate, filtered,
concentrated in vacuo and purified by silica gel chromatography
(Gradient: 0.5% to 5% methanol in dichloromethane) to give the
product as a solid. Yield: 300 mg, 1.19 mmol, 31%. .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 10.88 (br s, 1H), 8.98 (s, 1H),
8.49-8.55 (m, 2H), 8.04 (br d, J=6 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H),
7.21 (d, J=7.8 Hz, 1H), 2.07 (s, 6H).
Preparation P15
4-(3,5-Dimethylpyridazin-4-yl)-3-methoxyphenol (P15)
##STR00081##
[0535] Step 1. Synthesis of
4-(2,4-dimethoxyphenyl)-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(-
2H)-one (C84).
[0536] A mixture of
4-chloro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one
(C18) (30 g, 130 mmol), (2,4-dimethoxyphenyl)boronic acid (26 g,
140 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.69 g, 10.6
mmol), tricyclohexylphosphine (7.5 g, 27 mmol) and potassium
phosphate monohydrate (69 g, 300 mmol) in 1,4-dioxane (250 mL) was
heated at reflux for 3 hours and then cooled to room temperature,
filtered, and concentrated in vacuo. Silica gel chromatography
(Gradient: 9% to 17% ethyl acetate in petroleum ether) afforded the
product as a yellow solid. Yield: 40 g, 120 mmol, 92%. .sup.1H NMR
(400 MHz, CDCl.sub.3), mixture of diastereomers, characteristic
peaks: .delta. 7.76 and 7.77 (2 s, total 1H), [7.10 (d, J=8.3 Hz)
and 7.07 (d, J=8.3 Hz), total 1H], 6.51-6.59 (m, 2H), 6.06-6.12 (m,
1H), 4.11-4.20 (m, 1H), 3.85 (s, 3H), 3.74 and 3.76 (2 s, total
3H), 1.99 and 2.00 (2 s, total 3H).
Step 2. Synthesis of
3-chloro-4-(2,4-dimethoxyphenyl)-5-methylpyridazine (C85).
[0537]
4-(2,4-Dimethoxyphenyl)-5-methyl-2-(tetrahydro-2H-pyran-2-yl)pyrida-
zin-3(2H)-one (C84) (30 g, 91 mmol) was dissolved in phosphorus
oxychloride (158 mL) and the mixture was heated at reflux for 5
hours, cooled to room temperature, and poured into ice water.
Careful addition of potassium carbonate to neutralize the reaction
was followed by extraction with ethyl acetate (3.times.500 mL). The
combined organic extracts were concentrated in vacuo. Silica gel
chromatography (Gradient: 17% to 50% ethyl acetate in petroleum
ether) gave the product as an orange solid. Yield: 20 g, 76 mmol,
83%. LCMS m/z 264.7 (M+H). .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.90 (s, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.60 (d, J=2.3 Hz,
1H), 6.53 (dd, J=8.2, 2.1 Hz, 1H), 3.73 (s, 3H), 2.36 (s, 3H), 2.10
(s, 3H).
Step 3. Synthesis of 4-(2,4-dimethoxyphenyl)-3,5-dimethylpyridazine
(C86).
[0538] A mixture of
3-chloro-4-(2,4-dimethoxyphenyl)-5-methylpyridazine (C85) (18 g, 68
mmol), methylboronic acid (17 g, 280 mmol),
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (5.2 g,
70 mmol), and cesium carbonate (46 g, 140 mmol) in 1,4-dioxane (300
mL) was heated at reflux for 2.5 hours and then cooled to room
temperature, filtered, and concentrated in vacuo. Silica gel
chromatography (Gradient: 17% to 50% ethyl acetate in petroleum
ether) gave the product as an orange solid. Yield: 14 g, 57 mmol,
84%). LCMS m/z 245.0 (M+H).
Step 4. Synthesis of 4-(3,5-dimethylpyridazin-4-yl)-3-methoxyphenol
(P15).
[0539] Trimethylsilyl iodide (58 g, 290 mmol) was added to a
stirred solution of 4-(2,4-dimethoxyphenyl)-3,5-dimethylpyridazine
(C86) (12 g, 49 mmol) in acetonitrile (100 mL), and the mixture was
heated at reflux for 18 hours. The reaction mixture was cooled to
0.degree. C., slowly diluted with methanol, and concentrated in
vacuo. The residue was partitioned between ethyl acetate and
saturated aqueous sodium thiosulfate solution. The aqueous layer
was extracted with ethyl acetate (4.times.150 mL) and the combined
organic extracts were dried over sodium sulfate, filtered, and
concentrated in vacuo. Silica gel chromatography (Gradient: 50% to
100% ethyl acetate in petroleum ether) provided the product as a
yellow solid. Yield: 3.0 g, 13 mmol, 26%. LCMS m/z 230.7 (M+H).
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.90 (s, 1H), 6.88 (d,
J=8.0 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.53 (dd, J=8.3, 2.3 Hz,
1H), 3.73 (s, 3H), 2.36 (s, 3H), 2.10 (s, 3H).
Methods
[0540] Methods M1-M7 describe specific methods for preparations of
certain compounds of the invention.
Method M1: Palladium-catalyzed reaction of phenols with
4-chlorofuro[3,2-c]pyridines
##STR00082##
[0542] Solutions of the appropriate phenol and
4-chlorofuro[3,2-c]pyridine were prepared at 0.2 M using degassed
1,4-dioxane. A 2-dram vial was charged with the phenol solution
(0.5 mL, 0.1 mmol) and the 4-chlorofuro[3,2-c]pyridine solution
(0.5 mL, 0.1 mmol). Cesium carbonate (100 mg, 0.3 mmol),
palladium(II) acetate (2.5 mg, 0.01 mmol) and
di-tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tri(propan-2-yl)biphenyl-2-yl]-
phosphane (10 mg, 0.02 mmol) were added. The vial was subjected to
three rounds of vacuum evacuation followed by nitrogen fill and the
resulting mixture was shaken and heated at 100.degree. C. for 12
hours. The reaction mixture was cooled to room temperature,
partitioned between water (1.5 mL) and ethyl acetate (2.5 mL),
vortexed, and allowed to settle. The organic layer was passed
through a solid phase extraction cartridge filled with sodium
sulfate (1.0 g); this extraction procedure was repeated twice, and
the combined filtrates were concentrated in vacuo. The products
were generally purified by HPLC (Column: Waters XBridge C18, 5
.mu.m; Mobile phase A: 0.03% ammonium hydroxide in water (v/v);
Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v);
Gradient: increasing percentage of B, starting with 10% or 20%
B).
Method M2: Alkylation of Phenols
##STR00083##
[0544] A solution of the appropriate phenol (0.050 mmol, 1.0 eq) in
anhydrous N,N-dimethylformamide dimethyl acetal or
N,N-dimethylformamide (0.2 mL) was treated with either cesium
carbonate or potassium carbonate (0.10 mmol, 2.0 eq), sodium iodide
(0.008 mmol, 0.2 eq), and the appropriate bromide or chloride
reagent (0.075 mmol, 1.5 eq). The reaction vial was capped and
shaken at 80.degree. C. for 16 hours. The reaction mixture was
concentrated and the crude residue was purified by reversed phase
HPLC (Gradient: increasing concentration of either acetonitrile in
water containing 0.225% formic acid, or acetonitrile in aqueous pH
10 ammonium hydroxide solution) to provide the final compound.
Method M3: Amide Formation Employing
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate
##STR00084##
[0546] A solution of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridine-5-yl)benzoic
acid (P12) (0.060 mmol, 1.0 eq) in anhydrous N,N-dimethylformamide
(0.2 mL) was treated with the appropriate commercially available
amine (0.090 mmol, 1.5 eq),
0-(7-azabenzotriazol-1-yl)-N,N,N',N'-etramethyluronium
hexafluorophosphate (HATU, 0.060 mmol, 1.0 eq), and
diisopropylethylamine (0.240 mmol, 4.0 eq). The reaction vial was
capped and shaken at 30.degree. C. for 16 hours. The reaction
mixture was concentrated and the crude residue was purified by
reversed phase HPLC (Gradient: increasing concentration of either
acetonitrile in water containing 0.225% formic acid, or
acetonitrile in aqueous pH 10 ammonium hydroxide solution) to
provide the final compound.
Method M4: Mitsunobu Reaction of Phenols
##STR00085##
[0548] A solution of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(2-methylpyridin-3-yl)phenol
(prepared via methyl ether cleavage of Example 181) (0.075 mmol,
1.0 eq) in tetrahydrofuran/dichloromethane (v/v=1:1, 1.0 mL) was
added to a vial containing the appropriate commercially available
primary alcohol (0.120 mmol, 1.6 eq) and polymer-supported
triphenylphosphine (0.225 mmol, 3.0 eq). Diisopropyl
azodicarboxylate (DIAD; 0.150 mmol, 2.0 eq) was added to the
reaction vial, which was then capped and shaken at 30.degree. C.
for 16 hours. The reaction mixture was concentrated and the crude
residue was purified by reversed phase HPLC (Gradient: increasing
concentration of either acetonitrile in water containing 0.225%
formic acid, or acetonitrile in aqueous pH 10 ammonium hydroxide
solution) to provide the final compound.
Method M5: Reductive Amination of Aldehydes
##STR00086##
[0550] A solution of
5-(furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridine-5-yl)benzaldehyd-
e [prepared from 4-bromo-3-(1,3-dioxan-2-yl)phenol (see F. Kaiser
et al., J. Org. Chem. 2002, 67, 9248-9256) using the procedures of
Example 1, followed by deprotection with aqueous hydrochloric acid
in tetrahydrofuran] (0.094 mmol, 1.25 eq) in dichloromethane (1.0
mL) was added to a vial containing the appropriate commercially
available amine (0.075 mmol, 1.0 eq). Sodium bicarbonate (18 mg,
0.225 mmol, 3.0 eq) was added, and the reaction vial was capped and
shaken at 30.degree. C. for 16 hours. Sodium triacetoxyborohydride
(47 mg, 0.225 mmol, 3.0 eq) was added, and the reaction mixture was
shaken at 30.degree. C. for an additional 5 hours. The reaction
mixture was concentrated and the crude residue was purified by
reversed phase HPLC (Gradient: increasing concentration of
acetonitrile in water containing 0.1% trifluoroacetic acid) to
provide the final compound.
Method M6: Amine Displacement of Heteroaryl Chlorides
##STR00087##
[0552] A solution of
4-[4-(4-chloro-6-methylpyrimidin-5-yl)-3-methylphenoxy]furo[3,2-c]pyridin-
e (Example 18) (0.50 mmol, 1.0 eq) in anhydrous dimethyl sulfoxide
(0.5 mL) was added to a vial containing the appropriate
commercially available amine (0.110 mmol, 2.2 eq).
Diisopropylethylamine (0.170 mmol, 3.4 eq) and cesium fluoride (15
mg, 0.100 mmol, 2.0 eq) were added, and the reaction vial was
capped and shaken at 120.degree. C. for 16 hours. The reaction
mixture was concentrated and the crude residue was purified by
reversed phase HPLC (Gradient: increasing concentration of
acetonitrile in water containing either 0.225% formic acid or 0.1%
trifluoroacetic acid) to provide the final compounds.
Method M7: Microbial Oxidation Employing Pseudomonas putida
Step 1. Biocatalyst Production
[0553] A frozen seed vial containing Pseudomonas putida (ATCC
17453) was removed from a -80.degree. C. freezer, thawed and used
to inoculate IOWA medium (1 L; IOWA medium consists of glucose [20
g], sodium chloride [5 g], potassium hydrogenphosphate [5 g], soy
flour [5 g] and yeast extract [5 g]; the mixture was adjusted to pH
7.0 before sterilization in an autoclave) in a 3-liter baffled
shake flask (Corning, #431253). The cultures were grown for 2-4
days while shaking at 30.degree. C. and 160 rpm on an orbital
shaker with a 2 inch throw. The cells were harvested by
centrifugation; the cell pellet was frozen at -80.degree. C.
Step 2. Oxidation Reaction
[0554] Cells of Pseudomonas putida (ATCC 17453) were suspended in
aqueous potassium phosphate buffer (25 mM, pH 7.0) at a
concentration of 45 g cells per 150 mL buffer. This suspension was
added to a 1 liter baffled shake flask (Nalge, 4116-1000) and a
solution of substrate (30 mg) in dimethyl sulfoxide (3 mL) was
added to the suspension. The flask was incubated at 30 to
40.degree. C. and 300 rpm for 24-96 hours on an orbital shaker with
a 1 inch throw.
Step 3. Reaction Work-Up
[0555] The reaction was extracted with ethyl acetate, and the
combined organic layers were concentrated in vacuo. The product was
isolated using chromatographic techniques.
TABLE-US-00001 TABLE 1 Examples 31-208 ##STR00088## each of
R.sup.1, R.sup.2, R.sup.T1, and R.sup.T2 is H; and X.sup.1 = O
Example No. ##STR00089## Method of Preparation; Non-commercial
Starting Materials .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.
(ppm); Mass spectrum, observed ion m/z (M + H) or HPLC retention
time (minutes); Mass spectrum m/z (M + H) (unless otherwise
indicated) 31 ##STR00090## Ex 5 9.07 (br s, 1H), 8.40 (d, J = 5.7
Hz, 1H), 8.07 (d, J = 5.8 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.45
(br AB quartet, J.sub.AB = 8.9 Hz, .DELTA..nu..sub.AB = 28.6 Hz,
4H), 7.30 (dd, J = 5.8, 0.8 Hz, 1H), 7.17 (dd, J = 5.6, 0.8 Hz,
1H), 6.98 (dd, J = 2.2, 0.8 Hz, 1H), 2.60 (s, 3H); 343.1 32
##STR00091## Ex 15 3.012 min.sup.1; 332 33 ##STR00092## Ex 1.sup.65
2.501 min.sup.2; 369 34 ##STR00093## Ex 16; C10 8.08 (d, J = 5.8
Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.65 (br d, J = 9.0 Hz, 1H),
7.60 (d, J = 1.4 Hz, 1H), 7.40-7.43 (m, 1H), 7.30-7.31 (m, 1H),
7.28 (dd, J = 5.8, 1.0 Hz, 1H, assumed; partially obscured by
solvent peak), 7.26 (dd, J = 9.0, 6.8 Hz, 1H, assumed; partially
obscured by solvent peak), 6.94-6.98 (m, 3H), 6.77 (dd, J = 6.8,
1.0 Hz, 1H), 3.75 (s, 3H); 358.0 35 ##STR00094## Ex 6; C2, C55
Selected peaks: 8.08 (d, J = 5.8 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H),
7.17 (d, J = 9.3 Hz, 1H), 6.93 (dd, J = 2.2, 1.0 Hz, 1H), 2.12 (s,
3H), 2.02 (s, 3H); 356.3 36 ##STR00095## Ex 6; C2 .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. 6 9.15 (s, 1H), 8.18 (d, J = 2.2 Hz,
1H), 8.05 (d, J = 5.9 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 1.1 Hz,
1H), 7.57-7.58 (m, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.53 (dd, J =
5.7, 1.0 Hz, 1H), 7.37 (br d, J = 2.2 Hz, 1H), 7.27 (br dd, J =
8.3, 2.4 Hz, 1H), 7.14 (dd, J = 2.2, 1.0 Hz, 1H), 2.10 (s, 3H);
343.0 37 ##STR00096## Ex 6; C10, C55 A. 8.10 (d, J = 5.8 Hz, 1H),
7.70 (d, J = 2.3 Hz, 1H), 7.57 (br d, J = 9.2 Hz, 1H), 7.52 (d, J =
1.2 Hz, 1H), 7.28-7.31 (m, 2H), 7.16 (d, J = 9.2 Hz, 1H), 7.11-7.13
(m, 1H), 7.02 (d, half of AB pattern, J = 2.2 Hz, 1H), 6.99 (dd,
half of ABX pattern, J = 8.2, 2.2 Hz, 1H), 6.94 (dd, J = 2.2, 1.0
Hz, 1H), 3.73 (s, 3H), 2.17 (s, 3H); 372.2 38 ##STR00097## Ex
16.sup.3 .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.14 (d, J =
2.0 Hz, 1H), 8.05 (d, J = 5.9 Hz, 1H), 7.61 (br d, J = 9.0 Hz, 1H),
7.56 (br s, 1H), 7.49 (br d, J = 5.9 Hz, 1H), 7.33 (dd, J = 9.0,
7.0 Hz, 1H), 7.24 (br s, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.05-7.09
(m, 1H), 6.88 (d, J = 6.6 Hz, 1H), 6.53-6.56 (m, 1H), 6.51 (dd, J =
8.2, 2.0 Hz, 1H), 5.14-5.20 (m, 1H), 2.59 (d, J = 5.1 Hz, 3H);
357.0 39 ##STR00098## Ex 5.sup.4 9.06 (d, J = 0.8 Hz, 1H), 8.39 (d,
J = 5.6 Hz, 1H), 8.07 (d, J = 5.8 Hz, 1H), 7.71 (d, J = 2.2 Hz,
1H), 7.61 (dd, J = 2.2, 0.8 Hz, 1H), 7.39- 7.44 (m, 2H), 7.32 (dd,
J = 5.8, 1.0 Hz, 1H), 7.02 (dd, J = 5.5, 1.0 Hz, 1H), 6.97 (dd, J =
2.2, 1.0 Hz, 1H), 2.51 (s, 3H); 377.0 40 ##STR00099## Method M2
2.353 min.sup.5; 441 41 ##STR00100## Method M2 2.388 min.sup.5; 414
42 ##STR00101## Method M2 2.437 min.sup.6; 388 43 ##STR00102##
Method M2 2.457 min.sup.6; 441 44 ##STR00103## Method M2 2.574
min.sup.6; 416 45 ##STR00104## Ex 20; C2, P3 .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta. 8.83 (s, 1H), 8.43 (s, 1H), 8.08 (d, J = 5.7
Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.28-7.33 (m, 4H), 6.93 (dd, J =
2.2, 1.0 Hz, 1H), 2.32 (s, 3H), 2.08 (br s, 3H); 358.0 46
##STR00105## Method M3 2.329 min.sup.5; 425 47 ##STR00106## Ex
16.sup.76 2.574 min.sup.6; 429 48 ##STR00107## Ex 16.sup.7 2.25
min.sup.6; 437 49 ##STR00108## Method M5 2.097 min.sup.6; 468 50
##STR00109## Method M5 1.907 min.sup.5; 462 51 ##STR00110## Ex 6;
C10.sup.8 3.17 min.sup.9; 358.1 52 ##STR00111## Ex 6; C2 2.31
min.sup.9; 317.1 53 ##STR00112## Ex 6; C2, C60 2.40 min.sup.9;
333.2 54 ##STR00113## Ex 20; P5 characteristic peaks: 8.07 (d, J =
6.0 Hz, 1H), 7.80 (d, J = 2.0 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H),
7.65 (br dd, J = 8, 2 Hz, 1H), 7.54 (br d, J = 8.5 Hz, 1H), 7.33
(d, J = 6.0 Hz, 1H), 7.14- 7.17 (m, 1H), 6.99-7.01 (m, 1H); 396.0
55 ##STR00114## Ex 17.sup.10 characteristic peaks: 8.20 (d, J = 5.8
Hz, 1H), 7.72-7.78 (m, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.38-7.46 (m,
1H), 7.31 (d, J = 8.3 Hz, 1H), 7.19-7.23 (m, 2H), 7.16 (dd, J =
8.2, 2.1 Hz, 1H), 7.06 (br d, J = 5.8 Hz, 1H), 6.88 (br d, J = 6.5
Hz, 1H), 5.73-5.76 (m, 1H), 3.68 (s, 3H), 2.07 (s, 3H); 355.5 56
##STR00115## Ex 6; C2 2.40 min.sup.9; 332.3 57 ##STR00116## Ex
6.sup.11; C10, C45 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.95
(s, 1H), 8.02 (d, J = 5.8 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.76
(d, J = 1.2 Hz, 1H), 7.59-7.61 (m, 1H), 7.38-7.43 (m, 2H),
6.99-7.00 (m, 1H), 6.87-6.91 (m, 2H), 2.44 (s, 3H); 359.1 58
##STR00117## Ex 1 .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.12
(s, 1H), 8.50 (s, 1H), 8.07 (d, J = 5.9 Hz, 1H), 7.68 (d, J = 2.2
Hz, 1H), 7.25 (dd, J = 5.8, 0.9 Hz, 1H), 7.21-7.22 (m, 1H), 7.17
(AB quartet, J.sub.AB = 8 Hz, .DELTA..nu..sub.AB = 4 Hz, 2H), 6.94
(dd, J = 2.2, 1.0 Hz, 1H), 2.39 (s, 3H), 2.12 (br s, 3H); 318.1 59
##STR00118## Ex 1 3.06 min.sup.9; 369.0 60 ##STR00119## Ex 6; C2
3.77 min.sup.12; 347.2 61 ##STR00120## Method M2 2.497 min.sup.6;
405 62 ##STR00121## Ex 1.sup.13 8.47-8.50 (m, 2H), 8.05 (d, J = 6
Hz, 1H), 7.64 (d, J = 2 Hz, 1H), 7.12-7.26 (m, 4H, assumed;
partially obscured by solvent peak), 6.83-6.85 (m, 1H), 2.46 (s,
3H), 2.45 (q, J = 7 Hz, 2H), 1.06 (t, J = 7 Hz, 3H); 332.3 63
##STR00122## Ex 1 2.07 min.sup.9; 333.1 64 ##STR00123## Ex
1.sup.13; C45 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.36 (s,
1H), 8.16 (d, J = 1.4 Hz, 1H), 8.00 (d, J = 5.9 Hz, 1H), 7.95 (d, J
= 2.3 Hz, 1H), 7.82-7.85 (m, 1H), 7.45-7.49 (m, 2H), 7.43 (dd, J =
5.9, 0.9 Hz, 1H), 7.34 (dd, J = 8.3, 2.4 Hz, 1H), 7.06 (dd, J =
2.3, 0.9 Hz, 1H), 2.50 (s, 3H), 2.30- 2.47 (m, 2H), 1.08 (t, J =
7.5 Hz, 3H); 371.1 65 ##STR00124## Ex 1; C45, C49 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 9.02 (s, 1H), 8.04 (d, J = 5.8 Hz, 1H),
7.95 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 1.2 Hz, 1H), 7.64-7.69 (m,
2H), 7.45 (dd, J = 5.9, 0.9 Hz, 1H), 7.38 (dd, J = 10.5, 2.3 Hz,
1H), 7.33 (br dd, J = 8.3, 2.3 Hz, 1H), 7.07 (dd, J = 2.3, 1.0 Hz,
1H), 2.44 (s, 3H); 361.3 66 ##STR00125## Method M2 3.091 min.sup.6;
429 67 ##STR00126## P1.sup.14 8.46-8.49 (m, 2H), 8.05 (d, J = 5.9
Hz, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H),
7.26-7.29 (m, 1H, assumed; partially obscured by solvent peak),
7.04 (dd, J = 8.3, 2.0 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 6.88 (dd,
J = 2.2, 0.9 Hz, 1H), 5.17 (s, 2H), 2.54 (s, 3H), 2.04-2.12 (m,
1H), 1.01-1.08 (m, 2H), 0.94-0.99 (m, 2H); 441.9 68 ##STR00127##
Method M2 2.623 min.sup.6; 425 69 ##STR00128## Ex 23.sup.15 8.99
(s, 1H), 8.08 (d, J = 5.8 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.31
(dd, J = 5.8, 0.9 Hz, 1H), 7.17-7.22 (m, 3H), 6.94 (dd, J = 2.2,
1.0 Hz, 1H), 2.37 (s, 6H); 336.2 70 ##STR00129## Ex 1; C49 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 9.21 (s, 1H), 8.05 (d, J = 5.9
Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.57 (dd, J = 8.4, 8.4 Hz, 1H),
7.44 (dd, J = 5.9, 1.0 Hz, 1H), 7.32 (dd, J = 10.7, 2.3 Hz, 1H),
7.27 (ddd, J = 8.4, 2.3, 0.5 Hz, 1H), 7.00 (dd, J = 2.2, 0.9 Hz,
1H), 2.54 (s, 3H); 347.1 71 ##STR00130## Ex 1; C10 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 8.84 (s, 1H), 8.00 (d, J = 5.8 Hz, 1H),
7.91 (d, J = 2.0 Hz, 1H), 7.40 (br d, J = 6.0 Hz, 1H), 7.19 (d, J =
8.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.94- 6.96 (m, 1H), 6.91
(dd, J = 8.3, 2.3 Hz, 1H), 3.77 (s, 3H), 2.31 (s, 6H); 347.9 72
##STR00131## Ex 71.sup.11 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.
8.84 (s, 1H), 8.01 (d, J = 6.0 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H),
7.38-7.41 (m, 1H), 7.11-7.14 (m, 1H), 6.88-6.90 (m, 1H), 6.78-6.82
(m, 2H), 2.35 (s, 6H); 333.9 73 ##STR00132## Method M4 1.997
min.sup.5; 404 74 ##STR00133## Method M4 1.997 min.sup.5; 404 75
##STR00134## Ex 1 2.32 min.sup.9; 347.2 76 ##STR00135## Ex
20.sup.16; C49 8.72 (s, 1H), 8.08 (d, J = 5.8 Hz, 1H), 7.69 (d, J =
2.0 Hz, 1H), 7.23-7.31 (m, 2H, assumed; partially obscured by
solvent peak), 7.11- 7.16 (m, 2H), 6.91-6.94 (m, 1H), 3.96 (s, 3H),
2.37 (br s, 3H); 351.9 77 ##STR00136## Ex 5 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.86 (s, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.90
(d, J = 2.2 Hz, 1H), 7.38 (dd, J = 5.9, 1.0 Hz, 1H), 7.32-7.37 (m,
4H), 6.94 (dd, J = 2.2, 1.0 Hz, 1H), 2.35 (s, 6H); 318.1 78
##STR00137## Method M4 2.691 min.sup.6; 429 79 ##STR00138## Ex 1;
C52 .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.05 (d, J = 5.6 Hz,
1H), 7.68 (d, J = 2.2 Hz, 1H), 7.34 (br d, J = 8.5 Hz, 2H),
7.25-7.28 (m, 1H, assumed; partially obscured by solvent peak),
7.22 (br d, J = 8.5 Hz, 2H), 6.92 (dd, J = 2.2, 0.7 Hz, 1H), 2.26
(s, 6H); 334.1 80 ##STR00139## Ex 6; C2.sup.17 9.17 (s, 1H), 8.09
(d J = 5.8 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.46 (s, 1H),
7.35-7.38 (m, 1H), 7.29-7.33 (m, 3H), 6.97 (dd, J = 2.1, 0.9 Hz,
1H), 2.41 (s, 3H), 2.09 (s, 3H); 425.0 81 ##STR00140## Ex 18.sup.18
8.61 (s, 1H), 8.05 (d, J = 6.0 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H),
7.24-7.28 (m, 2H, assumed; partially obscured by solvent peak),
7.18- 7.22 (m, 1H), 7.14 (d, half of AB quartet, J = 8.3 Hz, 1H),
6.95 (dd, J = 2.3, 1.0 Hz, 1H), 4.64 (br s, 1H), 2.98 (d, J = 5.0
Hz, 3H), 2.13 (s, 3H), 2.09 (s, 3H); 347.0 82 ##STR00141## Ex 20;
C2.sup.19,20 9.19 (s, 1H), 8.06 (d, J = 5.9 Hz, 1H), 7.65 (br d, J
= 2.2 Hz, 1H), 7.21-7.28 (m, 3H), 7.16 (d, J = 8.2 Hz, 1H),
6.82-6.84 (m, 1H), 2.45 (s, 3H), 2.12 (s, 3H); 343.4 83
##STR00142## Ex 20; C2.sup.19,20 9.19 (s, 1H), 8.06 (d, J = 5.9 Hz,
1H), 7.65 (d, J = 2.2 Hz, 1H), 7.21-7.28 (m, 3H), 7.16 (d, J = 8.2
Hz, 1H), 6.82-6.84 (m, 1H), 2.45 (s, 3H), 2.11 (s, 3H); 343.4 84
##STR00143## Ex 1.sup.21 8.08 (d, J = 6.0 Hz, 1H), 7.64 (d, J = 2.3
Hz, 1H), 7.25-7.28 (m, 1H, assumed; partially obscured by solvent
peak), 7.22-7.24 (m, 1H), 7.17-7.20 (m, 1H), 7.15 (d, half of AB
quartet, J = 8.3 Hz, 1H), 6.79-6.81 (m, 1H), 5.29 (br s, 2H), 2.25
(s, 3H), 2.15 (s, 3H); 358.0 85 ##STR00144## Ex 20; C2, P4 9.06 (d,
J = 1.5 Hz, 1H), 8.08 (d, J = 5.9 Hz, 1H), 7.84 (d, J = 4.5 Hz,
1H), 7.70 (d, J = 2.2 Hz, 1H), 7.65 (dd, J = 4.6, 1.5 Hz, 1H), 7.34
(d, J = 8.2 Hz, 1H), 7.30-7.32 (m, 1H), 7.28 (dd, J = 5.9, 1.0 Hz,
1H), 7.24 (br dd, J = 8.3, 2.4 Hz, 1H), 6.96 (dd, J = 2.2, 1.0 Hz,
1H), 2.46 (s, 3H), 2.10 (br s, 3H); 357.2 86 ##STR00145## Ex 16; C2
.sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.94 (d, J = 6.0 Hz, 1H),
7.91 (d, J = 2.7 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.33 (br d, J =
6.0 Hz, 1H), 7.10-7.13 (m, 2H), 7.04 (dd, J = 8.3, 2.3 Hz, 1H),
6.90 (d, J = 2.7 Hz, 1H), 6.84-6.86 (m, 1H), 2.15 (s, 3H), 2.07 (s,
3H); 332.2 87 ##STR00146## Ex 18.sup.18 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.40 (s, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.89
(d, J = 2.3 Hz, 1H), 7.39 (dd, J = 5.9, 0.9 Hz, 1H), 7.24 (d, J =
8.3 Hz, 1H), 7.18 (br d, J = 2.3 Hz, 1H), 7.11 (br dd, J = 8.3, 2.5
Hz, 1H), 6.89 (dd, J = 2.1, 0.9 Hz, 1H), 2.86 (s, 6H), 2.10 (2 s,
total 6H); 361.1 88 ##STR00147## Ex 20; C2.sup.22 8.47 (dd, J =
4.9, 1.8 Hz, 1H), 8.07 (d, J = 5.9 Hz, 1H), 7.66 (d, J = 2.2 Hz,
1H), 7.43 (dd, J = 7.6, 1.8 Hz, 1H), 7.23-7.27 (m, 2H, assumed;
partially obscured by solvent peak), 7.18 (br d, J = 2.2 Hz, 1H),
7.14 (br dd, J = 8.2, 2.5 Hz, 1H), 7.09 (dd, J = 7.6, 4.7 Hz, 1H),
6.92 (dd, J = 2.2, 0.9 Hz, 1H), 2.18 (s, 3H), 1.78-1.86 (m, 1H),
1.08-1.16 (m, 2H), 0.78-0.93 (m, 2H); 343 89 ##STR00148## Ex 6; C2
4.07 min.sup.9; 330.2 90 ##STR00149## Ex 1.sup.77 2.455 min.sup.5;
352
91 ##STR00150## Ex 6; P5, C60 .sup.1H NMR (400 MHz, CD.sub.3CN)
.delta. 7.99 (d, J = 5.8 Hz, 1H), 7.93 (s, 1H), 7.85 (d, J = 2.3
Hz, 1H), 7.68-7.69 (m, 1H), 7.54 (ddq, J = 8.4, 2.4, 0.6 Hz, 1H),
7.41-7.45 (m, 1H), 7.36 (dd, J = 5.8, 1.0 Hz, 1H), 7.02 (dd, J =
2.2, 1.1 Hz, 1H), 5.02 (br s, 2H), 2.14 (s, 3H); 386.9 92
##STR00151## Ex 1; C49 2.25 min.sup.5; 321 93 ##STR00152## Ex 1;
C49 2.751 min.sup.6; 337 94 ##STR00153## Ex 1; C10 2.423 min.sup.5;
399 95 ##STR00154## Method M6 2.463 min.sup.5; 373 96 ##STR00155##
Method M6 2.286 min.sup.5; 425 97 ##STR00156## Method M6 2.464
min.sup.5; 391 98 ##STR00157## Method M6 2.522 min.sup.5; 405 99
##STR00158## Ex 1 8.98 (s, 1H), 8.01 (d, J = 5.8 Hz, 1H), 7.66 (d,
J = 2.3 Hz, 1H), 7.23 (br d, J = 5.8 Hz, 1H), 7.12 (d, J = 8.3 Hz,
1H), 6.94 (d, J = 8.3 Hz, 1H), 6.87-6.89 (m, 1H), 2.27 (s, 6H),
2.23 (s, 3H), 2.00 (s, 3H); 346.0 100 ##STR00159## Ex 2; Ex 91
.sup.1H NMR (400 MHz, CD.sub.3CN) .delta. 9.00 (s, 1H), 8.05 (d, J
= 5.8 Hz, 1H), 7.91 (br d, J = 2.5 Hz, 1H), 7.88 (br d, J = 2 Hz,
1H), 7.75 (ddq, J = 8.4, 2.3, 0.6 Hz, 1H), 7.67 (d, J = 1.0 Hz,
1H), 7.60 (br d, J = 8.4 Hz, 1H), 7.42 (dd, J = 5.8, 1.1 Hz, 1H),
7.15-7.16 (m, 1H), 7.05 (dd, J = 2.2, 1.0 Hz, 1H), 2.25 (s, 3H);
410.9 101 ##STR00160## Ex 5; P6 2.51 min.sup.9; 371.2 102
##STR00161## Ex 6; C2.sup.23 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.92 (s, 1H), 7.98 (d, J = 5.8 Hz, 1H), 7.92 (d, J = 2.3
Hz, 1H), 7.37-7.43 (m, 2H), 7.30 (br d, J = 2.3 Hz, 1H), 7.21 (dd,
J = 8.5, 2.3 Hz, 1H), 6.99 (dd, J = 2.2, 0.9 Hz, 1H), 3.65 (s, 3H),
3.01 (s, 3H), 2.19 (br s, 3H); 319.9 103 ##STR00162## Ex 5.sup.24
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.01 (s, 1H), 8.07 (d, J
= 5.9 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 5.9, 0.8 Hz,
1H), 7.05-7.08 (m, 2H), 6.87 (dd, J = 2.2, 0.9 Hz, 1H), 2.24 (s,
6H), 1.95 (br s, 6H); 346.2 104 ##STR00163## Ex 6; C2 1.90
min.sup.9; 331.1 105 ##STR00164## Ex 19.sup.25 11.15 (br s, 1H),
8.08 (d, J = 5.8 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.51-7.53 (m,
1H), 7.35 (d, J = 8.5 Hz, 1H), 7.22-7.31 (m, 3H, assumed; partially
obscured by solvent peak), 6.93-6.97 (m, 2H), 2.20 (s, 3H), 2.15
(s, 3H); 372.8 106 ##STR00165## Ex 19.sup.26 11.28 (br s, 1H), 8.08
(d, J = 5.8 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.50-7.53 (m, 1H),
7.34 (d, J = 8.0 Hz, 1H), 7.22-7.31 (m, 3H, assumed; partially
obscured by solvent peak), 6.92-6.97 (m, 2H), 2.20 (s, 3H), 2.15
(s, 3H); 372.8 107 ##STR00166## C4.sup.27 8.08 (d, J = 5.5 Hz, 1H),
7.69 (d, J = 2.0 Hz, 1H), 7.61 (br s, 1H), 7.23-7.33 (m, 4H,
assumed; partially obscured by solvent peak), 7.08 (br s, 1H),
6.93-6.96 (m, 1H), 4.21 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H); 387.1
108 ##STR00167## Ex 72.sup.14 8.96 (s, 1H), 8.06 (d, J = 5.8 Hz,
1H), 7.68 (d, J = 2.1 Hz, 1H), 7.28 (dd, J = 5.8, 0.8 Hz, 1H), 7.14
(d, J = 8.3 Hz, 1H), 7.02 (dd, J = 8.3, 2.1 Hz, 1H), 6.94 (d, J =
2.1 Hz, 1H), 6.88 (dd, J = 2.1, 0.8 Hz, 1H), 5.17 (s, 2H), 2.33 (s,
6H), 2.03-2.11 (m, 1H), 1.01-1.08 (m, 2H), 0.92-0.98 (m, 2H); 455.9
109 ##STR00168## C4.sup.28 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.26 (s, 1H), 8.11 (d, J = 6.0 Hz, 1H), 8.01-8.03 (m, 1H),
7.86-7.90 (m, 1H), 7.52-7.60 (m, 2H), 7.48- 7.51 (m, 1H), 7.37-7.43
(m, 1H), 6.92-6.96 (m, 1H), 3.06 (s, 3H), 2.48 (s, 3H), 2.15 (s,
3H); 370.9 110 ##STR00169## Ex 1.sup.29 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.63 (s, 1H), 8.00 (d, J = 5.9 Hz, 1H), 7.93
(d, J = 2.3 Hz, 1H), 7.67-7.69 (m, 1H), 7.41-7.44 (m, 2H),
7.36-7.38 (m, 1H), 7.27-7.31 (m, 2H), 7.03 (dd, J = 2.1, 0.9 Hz,
1H), 2.23 (s, 3H), 2.08 (br s, 3H); 357.1 111 ##STR00170## Ex
1.sup.29 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 8.64 (s, 1H),
8.00 (d, J = 6.0 Hz, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.68-7.70 (m,
1H), 7.40-7.45 (m, 2H), 7.36-7.39 (m, 1H), 7.27-7.32 (m, 2H), 7.03-
7.05 (m, 1H), 2.23 (s, 3H), 2.08 (br s, 3H); 357.1 112 ##STR00171##
C4.sup.30 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.99 (d, J =
5.9 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.58-7.60 (m, 1H), 7.39-7.43
(m, 2H), 7.30-7.33 (m, 2H), 7.21-7.25 (m, 1H), 7.02 (dd, J = 2.3,
0.9 Hz, 1H), 2.17 (s, 3H), 2.11 (br s, 3H); 371.9 113 ##STR00172##
Ex 16; C10 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 7.97 (d, J =
6.0 Hz, 1H), 7.86-7.88 (m, 2H), 7.36 (dd, J = 6.0, 1.0 Hz, 1H),
7.15 (d, J = 8.2 Hz, 1H), 6.96 (br d, J = 2.7 Hz, 1H), 6.95 (br d,
J = 2.2 Hz, 1H), 6.88 (dd, J = 2.2, 1.0 Hz, 1 H), 6.82 (dd, J =
8.2, 2.2 Hz, 1H), 3.74 (s, 3H), 2.20 (s, 3H); 348.1 114
##STR00173## Prep P7; C63.sup.31 .sup.1H NMR (400 MHz, CD.sub.3CN)
.delta. 8.95 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.86 (d, J = 2.2
Hz, 1H), 7.42 (dd, J = 5.8, 1.0 Hz, 1H), 7.10-7.15 (m, 2H), 7.00
(dd, J = 2.2, 1.0 Hz, 1H), 2.33 (s, 6H); 354.0 115 ##STR00174## Ex
11.sup.32 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.27 (s, 1H),
8.15 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 6.1 Hz, 1H), 7.49 (dd, J =
5.9, 1.1 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.25 (br d, J = 2.6 Hz,
1H), 7.17 (br dd, J = 8.4, 2.2 Hz, 1H), 7.10 (dd, J = 2.2, 0.9 Hz
1H), 2.09 (s, 3H), 2.03 (s, 3H); 374.0 116 ##STR00175## Method M1;
P14 .sup.1H NMR (400 MHz, CD.sub.3OD) .delta. 9.04 (s, 1H), 8.74
(s, 1H), 8.54 (d, J = 5.5 Hz, 1H), 7.97- 8.00 (m, 2H), 7.92 (d, J =
6.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.41-7.45 (m, 1H), 7.17 (dd, J = 2.0, 1.0 Hz, 1H), 2.26 (s, 6H);
369.0 117 ##STR00176## Ex 5; P8.sup.33 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.15 (d, J = 2.2 Hz, 1H), 8.04 (d, J = 5.8
Hz, 1H), 7.51 (dd, J = 5.8, 1.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H),
7.30 (br d, J = 2 Hz, 1H), 7.22 (br dd, J = 8, 2 Hz, 1H), 7.09 (dd,
J = 2.2, 1.0 Hz, 1H), 3.08 (s, 3H), 2.35 (s, 3H), 2.08 (s, 3H),
1.90 (s, 3H); 362.2 118 ##STR00177## Ex 82.sup.34 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 9.10 (s, 1H), 8.01 (d, J = 5.8 Hz, 1H),
7.85 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 6.0 Hz, 1H), 7.08-7.20 (m,
3H), 6.75-6.78 (m, 1H), 2.38 (s, 3H), 2.08 (s, 3H); 362.1 119
##STR00178## Ex 6; C52 8.60 (d, J = 5.7 Hz, 1H), 8.03-8.08 (m, 3H),
7.72 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.44 (dd, J =
5.8, 1.1 Hz, 1H), 7.38-7.42 (m, 2H), 7.25 (dd, J = 5.8, 1.0 Hz,
1H), 7.14 (dd, J = 2.3, 1.0 Hz, 1H), 6.90 (dd, J = 2.2, 1.0 Hz,
1H); 329.1 120 ##STR00179## Ex 5; P8.sup.35 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.10 (s, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.91
(d, J = 2.2 Hz, 1H), 7.40 (dd, J = 5.8, 1.0 Hz, 1H), 7.31 (d, J =
8.4 Hz, 1H), 7.29 (br d, J = 2.3 Hz, 1H), 7.22 (br dd, J = 8.3, 2.2
Hz, 1H), 6.97 (dd, J = 2.2, 0.9 Hz, 1H), 3.28 (s, 3H), 2.15 (br s,
3H), 2.06 (s, 3H); 348.1 121 ##STR00180## Ex 5; P8.sup.35 .sup.1H
NMR (400 MHz, CD.sub.3OD) .delta. 8.10 (s, 1H), 7.99 (d, J = 5.8
Hz, 1H), 7.91 (d, J = 2.2 Hz, 1H), 7.40 (dd, J = 5.8, 1.0 Hz, 1H),
7.31 (d, J = 8.4 Hz, 1H), 7.28-7.30 (m, 1H), 7.22 (br dd, J = 8, 2
Hz, 1H), 6.97 (dd, J = 2.2, 1.0 Hz, 1H), 3.28 (s, 3H), 2.15 (br s,
3H), 2.06 (s, 3H); 348.1 122 ##STR00181## Footnote 36 9.17 (s, 1H),
8.59 (s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H),
7.47 (d, J = 2.5 Hz, 1H), 7.32 (dd, J = 8.3, 2.5 Hz, 1H), 7.29 (br
d, J = 5.8 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.94-6.97 (m, 1H),
2.42 (s, 3H), 1.74 (s, 3H), 1.66 (s, 3H); 371.1 123 ##STR00182## Ex
5; P9 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.18 (d, J = 2.2
Hz, 1H), 8.14 (d, J = 0.9 Hz, 1H), 8.08 (d, J = 5.7 Hz, 1H), 7.56
(d, J = 8.4 Hz, 1H), 7.55 (dd, J = 5.7, 0.9 Hz, 1H), 7.49 (d, J =
1.3 Hz, 1H), 7.42 (br d, J = 2.2 Hz, 1H), 7.33 (dd, J = 8.4, 2.6
Hz, 1H), 7.13 (dd, J = 2.2, 0.9 Hz, 1H), 2.55 (s, 3H), 2.02 (s,
3H); 358.2 124 ##STR00183## C24.sup.37 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.58 (s, 1H), 7.99 (d, J = 5.8 Hz, 1H), 7.91 (d
J = 2.3 Hz, 1H), 7.40 (dd, J = 5.9, 0.9 Hz, 1H), 7.23-7.32 (m, 3H),
6.98 (dd, J = 2.3, 1.0 Hz, 1H), 3.33 (s, 3H), 2.16 (s, 3H), 1.88
(s, 3H); 348.1 125 ##STR00184## Ex 1.sup.38; C19 .sup.1H NMR (400
MHz, CD.sub.3OD) .delta. 7.97 (d, J = 6.0 Hz, 1H), 7.89 (d, J = 2.3
Hz, 1H), 7.75 (s, 1H), 7.38 (dd, J = 5.8, 0.8 Hz, 1H), 7.23 (d, J =
8.3 Hz, 1H), 7.21 (br d, J = 2.3 Hz, 1H), 7.14 (dd, J = 8.3, 2.5
Hz, 1H), 6.93 (dd, J = 2.1, 0.9 Hz, 1H), 2.18 (br s, 3H), 2.01 (s,
3H); 333.9 126 ##STR00185## Ex 16; C2 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.15 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 5.7
Hz, 1H), 7.50 (dd, J = 5.7, 0.7 Hz, 1H), 7.47 (dd, J = 9.1, 6.7 Hz,
1H), 7.33 (d, J = 8.4 Hz, 1H), 7.25 (br d, J = 2.2 Hz, 1H), 7.17
(br dd, J = 8.1, 2.4 Hz, 1H), 7.11 (dd, J = 2.2, 0.9 Hz, 1H), 6.45
(dd, J = 9.1, 1.2 Hz, 1H), 6.13 (dd, J = 6.8, 1.3 Hz, 1H), 3.13 (s,
3H), 2.12 (s, 3H); 333.2 127 ##STR00186## Method M1; P7 1.06
min.sup.39; 352.0 128 ##STR00187## Method M1, Prep P7 1.03
min.sup.39; 354.1 129 ##STR00188## Method M1, Prep P7.sup.40 1.03
min.sup.39; 350.1 130 ##STR00189## Method M1, Prep P7 0.97
min.sup.39; 336.1 131 ##STR00190## Method M1, Prep P7 1.02
min.sup.39; 350.1 132 ##STR00191## Ex 17.sup.41 1.85 min.sup.5; 331
133 ##STR00192## Method M7.sup.42; Ex 146 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 7.98 (d, J = 5.9 Hz, 1H), 7.92 (d, J = 2.2 Hz,
1H), 7.41 (br d, J = 8.4 Hz, 1H), 7.40 (dd, J = 5.9, 1.0 Hz, 1H),
7.32 (br d, J = 2.4 Hz, 1H), 7.25 (br dd, J = 8.3, 2.4 Hz, 1H),
7.11 (br d, J = 2 Hz, 1H), 7.02 (dd, J = 2.2, 1.0 Hz, 1H), 6.80 (br
d, J = 2 Hz, 1H), 2.17 (br s, 3H), 1.91 (s, 3H); 373.2 134
##STR00193## Ex 27.sup.43; C2 .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.82 (br s, 1H), 8.15 (d, J = 2.3 Hz, 1H), 8.04 (d, J =
5.8 Hz, 1H), 7.50 (br d, J = 5.8 Hz, 1H), 7.24-7.27 (m, 1H), 7.18
(br dd, half of ABX pattern, J = 8.4, 2.2 Hz, 1H), 7.15 (br d, half
of AB quartet, J = 8.2 Hz, 1H), 7.05-7.07 (m, 1H), 2.03 (s, 3H),
1.88 (s, 3H), 1.75 (s, 3H); 348.0 135 ##STR00194## Ex 12; C2.sup.44
8.99 (s, 1H), 8.06 (d, J = 5.9 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H),
7.26 (dd, J = 5.9, 1.0 Hz, 1H), 7.21 (br d, J = 2 Hz, 1H), 7.17 (br
dd, J = 8, 2 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 2.2,
1.0 Hz, 1H), 3.93 (s, 3H), 2.46 (s, 3H), 2.04 (br s, 3H); 348.2 136
##STR00195## Ex 5; C68.sup.45 .sup.1H NMR (600 MHz, DMSO-d.sub.6)
.delta. 8.15 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.99
(s, 1H), 7.49 (dd, J = 6, 1 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.22
(br d, J = 2 Hz, 1H), 7.15 (br dd, J = 8.4, 2.2 Hz, 1H), 7.07 (dd,
J = 2.2, 0.9 Hz, 1H), 2.13 (s, 3H), 2.07 (br s, 3H); 334.1 137
##STR00196## Ex 1.sup.46,38 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 8.01 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 6.0 Hz, 1H), 7.94
(d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 8.3 Hz,
1H), 7.43 (dd, J = 5.9, 0.9 Hz, 1H), 7.24-7.35 (m, 4H), 7.02 (dd, J
= 2.1, 0.9 Hz, 1H), 2.14 (s, 3H); 357.8 138 ##STR00197## Ex
12.sup.47 .sup.1H NMR (600 MHz, DMSO-d.sub.6), roughly 1:1 mixture
of regioisomeric N-oxides; .delta. 8.35 and 8.51 (2 s, total 1H),
8.14-8.16 (m, 1H), 8.04 (br s, J = 5.7 Hz, 1H), 7.49-7.52 (m, 1H),
7.26-7.30 (m, 1H), 7.18-7.23 (m, 2H), [7.07 (dd, J = 2.2, 0.9 Hz)
and 7.08 (dd, J = 2.2, 0.9 Hz), total 1H], 2.08 and 2.10 (2 s,
total 3H), 2.00 and 2.02 (2 s, total 3H), 1.94 (s, 3H); 348.2
##STR00198## 139 ##STR00199## Ex 5.sup.48 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.97 (s, 1H), 8.21 (d, J = 2.2 Hz, 1H), 8.03
(d, J = 5.7 Hz, 1H), 7.68 (dd, J = 9.6, 6.7 Hz, 1H), 7.62 (dd, J =
10.3, 6.8 Hz, 1H), 7.55 (dd, J = 5.8, 0.5 Hz, 1H), 7.22 (dd, J =
2.1, 0.8 Hz, 1H), 2.29 (s, 6H); 354.1 140 ##STR00200## Ex 12; C49
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.12 (s, 1H), 8.18 (d,
J = 2.3 Hz, 1H), 8.07 (d, J = 5.9 Hz, 1H), 7.55 (dd, J = 5.9, 1.0
Hz, 1H), 7.46 (dd, J = 8.4, 8.4 Hz, 1H), 7.44 (dd, J = 10.8, 2.2
Hz, 1H), 7.27 (br dd, J = 8.4, 2.3 Hz, 1H), 7.14 (dd, J = 2.2, 1.0
Hz, 1H), 2.41 (s, 3H), 2.12 (s, 3H); 336.2 141 ##STR00201## Ex
5.sup.49 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.98 (s, 1H),
8.21 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 5.7 Hz, 1H), 7.56 (dd, J =
5.9, 0.9 Hz, 1H), 7.43- 7.47 (m, 1H), 7.32-7.36 (m, 1H), 7.23 (dd,
J = 2.2, 0.9 Hz, 1H), 2.29 (s, 6H); 354.1 142 ##STR00202## Ex 12;
C10.sup.50 8.95 (s, 1H), 8.08 (d, J = 5.9 Hz, 1H), 7.68 (d, J = 2.2
Hz, 1H), 7.28 (dd, J = 5.9, 1.0 Hz, 1H), 7.03-7.06 (m, 1H),
6.93-6.96 (m, 2H), 6.91 (dd, J = 2.2, 1.0 Hz, 1H), 3.74 (s, 3H),
2.47 (s, 3H), 2.12 (s, 3H); 348.2 143 ##STR00203## Ex 12;
C10.sup.50 8.96 (s, 1H), 8.08 (d, J = 5.9 Hz, 1H), 7.68 (d, J = 2.2
Hz, 1H), 7.28 (dd, J = 5.9, 1.0 Hz, 1H), 7.03-7.07 (m, 1H),
6.93-6.97 (m, 2H), 6.91 (dd, J = 2.3, 1.0 Hz, 1H), 3.75 (s, 3H),
2.47 (s, 3H), 2.12 (s, 3H); 348.2 144 ##STR00204## Method M1; P10
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.93 (s, 1H), 8.19 (s,
1H), 8.18 (d, J = 2.2 Hz, 1H), 8.02 (d, J
= 5.9 Hz, 1H), 7.53 (dd, J = 5.8, 1.0 Hz, 1H), 7.19 (d, J = 7.5 Hz,
1H), 7.13 (dd, J = 2.2, 1.1 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 4.06
(s, 3H), 2.20 (s, 6H); 372.0 145 ##STR00205## Ex 12.sup.51 .sup.1H
NMR (600 MHz, DMSO-d.sub.6) .delta. 9.16 (d, J = 5.0 Hz, 1H), 8.15
(d, J = 2.2 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.52 (d, J = 5.0 Hz,
1H), 7.49 (dd, J = 5.8, 1.0 Hz, 1H), 7.23-7.26 (m, 2H), 7.17 (br
dd, J = 8.2, 2.3 Hz, 1H), 7.10 (dd, J = 2.2, 0.9 Hz, 1H), 2.43 (s,
3H), 2.04 (s, 3H); 318.1 146 ##STR00206## Ex 20; C2.sup.52,53,54
Characteristic peaks: 8.57 (s, 1H), 8.08 (d, J = 5.5 Hz, 1H), 7.71
(d, J = 2.0 Hz, 1H), 7.05 (br s, 1H), 6.94-6.98 (m, 1H), 2.19 (s,
3H), 2.07 (s, 3H); 357.1 147 ##STR00207## Ex 20; C2.sup.52,53,54
Characteristic peaks: 8.56 (s, 1H), 8.08 (d, J = 6.0 Hz, 1H),
7.72-7.75 (m, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.02-7.05 (m, 1H),
6.95-6.97 (m, 1H), 2.19 (s, 3H), 2.07 (s, 3H); 357.0 148
##STR00208## Method M1; P11 .sup.1H NMR (600 MHz, DMSO-d.sub.6)
.delta. 9.01 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 5.7
Hz, 1H), 7.86 (s, 1H), 7.55 (br d, J = 6.2 Hz, 1H), 7.25 (d, J =
7.9 Hz, 1H), 7.15-7.17 (m, 1H), 7.10 (d, J = 7.5 Hz, 1H), 3.46 (s,
3H), 2.21 (s, 6H); 372.1 149 ##STR00209## Ex 152.sup.55 .sup.1H NMR
(400 MHz, CD.sub.3OD) .delta. 7.98 (d, J = 6.0 Hz, 1H), 7.88 (d, J
= 2.0 Hz, 1H), 7.38 (d, J = 6.0 Hz, 1H), 7.20-7.23 (m, 1H),
7.11-7.17 (m, 2H), 6.89-6.92 (m, 1H), 4.03 (s, 3H), 2.19 (s, 6H),
2.05 (s, 3H); 361.9 150 ##STR00210## Ex 12; C52 8.99 (s, 1H), 8.06
(d, J = 5.8 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.37-7.41 (m, 2H),
7.26-7.29 (m, 1H, assumed; partially obscured by solvent peak),
7.19-7.23 (m, 2H), 6.93 (dd, J = 2.3, 1.0 Hz, 1H), 2.53 (s, 3H),
2.17 (s, 3H); 318.0 151 ##STR00211## Ex 11.sup.56 2.80 min.sup.12;
361.2 152 ##STR00212## Ex 1.sup.57 8.06 (d, J = 6.0 Hz, 1H), 7.67
(d, J = 2.3 Hz, 1H), 7.25-7.28 (m, 1H, assumed; partially obscured
by solvent peak), 7.22 (br d, J = 2.3 Hz, 1H), 7.16 (br dd, half of
ABX pattern, J = 8, 2 Hz, 1H), 7.10 (d, half of AB quartet, J =
8.0, 1H), 6.90 (dd, J = 2, 1 Hz, 1H), 2.18 (s, 6H), 2.12 (br s,
3H); 347.9 153 ##STR00213## Ex 37.sup.11 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.39 (d, J = 6.6 Hz, 1H), 8.20 (d, J = 2.3 Hz,
1H), 8.03-8.06 (m, 2H), 7.97 (br d, half of AB quartet, J = 9.2 Hz,
1H), 7.92 (dd, J = 6.7, 0.9 Hz, 1H), 7.75 (dd, J = 2.2, 0.7 Hz,
1H), 7.63 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.22 (dd,
J = 8.4, 2.3 Hz, 1H), 6.65 (dd, J = 2.3, 1.0 Hz, 1H), 2.39 (s, 3H);
LCMS m/z 356.1 (M - H). 154 ##STR00214## Ex 22.sup.58; Ex 11
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 9.23 (s, 1H), 9.00 (s,
1H), 8.15 (d, J = 2.2 Hz, 1H), 8.02 (d, J = 5.7 Hz, 1H), 7.49 (dd,
J = 5.7, 0.9 Hz, 1H), 7.26 (br d, J = 2.2 Hz, 1H), 7.25 (d, J = 8.4
Hz, 1H), 7.18 (br dd, J = 8.4, 2.6 Hz, 1H), 7.10 (dd, J = 2.2, 0.9
Hz, 1H), 2.15 (s, 3H), 2.05 (s, 3H); 318.0 155 ##STR00215## Ex 8;
C63.sup.59 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.93 (s,
1H), 8.34 (d, J = 5.7 Hz, 1H), 8.10 (d, J = 2.2 Hz, 1H), 7.61-7.62
(m, 1H), 7.58 (dd, J = 5.7, 0.9 Hz, 1H), 7.49 (br dd, J = 7.9, 1.8
Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 6.59 (dd, J = 2.2, 0.9 Hz, 1H),
2.15 (s, 6H), 1.96 (s, 3H); 348.0 156 ##STR00216## Ex 6; P13
.sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.92 (s, 1H), 8.17 (d,
J = 2.2 Hz, 1H), 8.03 (d, J = 5.7 Hz, 1H), 7.50 (dd, J = 5.7, 0.9
Hz, 1H), 7.14 (dd, J = 2.2, 1.1 Hz, 1H), 6.92 (AB quartet, J.sub.AB
= 8.6 Hz, .DELTA..nu..sub.AB = 58.5 Hz, 2H), 6.04 (s, 2H), 2.32 (s,
6H), 362.0 157 ##STR00217## Ex 11.sup.60 .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.88 (s, 1H), 8.14 (d, J = 2.2 Hz, 1H), 8.03
(d, J = 5.7 Hz, 1H), 7.49 (dd, J = 5.7, 0.9 Hz, 1H), 7.21- 7.23 (m,
1H), 7.12-7.17 (m, 2H), 7.05 (dd, J = 2.2, 0.9 Hz, 1H), 4.53 (dq, J
= 10.8, 7.0 Hz, 1H), 4.43 (dq, J = 10.8, 7.0 Hz, 1H), 2.03 (s, 3H),
1.99 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H); 362.0 158 ##STR00218## Ex
10; C63.sup.61 .sup.1H NMR (500 MHz, CDCl.sub.3), 6 9.04 (s, 1H),
8.89 (dd, J = 4.2, 1.7 Hz, 1H), 8.51 (dd, J = 8.5, 1.8 Hz, 1H),
8.03 (d, J = 5.7 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.54 (AB
quartet, J.sub.AB = 7.8 Hz, .DELTA..nu..sub.AB = 28.4 Hz, 2H), 7.45
(dd, J = 8.4, 4.2 Hz, 1H), 7.30-7.32 (m, 1H), 7.00- 7.01 (m, 1H),
2.24 (s, 6H); 368.9 159 ##STR00219## Ex 134.sup.62 8.06 (d, J = 5.8
Hz, 1H), 7.66 (d, J = 2 Hz, 1H), 7.25-7.28 (m, 1H, assumed;
partially obscured by solvent peak), 7.20-7.22 (m, 1H), 7.17 (dd, J
= 8.2, 2.3 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.86-6.89 (m, 1H),
3.83 (s, 3H), 2.08 (s, 3H), 2.00 (s, 3H), 1.96 (s, 3H); 362.1 160
##STR00220## Ex 27.sup.77 8.08 (d, J = 5.9 Hz, 1H), 7.70 (d, J =
2.2 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.29-7.35 (m, 2H), 7.17 (d,
J = 8.4 Hz, 1H), 6.93 (dd, J = 2.4, 1.0 Hz, 1H), 2.07 (s, 3H), 2.00
(s, 3H); 368.0 161 ##STR00221## Ex 6; C52, C55 8.09 (d, J = 5.8 Hz,
1H), 7.70 (d, J = 2.2 Hz, 1H), 7.57 (br d, J = 9.2 Hz, 1H), 7.54
(d, J = 1.2 Hz, 1H), 7.43-7.49 (m, 4H), 7.29 (dd, J = 5.8, 1.0 Hz,
1H), 7.23-7.24 (m, 1H), 7.17 (d, J = 9.2 Hz, 1H), 6.96 (dd, J =
2.2, 1.0 Hz, 1H), 2.21 (s, 3H); 342.1 162 ##STR00222## Ex 5, Prep
P6.sup.63 2.53 min.sup.9; 371.1 163 ##STR00223## Method M6 2.511
min.sup.5; 405 164 ##STR00224## Method M6 2.382 min.sup.5; 439 165
##STR00225## Method M6 2.413 min.sup.5; 361 166 ##STR00226## Ex 16;
C10.sup.64 .sup.1H NMR (600 MHz, DMSO-d.sub.6) .delta. 8.16 (d, J =
2.2 Hz, 1H), 8.03 (d, J = 5.7 Hz, 1H), 7.51 (d, J = 5.7 Hz, 1H),
7.43 (dd, J = 9.0, 6.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.11 (br
d, J = 1.8 Hz, 1H), 7.08 (d, J = 2.2 Hz, 1H), 6.91 (dd, J = 8.3,
2.2 Hz, 1H), 6.42 (dd, J = 9.2, 0.9 Hz, 1H), 6.13 (dd, J = 6.6, 1.3
Hz, 1H), 3.78 (s, 3H), 3.18 (s, 3H); 349.2 167 ##STR00227## Method
M6 2.552 min.sup.5; 385 168 ##STR00228## Ex 8.sup.65; C52 .sup.1H
NMR (500 MHz, CD.sub.3OD) .delta. 9.16 (s, 1H), 8.26 (d, J = 6.3
Hz, 1H), 8.21 (d, J = 9.0 Hz, 1H), 8.00 (d, J = 6.1 Hz, 1H), 7.90
(d, J = 2.2 Hz, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 6.3 Hz,
1H), 7.37-7.42 (m, 3H), 7.31-7.36 (m, 2H), 6.93-6.98 (m, 1H), 3.96
(s, 3H); 369.0 169 ##STR00229## Ex 12; C10 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.94 (s, 1H), 7.97 (d, J = 6.0 Hz, 1H), 7.87
(d, J = 2.3 Hz, 1H), 7.37 (dd, J = 6.0, 1.1 Hz, 1H), 7.14 (d, J =
8.4 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 6.88- 6.93 (m, 2H), 3.73 (s,
3H), 2.40 (s, 3H), 2.14 (s, 3H); 348.0 170 ##STR00230## Ex 6.sup.77
2.554 min.sup.5; 363 171 ##STR00231## Ex 12; C2.sup.66 8.99 (s,
1H), 8.07 (d, J = 5.9 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.15-7.27
(m, 3H), 7.07 (d, J = 8.2 Hz, 1H), 6.89 (dd, J = 2.2, 1.0 Hz, 1H),
3.94 (s, 3H), 2.48 (s, 3H), 2.04 (s, 3H); 348.2 172 ##STR00232## Ex
6; C45, C52 2.00 min.sup.67; 343.1 173 ##STR00233## Ex 6; C45, C10
.sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 9.33 (br s, 1H), 8.10 (d,
J = 5.9 Hz, 1H), 7.82 (br s, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.37
(d, J = 8.0 Hz, 1H), 7.35-7.37 (m, 1H), 7.33 (dd, J = 5.7, 0.9 Hz,
1H), 7.04-7.08 (m, 2H), 6.98 (dd, J = 2.1, 0.8 Hz, 1H), 3.76 (s,
3H), 2.51 (s, 3H); 373.0 174 ##STR00234## Ex 16; C2 8.03 (d, J =
5.9 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.63 (br d, J = 9.2 Hz, 1H),
7.59 (d, J = 1.4 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.16- 7.27 (m,
5 H), 6.92 (dd, J = 2.1, 1.0 Hz, 1H), 6.70 (dd, J = 6.8, 1.0 Hz,
1H), 2.08 (s, 3H); 342.1 175 ##STR00235## Method M6 2.525
min.sup.6; 437 176 ##STR00236## Ex 6; C2.sup.68 3.26 min.sup.9;
342.1 177 ##STR00237## Ex 5; C67.sup.69 8.07 (d, J = 5.9 Hz, 1H),
7.67 (d, J = 2.4 Hz, 1H), 7.27-7.31 (m, 2H), 7.17-7.22 (m, 2H),
6.85 (dd, J = 2.2, 1.0 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H); 335.3
178 ##STR00238## Method M6 2.586 min.sup.5; 387 179 ##STR00239##
Method M6 2.521 min.sup.6; 417 180 ##STR00240## Method M6 2.388
min.sup.5; 417 181 ##STR00241## Ex 6; C10 .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. 8.71 (dd, J = 5.8, 1.3 Hz, 1H), 8.45 (dd, J =
7.8, 1.3 Hz, 1H), 7.95-8.02 (m, 2H), 7.92 (d, J = 2.5 Hz, 1H), 7.42
(dd, J = 6.0, 1.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.11 (d, J =
2.0 Hz, 1H), 6.95- 6.99 (m, 2H), 3.81 (s, 3H), 2.67 (s, 3H); 333.2
182 ##STR00242## Method M2 3.271 min.sup.6; 444 183 ##STR00243##
Method M6 2.422 min.sup.5; 436 184 ##STR00244## Ex 1; C52 2.174
min.sup.5; 303 185 ##STR00245## Method M6 2.519 min.sup.5; 405 186
##STR00246## Method M2 2.448 min.sup.5; 453 187 ##STR00247## Method
M6 2.393 min.sup.5; 417 188 ##STR00248## Method M2 3.175 min.sup.6;
442 189 ##STR00249## Ex 6; C2 2.45 min.sup.9; 343.2 190
##STR00250## Ex 72.sup.70 9.12 (s, 1H), 8.07 (d, J = 6.0 Hz, 1H),
7.70 (d, J = 2.0 Hz, 1H), 7.31 (d, J = 5.5 Hz, 1H), 7.11 (br d, J =
8.5 Hz, 1H), 6.99-7.04 (m, 2H), 6.93 (br s, 1H), 4.07-4.13 (m, 2H),
3.52-3.58 (m, 2H), 3.27 (s, 3H), 2.60 (s, 6H); 392.0 191
##STR00251## Ex 1; C10 2.569 min.sup.6; 348 192 ##STR00252## Ex 20;
C49.sup.71 8.68 (s 1H), 8.08 (d, J = 6.0 Hz, 1H), 7.68 (d, J = 2.5
Hz, 1H), 7.24-7.31 (m, 2H), 7.10-7.16 (m, 2H), 6.91 (br d, J = 2
Hz, 1H), 4.37-4.50 (m, 2H), 2.36 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H);
366.1 193 ##STR00253## Ex 1.sup.77 2.634 min.sup.5; 353 194
##STR00254## Method M4 2.646 min.sup.6 195 ##STR00255## Method M2
2.685 min.sup.72; 402 196 ##STR00256## Ex 1.sup.77 2.911 min.sup.5;
338 197 ##STR00257## Ex 8; C52 8.07 (d, J = 5.8 Hz, 1H), 7.74-7.76
(m, 1H), 7.69-7.73 (m, 3H), 7.63-7.67 (m, 2H), 7.42 (br d, J = 8.6
Hz, 2H), 7.26-7.31 (m, 2H, assumed; partially obscured by solvent
peak), 6.97 (dd, J = 2.2, 1.0 Hz, 1H), 6.79 (dd, J = 6.9, 1.1 Hz,
1H); 328.0 198 ##STR00258## Method M6 2.452 min.sup.6; 430 199
##STR00259## Method M2 3.121 min.sup.6; 430 200 ##STR00260## Ex 6;
C1 .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.08 (d, J = 5.9 Hz,
1H), 8.04 (s, 1H), 7.74 (dd, J = 6.6, 2.7 Hz, 1H), 7.67 (d, J = 2.2
Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.25 (d, J = 5.9 Hz, 1H), 7.18-
7.22 (m, 3H), 7.10-7.18 (m, 1H), 6.88-6.96 (m, 1H), 3.60 (s, 3H),
2.08 (s, 3H); 356.1 201 ##STR00261## Method M2 2.523 min.sup.6; 443
202 ##STR00262## Method M6 2.721 min.sup.72; 417 203 ##STR00263##
Method M6 2.427 min.sup.6; 389 204 ##STR00264## Ex 20.sup.73 8.05
(d, J = 6.0 Hz, 1H), 7.71 (d, J = 2.0 Hz, 1 H), 7.70 (d, J = 2.5
Hz, 1H), 7.51-7.57 (m, 2H), 7.42 (d, J = 8.5 Hz, 1H), 7.31 (br d, J
= 5.8 Hz, 1H), 6.97-6.99 (m, 1H), 6.31-6.33 (m, 1H), 3.70 (s, 3H);
360.3 205 ##STR00265## Method M4 2.616 min.sup.6; 403 206
##STR00266## Ex 24.sup.74 8.71 (s, 1H), 8.07 (d, J = 5.9 Hz, 1H),
7.66 (d, J = 2.2 Hz, 1H), 7.25 (dd, J = 5.9, 0.8 Hz, 1H), 7.19 (br
d, J = 2.2 Hz, 1H), 7.14 (dd, half of ABX pattern, J = 8.2, 2.4 Hz,
1H), 7.10 (d, half of AB pattern, J = 8.2 Hz, 1H), 6.88 (dd, J =
2.2, 0.8 Hz, 1H), 3.93 (s, 3H), 2.27 (s, 3H), 2.06 (br s, 3H);
348.4 207 ##STR00267## Ex 2.sup.75; C4 8.09 (d, J = 5.8 Hz, 1H),
7.91 (br s, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.30-7.38 (m, 5H), 6.97
(br d, J = 2 Hz, 1H), 2.43 (s, 3H), 2.07 (s, 3H); 381.9 208
##STR00268## Ex 18, step1; C52 .sup.1H NMR (400 MHz, CD.sub.3OD)
.delta. 9.26 (s, 1H), 8.01 (d, J = 5.9 Hz, 1H), 7.87-7.93 (m, 3H),
7.81 (dd, J = 8.6, 1.0 Hz, 1H), 7.67-7.72 (m, 1H), 7.51 (dd, J =
7.8, 2.0 Hz, 1H), 7.40-7.46 (m, 3H), 6.98 (dd, J = 2.2, 0.9 Hz,
1H), 4.12 (s, 3H); 370.1
1. HPLC conditions. Column: Welch XB-C18, 2.1.times.50 mm, 5 .mu.m;
Mobile phase A: 0.05% ammonium hydroxide in water (v/v); Mobile
phase B: acetonitrile. 2. HPLC Conditions. Column: Welch XB-C18,
2.1.times.50 mm, 5 .mu.m; Mobile phase A: 0.05% trifluoroacetic
acid in water (v/v); Mobile phase B: acetonitrile. 3. Example 16
was N-formylated to provide
N-[5-(furo[3,2-c]pyridin-4-yloxy)-2-(imidazo[1,2-a]pyridin-5-yl)phenyl]fo-
rmamide by heating in methyl formate in the presence of sodium
hydride and
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II).
Reduction with borane-dimethylsulfide complex provided Example 38.
4. In this case, 4-amino-3-chlorophenol was used as starting
material, and the phenol was carried through construction of the
imidazo[4,5-c]pyridine without protection. 5. HPLC conditions.
Column: Waters XBridge C18, 2.1.times.50 mm, 5 .mu.m; Mobile phase
A: 0.0375% trifluoroacetic acid in water; Mobile phase B: 0.01875%
trifluoroacetic acid in acetonitrile; Gradient: 10% to 100% B over
4.0 minutes; Flow rate: 0.8 mL/minute. 6. HPLC conditions. Column:
Waters XBridge C18, 2.1.times.50 mm, 5 .mu.m; Mobile phase A:
0.0375% trifluoroacetic acid in water; Mobile phase B: 0.01875%
trifluoroacetic acid in acetonitrile; Gradient: 1% to 5% B over 0.6
minutes, then 5% to 100% B over 3.4 minutes; Flow rate: 0.8
mL/minute. 7. This example was prepared via reductive amination of
Example 16 with 1-methyl-1H-imidazole-5-carbaldehyde. 8. Coupling
partner 3-bromo-4-methylpyridine-2-carbonitrile may be prepared
from 3-bromo-4-methylpyridine by generation of the pyridine N-oxide
through reaction with hydrogen peroxide, followed by cyanation
according to the method of T. Sakamoto et al., Chem. Pharm. Bull.
1985, 33, 565-571. 9. HPLC conditions. Column: Waters Atlantis
dC18, 4.6.times.50 mm, 5 .mu.m; Mobile phase A: 0.05%
trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%
trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B
over 4.0 minutes, linear; Flow rate: 2 mL/minute. 10. Example 17
was N-methylated using sodium hydride and methyl iodide. 11. The
final step in the synthesis was cleavage of the methyl ether using
boron tribromide. 12. HPLC conditions. Column: Waters XBridge C18,
4.6.times.50 mm, 5 .mu.m; Mobile phase A: 0.03% ammonium hydroxide
in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in
acetonitrile (v/v); 5.0% to 95% B over 4.0 minutes, linear; Flow
rate: 2 mL/minute. 13. In this case, the Suzuki coupling was
carried out using tetrakis(triphenylphosphine)palladium(0) and
potassium carbonate or sodium carbonate. 14. The starting material
was alkylated using 5-(Chloromethyl)-3-cyclopropyl-1,2,4-oxadiazole
and cesium carbonate. 15. 1-Bromo-2-fluoro-4-methoxybenzene was
used as starting material. 16. 5-Bromo-4-methoxy-6-methylpyrimidine
was prepared by reaction of 5-bromo-4-chloro-6-methylpyrimidine
with sodium methoxide. 17. The requisite
5-bromo-6-methyl-2-(trifluoromethyl)imidazo[1,2-a]pyrazine was
prepared via reaction of C60 with
3-bromo-1,1,1-trifluoropropan-2-one. 18. Example 18 was treated
with the appropriate amine. 19. The requisite
5-bromo-6-methylpyrimidine-4-carbonitrile was prepared via reaction
of 5-bromo-4-chloro-6-methylpyrimidine with tetra-n-butylammonium
cyanide. 20. The product was separated into its component
atropenantiomers using supercritical fluid chromatography (Column:
Chiralpak AD-H, 5 .mu.m; Eluent: 3:1 carbon dioxide/propanol). The
first-eluting compound was Example 83 and the second-eluting
atropenantiomer was Example 82. 21. The requisite
2-amino-5-bromo-6-methylpyrimidine-4-carbonitrile may be prepared
via reaction of 5-bromo-4-chloro-6-methylpyrimidin-2-amine with
tetraethylammonium cyanide and 1,4-diazabicyclo[2.2.2]octane in a
mixture of acetonitrile and N,N-dimethylformamide. 22. The required
3-bromo-2-cyclopropylpyridine was prepared via reaction of
2,3-dibromopyridine with cyclopropylboronic acid at 100.degree. C.
in the presence of palladium(II) acetate, tricyclohexylphosphine
and potassium phosphate. 23. The requisite
5-bromo-1,4-dimethyl-1H-imidazole may be prepared via methylation
of 5-bromo-4-methyl-1H-imidazole using sodium hydride and methyl
iodide. 24. Suzuki reaction of
(4-methoxy-2,6-dimethylphenyl)boronic acid with
5-bromo-4,6-dimethylpyrimidine, mediated by
tris(dibenzylideneacetone)dipalladium(0) and
dicyclohexyl(2',6'-dimethoxybiphenyl-2-yl)phosphane, followed by
cleavage of the methyl ether, afforded the requisite phenol. 25.
Obtained from supercritical fluid chromatographic separation of
Example 19 [Column: Chiralcel AS, 20 .mu.m; Mobile phase 7:3 carbon
dioxide/(methanol containing 0.2% diethylamine)]. This Example was
the second-eluting atropenantiomer from the column. 26. This was
the first-eluting atropenantiomer from the separation described in
footnote 25. 27. Compound C4 was heated with aqueous
chloroacetaldehyde at reflux for 2 hours, affording
8-bromo-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo-
[1,2-a]pyrazine. Reaction of this intermediate with sodium
methoxide in methanol provided Example 107. 28. The 8-bromo
intermediate from footnote 27 was subjected to reaction with
trimethylboroxin in the presence of
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and
potassium carbonate to provide Example 109. 29. Reaction of
chloroacetaldehyde with 2-amino-5-methylpyrimidin-4-ol afforded a
mixture of 6-methylimidazo[1,2-a]pyrimidin-5-ol and
6-methylimidazo[1,2-a]pyrimidin-7-ol, which was subjected to
reaction with phosphorus oxychloride, providing a mixture of
5-chloro-6-methylimidazo[1,2-a]pyrimidine and
7-chloro-6-methylimidazo[1,2-a]pyrimidine. Reaction of this mixture
with C2 yielded a separable mixture of Examples 110 and 111. The
structures of these two compounds were subsequently assigned using
NOE studies carried out on the separated intermediates
6-methylimidazo[1,2-a]pyrimidin-5-ol and
6-methylimidazo[1,2-a]pyrimidin-7-ol. 30. The 8-bromo intermediate
from footnote 27 was subjected to reaction with tert-butyl
carbamate in the presence of palladium(II) acetate,
1,1'-binaphthalene-2,2'-diylbis(diphenylphosphane) and cesium
carbonate, at 120.degree. C. for 2 hours, to afford Example 112.
31. The requisite
4-(4-bromo-3,5-difluorophenoxy)furo[3,2-c]pyridine was prepared
from 4-chlorofuro[3,2-c]pyridine and 4-bromo-3,5-difluorophenol,
using the general method of Example 17, step 3. 32. Example 11 was
reacted with hydrazine. The resulting
4-[4-(3-hydrazinyl-5-methylpyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyr-
idine was cyclized with 1,1'-carbonyldiimidazole to provide the
product. 33. Example 117 was isolated as a side product during the
synthesis of Examples 120 and 121, derived from an over-methylated
contaminant in P8. 34. The racemic version of Example 82 was
hydrolyzed with aqueous sodium hydroxide in ethanol to provide the
product. 35. The racemic product was separated via supercritical
fluid chromatography (Column: Chiralcel OJ-H, 5 .mu.m; Eluent: 3:1
carbon dioxide/methanol). Example 121 eluted first, followed by
Example 120. 36. (2-Chloro-5-methoxyphenyl)acetonitrile (see C.
Pierre and O. Baudoin, Org. Lett. 2011, 13, 1816-1819) may be
dimethylated using sodium hydride and methyl iodide to provide
2-(2-chloro-5-methoxyphenyl)-2-methylpropanenitrile. Suzuki
reaction with
4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine
was followed by cleavage of the methyl ether with the sodium salt
of ethanethiol, which afforded the requisite
2-[5-hydroxy-2-(4-methylpyrimidin-5-yl)phenyl]-2-methylpropanenitrile.
Reaction with 4-chlorofuro[3,2-c]pyridine was mediated by
tris(dibenzylideneacetone)dipalladium(0), tricyclohexylphosphine
and cesium carbonate. 37. Compound C24 was reacted with
1-methylurea and p-toluenesulfonic acid to provide the product. 38.
The protecting group was removed in the final step, with a solution
of hydrogen chloride in methanol. 39. HPLC conditions: Column:
Acquity HSS T3, 2.1.times.50 mm, 1.8 .mu.m; Mobile phase A: 0.05%
trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%
trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 98% B
over 1.6 minutes; Flow rate: 1.3 mL/minute. 40. Reaction of
1-fluoro-2-methoxy-4-methylbenzene with N-bromosuccinimide provided
the requisite 1-bromo-5-fluoro-4-methoxy-2-methylbenzene. 41. In
this case, reduction of the nitro group to the aniline was achieved
by hydrogenation with Pd/C in a 1:1 mixture of ethanol and
methanol. The final coupling reaction employed
tris(dibenzylideneacetone)dipalladium(0) as the palladium source.
42. The crude metabolite mixture was first purified by silica gel
chromatography (Eluent: 10% 2-propanol in toluene), then subjected
to HPLC separation (Column: Kromasil C18, 10 .mu.m; Eluent: 3:2
methanol/water). Product fractions were concentrated in vacuo, and
the aqueous residue was extracted with ethyl acetate (2.times.50
mL). The combined organic layers were concentrated under reduced
pressure to provide the product. 43. The racemic product was
separated into atropenantiomers via HPLC (Column: Phenomenex Lux
Cellulose-3, 5 .mu.m; Gradient: 5% to 95% ethanol in heptane). The
first-eluting atropenantiomer is the compound of this Example. 44.
Compound C2 was coupled with
4-chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one,
which may be prepared according to B. Dyck et al., J. Med. Chem.
2006, 49, 3753-3756, in the presence of
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and
cesium carbonate. The resulting
4-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-5-methoxy-2-(tetrahydro-
-2H-pyran-2-yl)pyridazin-3(2H)-one was converted to the product
using the methods of Examples 10, 11 and 12. The racemic product
was separated into its component atropenantiomers using
supercritical fluid chromatography (Column: Chiralpak AS-H, 5
.mu.m; Eluent: 3:1 carbon dioxide/methanol). Example 135 was the
first-eluting atropenantiomer. 45. Cleavage of the methyl ether of
C68 with boron tribromide gave the requisite
6-(4-hydroxy-2-methylphenyl)-5-methylpyrazin-2-ol. 46. Reaction of
2-amino-6-bromopyridin-3-ol with chloroacetaldehyde, followed by
protection with benzyl chloromethyl ether, afforded the requisite
8-[(benzyloxy)methoxy]-5-bromoimidazo[1,2-a]pyridine. 47. Example
12 was reacted with hydrogen peroxide and maleic anhydride to
provide a roughly 1:1 mixture of
4-[4-(3,5-dimethyl-2-oxidopyridazin-4-yl)-3-methylphenoxy]furo[3,2-c]pyri-
dine and
4-[4-(3,5-dimethyl-1-oxidopyridazin-4-yl)-3-methylphenoxy]furo[3,-
2-c]pyridine. 48. 4-(4,6-Dimethylpyrimidin-5-yl)-2,5-difluorophenol
was prepared from (2,5-difluoro-4-methoxyphenyl)boronic acid and
5-bromo-4,6-dimethylpyrimidine using the general method of Example
6, followed by cleavage of the methyl ether. 49.
5-Bromo-4,6-dimethylpyrimidine was reacted with
(2,3-difluoro-4-methoxyphenyl)boronic acid according to the general
procedure for the synthesis of 1 in Example 1. The resulting
5-(2,3-difluoro-4-methoxyphenyl)-4,6-dimethylpyrimidine was
deprotected with boron tribromide to yield the requisite
4-(4,6-dimethylpyrimidin-5-yl)-2,3-difluorophenol. 50. The racemic
product was separated via supercritical fluid chromatography
(Column: Chiralpak AS-H, 5 .mu.m; Eluent: 4:1 carbon
dioxide/methanol). Example 143 eluted first, followed by Example
142. 51. Starting material
4-bromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one was
prepared according to C. Aciro et al., PCT Int. Appl. (2010) WO
2010131147 A1 20101118. 52. 2-Amino-5-methylpyrimidin-4-ol was
reacted with chloroacetaldehyde to afford
6-methylimidazo[1,2-a]pyrimidin-5-ol; this was chlorinated with
phosphorus oxychloride to provide the requisite
5-chloro-6-methylimidazo[1,2-a]pyrimidine. 53. Chiral separation
was carried out using supercritical fluid chromatography (Column:
Chiralpak AD-H, 5 .mu.m; Eluent: 65:35 carbon dioxide/ethanol). 54.
On Chiralpak AD-H analysis [5 .mu.m, supercritical fluid
chromatography; Gradient: 5% to 40% (ethanol containing 0.05%
diethylamine) in carbon dioxide], Example 147 eluted first,
followed by Example 146. 55. Reaction of Example 152 with
phosphorus oxychloride, followed by displacement with sodium
methoxide in methanol, provided this Example. 56. Example 11 was
reacted with dimethylamine and sodium carbonate to provide the
product. 57. 5-Bromo-4,6-dimethylpyrimidin-2-ol was protected as
its triisopropylsilyl ether, and used in the Suzuki reaction. 58.
In this case, potassium phosphate was used, and the catalyst for
the reaction with methylboronic acid was
bis(tri-tert-butylphosphine)palladium(0). Example 154 resulted from
dechlorination of Example 11. 59. The catalyst employed for the
Suzuki reaction was the same as that used during the synthesis of
Example 10, step 3. 60. The product was synthesized via reaction of
Example 11 with sodium ethoxide in ethanol. 61. The Suzuki reaction
was carried out using the conditions of Example 10. Coupling
partner 8-chloro-5-(furo[3,2-c]pyridin-4-yloxy)quinoline was
synthesized in the following manner: Skraup reaction of
2-chloro-5-methoxyaniline with propane-1,2,3-triol afforded
8-chloro-5-methoxyquinoline, which was demethylated with aqueous
hydrobromic acid. The resulting 8-chloroquinolin-5-ol was then
reacted with 4-chlorofuro[3,2-c]pyridine using cesium carbonate in
dimethyl sulfoxide. 62. Example 134 was reacted with lithium
bromide, sodium bis(trimethylsilyl)amide and methyl iodide to
afford the product. 63. In this case, the first step was carried
out using
[2'-(azanidyl-.kappa.N)biphenyl-2-yl-.kappa.C.sub.2](chloro){dicycl-
ohexyl[2',4',6'-tri(propan-2-yl)biphenyl-2-yl]-.lamda..sup.5-phosphanyl}pa-
lladium as catalyst. 64. 6-Bromo-1-methylpyridin-2(1H)-one was used
as the coupling partner. 65. The requisite
5-bromo-6-methoxyisoquinoline may be prepared according to P. Chen
et al., Bioorg. Med. Chem. Lett. 2003, 13, 1345-1348. 66. In this
case, C17 was reacted with sodium methoxide, to provide
4-chloro-5-methoxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-on-
e, prior to the Suzuki reaction. 67. HPLC conditions. Column:
Waters Sunfire C18, 4.6.times.50 mm, 5 .mu.m; Mobile phase A: 0.05%
trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%
trifluoroacetic acid in acetonitrile (v/v); Gradient: 5.0% to 95% B
over 4.0 minutes; Flow rate: 2 mL/minute. 68. The requisite
3-bromo-4-methylpyridine-2-carbonitrile may be prepared from the
N-oxide of 3-bromo-4-methylpyridine via the method of B. Elman,
Tetrahedron 1985, 41, 4941-4948. 69. Cyclization of C67 with
hydrazinecarboxamide, followed by boron tribromide-mediated
cleavage of the methyl ether, afforded
5-(4-hydroxy-2-methylphenyl)-6-methyl-1,2,4-triazin-3(2H)-one. 70.
Example 72 was reacted with 2-bromoethyl methyl ether and cesium
carbonate. 71. The requisite 5-bromo-4-ethoxy-6-methylpyrimidine
was prepared from 5-bromo-4-chloro-6-methylpyrimidine via treatment
with sodium ethoxide in ethanol. 72. HPLC conditions. Column:
XBridge C18, 2.1.times.50 mm, 5 .mu.m; Mobile phase A: 0.05%
ammonium hydroxide in water; Mobile phase B: acetonitrile;
Gradient: 5% to 100% B over 3.4 minutes; Flow rate: 0.8 mL/minute.
73. 4-[4-Bromo-3-(trifluoromethyl)phenoxy]furo[3,2-c]pyridine was
reacted with (1-methyl-1H-pyrazol-5-yl)boronic acid. 74. In this
case, the final reaction was carried out in methanol. 75. Compound
C4 was converted to
8-bromo-5-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-6-methylimidazo-
[1,2-a]pyrazine via reaction with chloroacetaldehyde. Subsequent
reaction with potassium cyanide and
1,4,7,10,13,16-hexaoxacyclooctadecane (18-crown-6) afforded the
product. 76. Example 16 was converted to the product by reaction
with ethoxyacetic acid and 2-chloro-1,3-dimethylimidazolinium
chloride (DMC) in the presence of N,N-diisopropylethylamine. 77.
Intermediate
4-[3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3-
,2-c]pyridine was synthesized by using the method of Example 1, but
employing 4-bromo-3-chlorophenol in place of
4-bromo-3-methylphenol.
TABLE-US-00002 TABLE 2 Examples 209-214 Method of Preparation; Ex-
Non- .sup.1H NMR (400 MHz, CDCl.sub.3), .delta. (ppm); Mass am-
commerical spectrum, observed ion m/z (M + H) or HPLC ple Starting
retention time (minutes); Mass spectrum m/z No. Structure Materials
(M + H) (unless otherwise indicated) 209 ##STR00269## C40.sup.1
3.39 min.sup.2; 372.0 210 ##STR00270## Ex 5.sup.3; C39, C38 2.75
min.sup.2; 357.1 211 ##STR00271## Ex 5.sup.4; C39.sup.5 2.97
min.sup.2; 412.0, 414.0 212 ##STR00272## Ex 211.sup.6 8.22 (s, 1H),
8.17 (d, J = 5.9 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.33 (d, J =
5.9 Hz, 1H), 7.19- 7.25 (m, 2H), 2.10 (s, 3H), 2.04 (s, 3H); 359.0
213 ##STR00273## Ex 5; C39.sup.7 8.21 (s, 1H), 8.07 (d, J = 6.0 Hz,
1H), 7.70 (s, 1H), 7.26-7.32 (m, 3H, assumed; partially obscured by
solvent peak), 7.19 (d, J = 8.2 Hz, 1H), 3.26 (s, 3H), 2.15 (s,
3H), 2.08 (s, 3H); 426.0, 428.0 214 ##STR00274## Ex 5.sup.8 2.15
min.sup.9; 344.1 215 ##STR00275## Method M7.sup.10; Ex 124.sup.11
14.04 min.sup.12; 8.31 (br s, 1H), 8.06 (d, J = 5.8 Hz, 1H), 7.69
(d, J = 2.2 Hz, 1H), 7.29 (dd, J = 5.8, 1.0 Hz, 1H), 7.22-7.26 (m,
2H), 7.15 (br d, J = 8.2 Hz, 1H), 6.91 (dd, J = 2.3, 1.0 Hz, 1H),
3.07 (s, 3H), 2.21 (br s, 3H), 1.69 (s, 3H)
1. Compound C40 was subjected to a Suzuki reaction with
cyclopropylboronic acid using the conditions described in footnote
22, Table 1. 2. HPLC conditions. Column: Waters Atlantis dC18,
4.6.times.50 mm, 5 .mu.m; Mobile phase A: 0.05% trifluoroacetic
acid in water (v/v); Mobile phase B: 0.05% trifluoroacetic acid in
acetonitrile (v/v); Gradient: 5.0% to 95% B over 4.0 minutes,
linear; Flow rate: 2 mL/minute. 3. Replacement of bromide by a
cyano group was carried out as the final step, using copper(I)
cyanide in N,N-dimethylformamide. 4. The protecting group was
removed in the final step, with a solution of hydrogen chloride in
methanol. 5. The required
5-(4-hydroxyphenyl)-4,6-dimethyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(-
2H)-one was prepared in the following manner:
(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)boronic acid and
2,4-dimethyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate
(C48) were reacted according to Example 27 to provide
4-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3,5-dimethylfuran-2(5H)-one.
The silyl protecting group was removed with tetrabutylammonium
fluoride, and replaced with a benzyl protecting group, yielding
4-[4-(benzyloxy)phenyl]-3,5-dimethylfuran-2(5H)-one. This was
subjected to reaction with oxygen, followed by hydrazine, as
described in Example 27, to afford
5-[4-(benzyloxy)phenyl]-4,6-dimethylpyridazin-3(2H)-one. Nitrogen
protection with 3,4-dihydro-2H-pyran as in Example 10, followed by
hydrogenolysis of the benzyl group, provided the requisite phenol.
6. Prior to the acidic removal of the tetrahydropyran protecting
group in Example 211, the bromine was replaced by a cyano group
using copper(I) cyanide in N,N-dimethylformamide. Removal of the
protecting group afforded Example 212. 7. The requisite
6-(4-hydroxy-2-methylphenyl)-1,5-dimethylpyrazin-2(1H)-one was
prepared in the following manner: Suzuki reaction between
(4-methoxy-2-methylphenyl)boronic acid and 2-bromo-3-methylpyrazine
afforded 2-(4-methoxy-2-methylphenyl)-3-methylpyrazine. After
formation of the N-oxide and rearrangement with acetic anhydride
(see A. Ohta et al., J. Het. Chem. 1985, 19, 465-473), the
resulting 6-(4-methoxy-2-methylphenyl)-5-methylpyrazin-2-ol was
N-methylated, and then deprotected with boron tribromide. 8.
4-(Imidazo[1,2-a]pyridin-5-yl)phenol was prepared from
(4-hydroxyphenyl)boronic acid and 5-bromoimidazo[1,2-a]pyridine,
using the method of Example 6. 9. HPLC conditions. Column: Waters
Atlantis dC18, 4.6.times.50 mm, 5 .mu.m; Mobile phase A: 0.05%
trifluoroacetic acid in water (v/v); Mobile phase B: 0.05%
trifluoroacetic acid in acetonitrile (v/v); 15.0% to 95% B, linear,
over 4.0 minutes; Flow rate: 2 mL/minute. 10. In this case, the
incubation was carried out for 2.25 hours rather than 24-96 hours.
11. Example 124 was separated into its component atropenantiomers
via supercritical fluid chromatography (Column: Chiralpak AD-H, 5
.mu.m; Eluent: 7:3 carbon dioxide/propanol). The second-eluting
enantiomer
[(-)-6-[4-(furo[3,2-c]pyridin-4-yloxy)-2-methylphenyl]-1,5-dimethylpyrimi-
din-2(1H)-one] was used in the biotransformation. The crude
biotransformation product was purified via silica gel
chromatography (Eluant: 70% ethyl acetate in heptane). 12.
Supercritical fluid chromatography conditions. Column: Phenomenex
Cellulose-4, 4.6.times.250 mm, 5 .mu.m; Eluent: 55:45 carbon
dioxide/methanol; Flow rate 2.5 mL/minute.
Example 216
6-[4-(Furo[3,2-c]pyridin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H)-
-dione, trifluoroacetate salt (216)
##STR00276##
[0556] Step 1. Synthesis of
6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione, hydrochloride salt
(C87).
[0557] 1-Methylurea (98%, 8.26 g, 109 mmol) and ethyl
2-cyanopropanoate (95%, 13.2 mL, 99.6 mmol) were dissolved in
methanol (75 mL) and treated with sodium methoxide (25 weight
percent solution in methanol, 27 mL, 120 mmol). The resulting
mixture was heated at reflux for 18 hours. After cooling to room
temperature, the reaction mixture was concentrated under reduced
pressure to remove the bulk of the methanol. The solvent was
subsequently exchanged by repeated addition of acetonitrile
(3.times.50 mL) followed by concentration in vacuo. The resulting
solid was dissolved in acetonitrile (100 mL) and water (100 mL),
and 6 M aqueous hydrochloric acid was added until the pH reached
approximately 2. During this acidification, a white precipitate
formed. After the mixture had stirred for an hour, the solid was
collected via filtration and washed with tert-butyl methyl ether,
providing the product as a white solid. Yield: 15.2 g, 79.3 mmol,
80%. LCMS m/z 156.3 [M+H]. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 10.37 (br s, 1H), 6.39 (br s, 2H), 3.22 (s, 3H), 1.67 (s,
3H).
Step 2. Synthesis of
6-bromo-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C88).
[0558] A 1:1 mixture of acetonitrile and water (60 mL) was added to
a mixture of 6-amino-1,5-dimethylpyrimidine-2,4(1H,3H)-dione,
hydrochloride salt (C87) (5.00 g, 26.1 mmol), sodium nitrite (98%,
2.76 g, 39.2 mmol) and copper(II) bromide (99%, 11.8 g, 52.3 mmol)
{Caution: bubbling and slight exotherm observed}, and the reaction
mixture was allowed to stir at room temperature for 18 hours. Upon
dilution with aqueous sulfuric acid (1 N, 100 mL) and ethyl acetate
(100 mL), a precipitate formed; this was isolated via filtration
and washed with water and with ethyl acetate to afford the product
as a solid (3.65 g). The filtrate was concentrated in vacuo to
approximately 25% of its original volume, during which more
precipitate was observed. Filtration and washing of this solid with
water and ethyl acetate afforded additional product (0.60 g). Total
yield: 4.25 g, 19.4 mmol, 74%. LCMS m/z 219.0, 221.0 [M+H]. NMR
(400 MHz, DMSO-d.sub.6) .delta. 11.58 (br s, 1H), 3.45 (s, 3H),
1.93 (s, 3H).
Step 3. Synthesis of
6-[4-(furo[3,2-c]pyridin-4-yloxy)phenyl]-1,5-dimethylpyrimidine-2,4(1H,3H-
)-dione, trifluoroacetate salt (216).
[0559] 6-Bromo-1,5-dimethylpyrimidine-2,4(1H,3H)-dione (C88) (78.0
mg, 0.356 mmol),
4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]furo[3,2-c]pyri-
dine (C52) (60.0 mg, 0.178 mmol), potassium carbonate (99%, 74.5
mg, 0.534 mmol) and tetrakis(triphenylphosphine)palladium(0) (99%,
10.5 mg, 0.0090 mmol) were combined in ethanol (5 mL) and heated to
80.degree. C. for 18 hours. The reaction mixture was diluted with
water, made slightly acidic by addition of 1.0 M aqueous
hydrochloric acid, and extracted several times with ethyl acetate.
The combined organic layers were washed with saturated aqueous
sodium chloride solution, dried over magnesium sulfate, filtered,
and concentrated in vacuo. Purification via silica gel
chromatography (Gradient: 75% to 100% ethyl acetate in heptane)
followed by reversed-phase HPLC (Column: Waters Sunfire C18, 5
.mu.m; Mobile phase A: 0.05% trifluoroacetic acid in water (v/v);
Mobile phase B: 0.05% trifluoroacetic acid in acetonitrile (v/v);
Gradient: 20% to 100% B) afforded the product as a solid. Yield: 20
mg, 0.057 mmol, 32%. LCMS m/z 350.0 [M+H]. .sup.1H NMR (600 MHz,
DMSO-d.sub.6) .delta. 8.14 (d, J=2.2 Hz, 1H), 8.04 (d, J=5.9 Hz,
1H), 7.51 (br d, J=5.9 Hz, 1H), 7.42 (br AB quartet, J.sub.AB=8.8
Hz, .DELTA..nu..sub.AB=16.7 Hz, 4H), 7.08 (dd, J=2.2, 0.9 Hz, 1H),
2.94 (s, 3H), 1.55 (s, 3H).
Example AA
Human D1 Receptor Binding Assay and Data
[0560] The affinity of the compounds described herein was
determined by competition binding assays similar to those described
in Ryman-Rasmussen et al., "Differential activation of adenylate
cyclase and receptor internalization by novel dopamine D1 receptor
agonists", Molecular Pharmacology 68(4):1039-1048 (2005). This
radioligand binding assay used [.sup.3H]-SCH23390, a radio D1
ligand, to evaluate the ability of a test compound to compete with
the radioligand when binding to a D1 receptor.
[0561] D1 binding assays were performed using over-expressing LTK
human cell lines. To determine basic assay parameters, ligand
concentrations were determined from saturation binding studies
where the Kd for [.sup.3H]-SCH23390 was found to be 1.3 nM. From
tissue concentration curve studies, the optimal amount of tissue
was determined to be 1.75 mg/mL per 96 well plate using 0.5 nM of
[.sup.3H]-SCH23390. These ligand and tissue concentrations were
used in time course studies to determine linearity and equilibrium
conditions for binding. Binding was at equilibrium with the
specified amount of tissue in 30 minutes at 37.degree. C. From
these parameters, K.sub.i values were determined by homogenizing
the specified amount of tissue for each species in 50 mM Tris (pH
7.4 at 4.degree. C.) containing 2.0 mM MgCl.sub.2 using a Polytron
and spun in a centrifuge at 40,000.times.g for 10 minutes. The
pellet was resuspended in assay buffer (50 mM Tris (pH 7.4@ RT)
containing 4 mM MgSO.sub.4 and 0.5 mM EDTA). Incubations were
initiated by the addition of 200 .mu.L of tissue to 96-well plates
containing test drugs (2.5 .mu.L) and 0.5 nM [.sup.3H]-SCH23390 (50
.mu.L) in a final volume of 250 Non-specific binding was determined
by radioligand binding in the presence of a saturating
concentration of (+)-Butaclamol (10 .mu.M), a D1 antagonist. After
a 30 minute incubation period at 37.degree. C., assay samples were
rapidly filtered through Unifilter-96 GF/B PEI-coated filter plates
and rinsed with 50 mM Tris buffer (pH 7.4 at 4.degree. C.).
Membrane bound [.sup.3H]-SCH23390 levels were determined by liquid
scintillation counting of the filterplates in Ecolume. The
IC.sub.50 value (Concentration at which 50% inhibition of specific
binding occurs) was calculated by linear regression of the
concentration-response data in Microsoft Excel. K.sub.i values were
calculated according to the Cheng-Prusoff equation.
K i = IC 50 1 + ( [ L ] / K d ) ##EQU00001##
[0562] where [L]=concentration of free radioligand and
K.sub.d=dissociation constant of radioligand for D1 receptor (1.3
nM for [.sup.3H]-SCH23390).
Example BB
D1 cAMP HTRF Assay and Data
[0563] The D1 cAMP (Cyclic Adenosine Monophosphate) HTRF
(Homogeneous Time-Resolved Fluorescence) Assay used and described
herein is a competitive immunoassay between native cAMP produced by
cells and cAMP labeled with XL-665. This assay was used to
determine the ability of a test compound to agonize (including
partially agonize) D1. A Mab anti-cAMP labeled Cryptate visualizes
the tracer. The maximum signal is achieved if the samples do not
contain free cAMP due to the proximity of donor (Eu-cryptate) and
acceptor (XL665) entities. The signal, therefore, is inversely
proportional to the concentration of cAMP in the sample. A time
resolved and ratiometric measurement (em 665 nm/em 620 nm)
minimizes the interference with medium. cAMP HTRF assays are
commercially available, for example, from Cisbio Bioassays, IBA
group.
Materials and Methods
[0564] Materials:
[0565] The cAMP Dynamic kit was obtained from Cisbio International
(Cisbio 62AM4PEJ). Multidrop Combi (Thermo Scientific) was used for
assay additions. Envision (PerkinElmer) reader was used to read
HTRF.
[0566] Cell Cuture:
[0567] A HEK293T/hD1#1 stable cell line was constructed internally
(Pfizer Ann Arbor). The cells were grown as adherent cells in
NuncT.sub.500 flasks in high glucose DMEM (Invitrogen 11995-065),
10% fetal bovine serum dialyzed (Invitrogen 26400-044), 1.times.MEM
NEAA (Invitrogen 1140, 25 mM HEPES (Invitrogen 15630), 1.times.
Pen/Strep (Invitrogen 15070-063) and 500 .mu.g/mL Genenticin
(Invitrogen 10131-035) at 37.degree. C. and 5% CO.sub.2. At 72 or
96 hours post growth, cells were rinsed with DPBS and 0.25%
Trypsin-EDTA was added to dislodge the cells. Media was then added
and cells were centrifuged and media removed. The cell pellets were
re-suspended in Cell Culture Freezing Medium (Invitrogen 12648-056)
at a density of 4e7 cells/mL. One mL aliquots of the cells were
made in Cryo-vials and frozen at -80.degree. C. for future use in
the D1 HTRF assay.
[0568] D1 cAMP HTRF Assay Procedure:
[0569] Frozen cells were quickly thawed, re-suspended in 50 mL warm
media and allowed to sit for 5 min prior to centrifugation (1000
rpm) at room temperature. Media was removed and cell pellet was
re-suspended in PBS/0.5 .mu.M IBMX generating 2e5 cells/mL. Using a
Multidrop Combi, 5 .mu.L cells/well was added to the assay plate
(Greiner 784085) which already contained 5 .mu.L of a test
compound. Compound controls [5 .mu.M dopamine (final) and 0.5% DMSO
(final)] were also included on every plate for data analysis. Cells
and compounds were incubated at room temperature for 30 min.
Working solutions of cAMP-D2 and anti-cAMP-cryptate were prepared
according to Cisbio instructions. Using Multidrop, 5 .mu.L cAMP-D2
working solution was added to the assay plate containing the test
compound and cells. Using Multidrop, 5 .mu.L anti-cAMP-cryptate
working solutions was added to assay plate containing test
compound, cells and cAMP-D2. Assay plate was incubated for 1 hour
at room temperature. Assay plate was read on Envision plate reader
using Cisbio recommended settings. A cAMP standard curve was
generated using cAMP stock solution provided in the Cisbio kit.
[0570] Data Analysis:
[0571] Data analysis was done using computer software. Percent
effects were calculated from the compound controls. Ratio EC.sub.50
was determined using the raw ratio data from the Envision reader.
The cAMP standard curve was used in an analysis program to
determine cAMP concentrations from raw ratio data. cAMP EC.sub.50
was determined using the calculated cAMP data.
TABLE-US-00003 TABLE 3 Biological Data for Examples 1-216 Human D1
Human D1 Human D1 Receptor cAMP HTRF, cAMP HTRF, Binding, K.sub.i
(nM); EC.sub.50 (.mu.M); EC.sub.50 (.mu.M); Geometric Geometric
Geometric Example mean of 2-4 mean of 2-6 mean of 2-4 Number
Compound Name determinations determinations determinations 1
4-[4-(4,6-Dimethylpyrimidin-5- .sup. 27.3.sup.a 0.135.sup.b
0.129.sup.a yl)-3-methylphenoxy]furo[3,2- c]pyridine 2
5-[4-(Furo[3,2-c]pyridin-4- 5.88 0.153 .sup. N.D..sup.c
yloxy)-2-methylphenyl]-6- methyl-[8-2H]-imidazo[1,2- a]pyrazine 3
(+)-5-[4-(Furo[3,2-c]pyridin-4- 2.56 0.0436 0.0629
yloxy)-2-methylphenyl]-6- methyl-[8-.sup.2H]-imidazo[1,2-
a]pyrazine 4 (-)-5-[4-(Furo[3,2-c]pyridin-4- 19.7 0.235 0.346.sup.d
yloxy)-2-methylphenyl]-6- methyl-[8-.sup.2H]-imidazo[1,2-
a]pyrazine 5 1-[4-(Furo[3,2-c]pyridin-4- .sup. 68.3.sup.a
0.423.sup.b 0.899.sup.a yloxy)-2-methylphenyl]-2-
methyl-1H-imidazo[4,5- c]pyridine 6 4-[3-Methoxy-4-(3- 169 0.804
0.897 methylpyrazin-2- yl)phenoxy]furo[3,2-c]pyridine 7
4-[4-(1-Methyl-1H-pyrazol-5- 788 N.D. N.D. yl)phenoxy]thieno[3,2-
c]pyridine 8 4-{[4-(1-Methyl-1H-pyrazol-5- 283 N.D. 0.854
yl)phenyl]sulfanyl}furo[3,2- c]pyridine, trifluoroacetate salt 9
2-(4,6-Dimethylpyrimidin-5-yl)- 116.sup.a 0.396.sup.b 0.696.sup.d
5-(furo[3,2-c]pyridin-4- yloxy)benzonitrile 10
4-[4-(Furo[3,2-c]pyridin-4- 2280.sup.d >30.0 N.D.
yloxy)-2-methylphenyl]-5- methylpyridazin-3(2H)-one,
bis-hydrochloride salt 11 4-[4-(3-Chloro-5- 11.8 0.186 N.D.
methylpyridazin-4-yl)-3- methylphenoxy]furo[3,2- c]pyridine 12
4-[4-(3,5-Dimethylpyridazin-4- 14.3 0.166 0.395.sup.d
yl)-3-methylphenoxy]furo[3,2- c]pyridine 13 (+)-4-[4-(3,5- 10.7
0.0807.sup.b N.D. Dimethylpyridazin-4-yl)-3-
methylphenoxy]furo[3,2- c]pyridine 14
(-)-4-[4-(3,5-Dimethylpyridazin- 212 1.04 N.D. 4-yl)-3-
methylphenoxy]furo[3,2- c]pyridine 15
4-[4-(1-tert-Butyl-4-methyl-1H- 121 N.D. 0.895.sup.d
pyrazol-5-yl)-3- methylphenoxy]furo[3,2- c]pyridine 16
5-(Furo[3,2-c]pyridin-4-yloxy)- 146 N.D. 0.415.sup.d
2-(imidazo[1,2-a]pyridin-5- yl)aniline 17
N-[4-(Imidazo[1,2-a]pyridin-5- 111 N.D. 0.957
yl)-3-methylphenyl]furo[3,2- c]pyridin-4-amine 18 4-[4-(4-Chloro-6-
.sup. 15.6.sup.d 0.118 0.511.sup.d methylpyrimidin-5-yl)-3-
methylphenoxy]furo[3,2- c]pyridine 19 5-[4-(Furo[3,2-c]pyridin-4-
24.7 0.246 0.426 yloxy)-2-methylphenyl]-6-
methylimidazo[1,2-a]pyrazin-8- ol 20
[2-(4,6-Dimethylpyrimidin-5-yl)- 138 0.622 N.D.
5-(furo[3,2-c]pyridin-4- yloxy)phenyl]methanol 21
4-[4-(4,6-Dimethylpyrimidin-5- 36.2 0.0858 N.D. yl)-3-
(fluoromethyl)phenoxy]furo[3,2- c]pyridine 22
4-[4-(4,6-Dimethylpyrimidin-5- 162 0.774 1.34.sup.d
yl)-3-methylphenoxy]-3- methylfuro[3,2-c]pyridine 23
4-{[4-(4,6-Dimethylpyrimidin-5- 30.6 0.848 N.D.
yl)-1H-indol-7-yl]oxy}furo[3,2- c]pyridine 24 4-[4-(4-Ethoxy-6-
33.0 2.06.sup.b 2.59.sup.a methylpyrimidin-5-yl)-3-
methylphenoxy]furo[3,2- c]pyridine 25
(+)-5-[4-(Furo[3,2-c]pyridin-4- .sup. 5.76.sup.a 0.037.sup.b
0.0457.sup.a yloxy)-2-methylphenyl]-6- methylimidazo[1,2-a]pyrazine
26 (-)-5-[4-(Furo[3,2-c]pyridin-4- .sup. 21.6.sup.a 0.170 0.128
yloxy)-2-methylphenyl]-6- methylimidazo[1,2-a]pyrazine 27
5-[2-Fluoro-4-(furo[3,2- 4.67 0.0239 N.D.
c]pyridin-4-yloxy)phenyl]-4,6- dimethylpyridazin-3(2H)-one 28
5-[4-(Furo[3,2-c]pyridin-4- 19.3 0.110.sup.b N.D.
yloxy)phenyl]-4,6- dimethylpyridazin-3(2H)-one 29
4-[3,5-Dimethyl-4-(3- 329.sup.d 2.82 N.D. methylpyridin-4-
yl)phenoxy]furo[3,2-c]pyridine 30 4-{[4-(Imidazo[1,2-a]pyridin-5-
220 N.D. 2.48 yl)naphthalen-1- yl]oxy}furo[3,2-c]pyridine,
trifluoroacetate salt 31 1-[4-(furo[3,2-c]pyridin-4- 316.sup.a
1.03.sup.b 1.19.sup.a yloxy)phenyl]-2-methyl-1H-
imidazo[4,5-c]pyridine 32 4-[4-(1-cyclopropyl-4-methyl- 281 N.D.
2.24 1H-pyrazol-5- yl)phenoxy]furo[3,2- c]pyridine,
trifluoroacetate salt 33 5-[4-(furo[3,2-c]pyridin-4- 111 N.D. 2.27
yloxy)phenyl]-6- methoxyisoquinoline 34
4-[4-(imidazo[1,2-a]pyridin-5- 20.0 N.D. 0.182 yl)-3-
methoxyphenoxy]furo[3,2- c]pyridine 35 4-[3-methyl-4-(6- 6.86 N.D.
0.0636 methylimidazo[1,2-a]pyridin- 5-yl)phenoxy]furo[3,2-
c]pyridine 36 5-[4-(furo[3,2-c]pyridin-4- 120 0.378 0.412 yloxy)-2-
methylphenyl]imidazo[1,2- a]pyrazine 37 4-[3-methoxy-4-(6- .sup.
3.54.sup.a N.D. 0.0469 methylimidazo[1,2-a]pyridin-
5-yl)phenoxy]furo[3,2- c]pyridine 38
5-(furo[3,2-c]pyridin-4-yloxy)- 36.0 N.D. 0.200.sup.d
2-(imidazo[1,2-a]pyridin-5-yl)- N-methylaniline 39
1-[2-chloro-4-(furo[3,2- 91.0 N.D. 0.415.sup.d
c]pyridin-4-yloxy)phenyl]-2- methyl-1H-imidazo[4,5- c]pyridine 40
4-[4-(imidazo[1,2-a]pyridin-5- 107 N.D. 1.27.sup.d
yl)-3-(1,3-thiazol-4- ylmethoxy)phenoxy]furo[3,2- c]pyridine,
trifluoroacetate salt 41 1-[5-(furo[3,2-c]pyridin-4- 72.1 N.D.
0.517.sup.d yloxy)-2-(imidazo[1,2- a]pyridin-5-yl)phenoxy]butan-
2-one, trifluoroacetate salt 42 2-[5-(furo[3,2-c]pyridin-4- 118
N.D. 0.406.sup.d yloxy)-2-(imidazo[1,2- a]pyridin-5-
yl)phenoxy]ethanol, trifluoroacetate salt 43
N-cyclopropyl-2-[5-(furo[3,2- 211 N.D. 0.605.sup.d
c]pyridin-4-yloxy)-2- (imidazo[1,2-a]pyridin-5-
yl)phenoxy]acetamide, trifluoroacetate salt 44 methyl
[5-(furo[3,2-c]pyridin- 129 N.D. 0.651.sup.d
4-yloxy)-2-(imidazo[1,2- a]pyridin-5- yl)phenoxy]acetate,
trifluoroacetate salt 45 7-[4-(furo[3,2-c]pyridin-4- 182 N.D. 1.14
yloxy)-2-methylphenyl]-6- methyl[1,2,4]triazolo[1,5- a]pyrimidine
46 N-cyclobutyl-5-(furo[3,2- 316 N.D. 2.12.sup.d
c]pyridin-4-yloxy)-2- (imidazo[1,2-a]pyridin-5- yl)benzamide,
trifluoroacetate salt 47 2-ethoxy-N-[5-(furo[3,2- 302 N.D.
0.935.sup.d c]pyridin-4-yloxy)-2- (imidazo[1,2-a]pyridin-5-
yl)phenyl]acetamide 48 5-(furo[3,2-c]pyridin-4-yloxy)- 68.8 N.D.
2.07.sup.d 2-(imidazo[1,2-a]pyridin-5-yl)-
N-[(1-methyl-1H-imidazol-5- yl)methyl]aniline, trifluoroacetate
salt 49 N-[5-(furo[3,2-c]pyridin-4- 121 N.D. 3.68.sup.d
yloxy)-2-(imidazo[1,2- a]pyridin-5-yl)benzyl]-1-(1,3-
thiazol-5-yl)ethanamine, trifluoroacetate salt 50
1-[5-(furo[3,2-c]pyridin-4- 55.1 N.D. 1.13.sup.d
yloxy)-2-(imidazo[1,2- a]pyridin-5-yl)phenyl]-N-
methyl-N-(pyridin-2- ylmethyl)methanamine, trifluoroacetate salt 51
3-[4-(furo[3,2-c]pyridin-4- 61.7 0.799 1.22.sup.a
yloxy)-2-methoxyphenyl]-4- methylpyridine-2-carbonitrile,
trifluoroacetate salt 52 4-[3-methyl-4-(2- .sup. 53.0.sup.a N.D.
0.463 methylpyridin-3- yl)phenoxy]furo[3,2-c]pyridine 53
6-[4-(furo[3,2-c]pyridin-4- 173 N.D. 0.953
yloxy)-2-methylphenyl]-5- methylpyrazin-2-amine, trifluoroacetate
salt 54 4-[4-(imidazo[1,2-a]pyridin-5-yl)-3- .sup. 10.2.sup.a N.D.
0.243 (trifluoromethyl)phenoxy]furo[3,2- c]pyridine 55
N-[4-(imidazo[1,2-a]pyridin-5- 244 N.D. >29.9
yl)-3-methylphenyl]-N- methylfuro[3,2-c]pyridin-4- amine 56
5-[4-(furo[3,2-c]pyridin-4- .sup. 98.7.sup.a 0.633 0.435
yloxy)-2-methylphenyl]-6- methylpyridin-2-amine 57
5-(furo[3,2-c]pyridin-4-yloxy)- 17.4 N.D. 0.116.sup.d
2-(6-methylimidazo[1,2- a]pyrazin-5-yl)phenol 58 4-[3-methyl-4-(4-
160 0.900 1.11 methylpyrimidin-5- yl)phenoxy]furo[3,2-c]pyridine 59
5-[4-(furo[3,2-c]pyridin-4- 103 1.01 1.15 yloxy)-2-
methylphenyl]quinolin-2(1H)- one 60 4-[4-(6-methoxy-2- 178 2.91
1.04.sup.a methylpyridin-3-yl)-3- methylphenoxy]furo[3,2-
c]pyridine, trifluoroacetate salt 61 3-[5-(furo[3,2-c]pyridin-4-
228 1.11 0.811 yloxy)-2-(3-methylpyrazin-2- yl)phenoxy]-N,N-
dimethylpropan-1-amine, formate salt 62
4-[3-ethyl-4-(3-methylpyrazin- 130 0.975 0.0966.sup.d
2-yl)phenoxy]furo[3,2- c]pyridine 63 5-[4-(furo[3,2-c]pyridin-4-
210 1.35 0.843.sup.a yloxy)-2-methylphenyl]-6-
methylpyrimidin-4-amine 64 5-[2-ethyl-4-(furo[3,2- 12.1 0.134 N.D.
c]pyridin-4-yloxy)phenyl]-6- methylimidazo[1,2-a]pyrazine
65 5-[2-fluoro-4-(furo[3,2- 61.1 0.193 0.300.sup.a
c]pyridin-4-yloxy)phenyl]-6- methylimidazo[1,2-a]pyrazine 66
4-{3-[(3,5-dimethyl-1,2- .sup. 85.4.sup.d N.D. 0.737.sup.d
oxazol-4-yl)methoxy]-4-(3- methylpyrazin-2- yl)phenoxy}furo[3,2-
c]pyridine, formate salt 67 4-{3-[(3-cyclopropyl-1,2,4- N.D. 0.809
N.D. oxadiazol-5-yl)methoxy]-4-(3- methylpyrazin-2-
yl)phenoxy}furo[3,2-c]pyridine 68 4-{4-(3-methylpyrazin-2-yl)-3-
154 N.D. 1.48.sup.d [(3-methylpyridin-2-
yl)methoxy]phenoxy}furo[3,2- c]pyridine, formate salt 69
4-[4-(4,6-dimethylpyrimidin-5- 77.7 0.201 0.203.sup.d
yl)-3-fluorophenoxy]furo[3,2- c]pyridine 70
5-[2-fluoro-4-(furo[3,2- 124 0.424 1.02
c]pyridin-4-yloxy)phenyl]-6- methylpyrimidine-4- carbonitrile 71
4-[4-(4,6-dimethylpyrimidin-5- 50.5 0.298 0.965 yl)-3-
methoxyphenoxy]furo[3,2- c]pyridine 72
2-(4,6-dimethylpyrimidin-5-yl)- 91.4 N.D. 0.989
5-(furo[3,2-c]pyridin-4- yloxy)phenol 73
3-[5-(furo[3,2-c]pyridin-4- 37.7 0.748 0.966
yloxy)-2-(2-methylpyridin-3- yl)phenoxy]-N,N-
dimethylpropan-1-amine, formate salt 74 1-[5-(furo[3,2-c]pyridin-4-
N.D. 0.832 N.D. yloxy)-2-(2-methylpyridin-3- yl)phenoxy]-N,N-
dimethylpropan-2-amine, formate salt 75 5-[4-(furo[3,2-c]pyridin-4-
21.6 N.D. 0.364 yloxy)-2-methylphenyl]-4,6-
dimethylpyrimidin-2-amine 76 4-[3-fluoro-4-(4-methoxy-6- 139 0.903
2.17 methylpyrimidin-5- yl)phenoxy]furo[3,2-c]pyridine 77
4-[4-(4,6-dimethylpyrimidin-5- 45.6 0.200 0.674
yl)phenoxy]furo[3,2-c]pyridine 78 4-{3-[(3-ethyl-1,2,4-oxadiazol-
48.3 0.885 1.23.sup.d 5-yl)methoxy]-4-(2- methylpyridin-3-
yl)phenoxy}furo[3,2-c]pyridine 79 5-[4-(furo[3,2-c]pyridin-4- 140
2.55 1.68 yloxy)phenyl]-4,6- dimethylpyrimidin-2-ol 80
5-[4-(furo[3,2-c]pyridin-4- 6.13 1.20 0.987.sup.d
yloxy)-2-methylphenyl]-6- methyl-2- (trifluoromethyl)imidazo[1,2-
a]pyrazine 81 5-[4-(furo[3,2-c]pyridin-4- 270.sup.d 1.77 N.D.
yloxy)-2-methylphenyl]-N,6- dimethylpyrimidin-4-amine 82
(+)-5-[4-(furo[3,2-c]pyridin-4- 21.3 0.113 0.781.sup.d
yloxy)-2-methylphenyl]-6- methylpyrimidine-4- carbonitrile 83
(-)-5-[4-(furo[3,2-c]pyridin-4- 82.1 0.854 0.944.sup.d
yloxy)-2-methylphenyl]-6- methylpyrimidine-4- carbonitrile 84
2-amino-5-[4-(furo[3,2- 116 0.360 N.D. c]pyridin-4-yloxy)-2-
methylphenyl]-6- methylpyrimidine-4- carbonitrile 85
3-[4-(furo[3,2-c]pyridin-4- .sup. 75.3.sup.d 1.12 4.88.sup.d
yloxy)-2-methylphenyl]-2- methylimidazo[1,2-a]pyrazine 86
5-[4-(furo[3,2-c]pyridin-4- 113 0.833 4.87
yloxy)-2-methylphenyl]-6- methylpyridin-3-amine 87
5-[4-(furo[3,2-c]pyridin-4- 22.5 0.600 0.482.sup.d
yloxy)-2-methylphenyl]-N,N,6- trimethylpyrimidin-4-amine 88
4-[4-(2-cyclopropylpyridin-3- 117 0.710 1.52.sup.d
yl)-3-methylphenoxy]furo[3,2- c]pyridine 89
4-[(2,2',6'-trimethylbiphenyl-4- 123 1.86 N.D.
yl)oxy]furo[3,2-c]pyridine, trifluoroacetate salt 90
5-[2-chloro-4-(furo[3,2- 25.4 0.448 N.D.
c]pyridin-4-yloxy)phenyl]-6- methylpyridin-2-amine 91
6-[4-(furo[3,2-c]pyridin-4- 61.2 0.580 N.D. yloxy)-2-
(trifluoromethyl)phenyl]-5- methylpyrazin-2-amine 92
4-[3-fluoro-4-(2-methylpyridin- 25.2 0.746 N.D.
3-yl)phenoxy]furo[3,2- c]pyridine 93 6-[2-fluoro-4-(furo[3,2- .sup.
88.0.sup.d 0.761 N.D. c]pyridin-4-yloxy)phenyl]-5-
methylpyrazin-2-amine 94 5-[4-(furo[3,2-c]pyridin-4- 7.08 0.837
N.D. yloxy)-2-methoxyphenyl]-6- methoxyisoquinoline, formate salt
95 4-{4-[4-(azetidin-1-yl)-6- 27.3 0.444 N.D.
methylpyrimidin-5-yl]-3- methylphenoxy}furo[3,2- c]pyridine,
formate salt 96 4-{4-[4-(4,6- 24.5 0.306 N.D.
dihydropyrrolo[3,4-c]pyrazol- 5(1H)-yl)-6-methylpyrimidin-5-
yl]-3-methylphenoxy}furo[3,2- c]pyridine, trifluoroacetate salt 97
4-{4-[4-(3-fluoroazetidin-1-yl)- 7.52 0.205 N.D.
6-methylpyrimidin-5-yl]-3- methylphenoxy}furo[3,2- c]pyridine,
formate salt 98 4-{4-[4-(3-fluoropyrrolidin-1- 28.6 0.956 N.D.
yl)-6-methylpyrimidin-5-yl]-3- methylphenoxy}furo[3,2- c]pyridine,
trifluoroacetate salt 99 4-[4-(4,6-dimethylpyrimidin-5-yl)-
1370.sup.d 3.04.sup.b >9.95.sup.d 2,3-dimethylphenoxy]furo[3,2-
c]pyridine 100 5-[4-(furo[3,2-c]pyridin-4- 11.0 0.112 0.580.sup.d
yloxy)-2- (trifluoromethyl)phenyl]-6- methylimidazo[1,2-a]pyrazine
101 5-[4-(furo[3,2-c]pyridin-4- 431.sup.d 3.45 N.D.
yloxy)-2,5-dimethylphenyl]-6- methylimidazo[1,2-a]pyrazine 102
4-[4-(1,4-dimethyl-1H- 84.6 0.714 N.D. imidazol-5-yl)-3-
methylphenoxy]furo[3,2- c]pyridine 103
4-[4-(4,6-dimethylpyrimidin-5-yl)- 23.9 0.392 0.870.sup.d
3,5-dimethylphenoxy]furo[3,2- c]pyridine 104
4-[4-(3,5-dimethylpyridin-4- 24.1 0.502 N.D.
yl)-3-methylphenoxy]furo[3,2- c]pyridine 105
5-[4-(furo[3,2-c]pyridin-4- 24.8 0.297 N.D.
yloxy)-2-methylphenyl]-6- methylimidazo[1,2-a]pyrazin- 8-ol 106
5-[4-(furo[3,2-c]pyridin-4- 106 1.31 N.D. yloxy)-2-methylphenyl]-6-
methylimidazo[1,2-a]pyrazin- 8-ol 107 5-[4-(furo[3,2-c]pyridin-4-
26.2 0.669 N.D. yloxy)-2-methylphenyl]-8- methoxy-6-
methylimidazo[1,2-a]pyrazine 108 4-{3-[(3-cyclopropyl-1,2,4- .sup.
55.5.sup.d 0.673 N.D. oxadiazol-5-yl)methoxy]-4-
(4,6-dimethylpyrimidin-5- yl)phenoxy}furo[3,2-c]pyridine 109
5-[4-(furo[3,2-c]pyridin-4- 57.5 0.429 N.D.
yloxy)-2-methylphenyl]-6,8- dimethylimidazo[1,2- a]pyrazine 110
5-[4-(furo[3,2-c]pyridin-4- 2.89 0.0338 N.D.
yloxy)-2-methylphenyl]-6- methylimidazo[1,2- a]pyrimidine 111
7-[4-(furo[3,2-c]pyridin-4- 41.2 0.335 N.D.
yloxy)-2-methylphenyl]-6- methylimidazo[1,2- a]pyrimidine 112
5-[4-(furo[3,2-c]pyridin-4- 13.8 0.156 N.D.
yloxy)-2-methylphenyl]-6- methylimidazo[1,2-a]pyrazin- 8-amine 113
5-[4-(furo[3,2-c]pyridin-4- 133 1.02 N.D.
yloxy)-2-methoxyphenyl]-6- methylpyridin-3-amine 114
4-[4-(4,6-dimethylpyrimidin-5-yl)- 21.2 0.103 N.D.
3,5-difluorophenoxy]furo[3,2- c]pyridine 115
8-[4-(furo[3,2-c]pyridin-4- 194 0.777 N.D.
yloxy)-2-methylphenyl]-7- methyl[1,2,4]triazolo[4,3-
b]pyridazin-3(2H)-one 116 8-(4,6-dimethylpyrimidin-5-yl)- 481 3.44
N.D. 5-(furo[3,2-c]pyridin-4- yloxy)isoquinoline 117
6-[4-(furo[3,2-c]pyridin-4- 23.1 0.452 N.D.
yloxy)-2-methylphenyl]-1,3,5- trimethylpyrazin-2(1H)-one 118
5-[4-(furo[3,2-c]pyridin-4- >986 >30.0 N.D.
yloxy)-2-methylphenyl]-6- methylpyrimidine-4-carboxylic acid 119
4-[4-(furo[3,2-c]pyridin-4- 2240.sup.d N.D. >11.2
yloxy)phenyl]furo[3,2- c]pyridine 120
(+)-6-[4-(furo[3,2-c]pyridin-4- 30.9 0.124.sup.b N.D.
yloxy)-2-methylphenyl]-1,5- dimethylpyrazin-2(1H)-one 121
(-)-6-[4-(furo[3,2-c]pyridin-4- .sup. 9.42.sup.a 0.0504.sup.b N.D.
yloxy)-2-methylphenyl]-1,5- dimethylpyrazin-2(1H)-one 122
2-[5-(furo[3,2-c]pyridin-4- 211 4.59 N.D.
yloxy)-2-(4-methylpyrimidin-5- yl)phenyl]-2- methylpropanenitrile
123 4-[4-(furo[3,2-c]pyridin-4- N.D. 0.878 N.D.
yloxy)-2-methylphenyl]-3- methylimidazo[2,1- c][1,2,4]triazine 124
6-[4-(furo[3,2-c]pyridin-4- 29.4 0.188.sup.b N.D.
yloxy)-2-methylphenyl]-1,5- dimethylpyrimidin-2(1H)-one 125
5-[4-(furo[3,2-c]pyridin-4- 23.0 0.0917.sup.b N.D.
yloxy)-2-methylphenyl]-4- methylpyridazin-3(2H)-one 126
6-[4-(furo[3,2-c]pyridin-4- 39.9 0.546 N.D.
yloxy)-2-methylphenyl]-1- methylpyridin-2(1H)-one 127
4-[3-chloro-4-(4,6- 14.0 0.127 N.D. dimethylpyrimidin-5-
yl)phenoxy]furo[3,2-c]pyridine 128
4-[4-(4,6-dimethylpyrimidin-5-yl)- 379.sup.d 5.48 N.D.
2,6-difluorophenoxy]furo[3,2- c]pyridine 129
4-[4-(4,6-dimethylpyrimidin-5- 32.3 0.268 N.D. yl)-2-fluoro-5-
methylphenoxy]furo[3,2- c]pyridine 130
4-[4-(4,6-dimethylpyrimidin-5- .sup. 73.0.sup.d 1.05 N.D.
yl)-2-fluorophenoxy]furo[3,2- c]pyridine 131
4-[4-(4,6-dimethylpyrimidin-5- 135.sup.d 1.55 N.D. yl)-2-fluoro-3-
methylphenoxy]furo[3,2- c]pyridine 132
N-[4-(4,6-dimethylpyrimidin-5- .sup. 39.9.sup.d 2.26 N.D.
yl)-3-methylphenyl]furo[3,2- c]pyridin-4-amine, formate salt 133
5-[4-(furo[3,2-c]pyridin-4- 31.5 0.172 N.D.
yloxy)-2-methylphenyl]-6- methylimidazo[1,2- a]pyrimidin-7-ol 134
(+)-5-[4-(furo[3,2-c]pyridin-4- .sup. 1.82.sup.a 0.0106.sup.b N.D.
yloxy)-2-methylphenyl]-4,6-
dimethylpyridazin-3(2H)-one 135 4-[4-(5-methoxy-3- 38.7 0.276 N.D.
methylpyridazin-4-yl)-3- methylphenoxy]furo[3,2- c]pyridine 136
6-[4-(furo[3,2-c]pyridin-4- 225 2.41 N.D. yloxy)-2-methylphenyl]-5-
methylpyrazin-2-ol 137 5-[4-(furo[3,2-c]pyridin-4- 42.0 0.209.sup.b
N.D. yloxy)-2- methylphenyl]imidazo[1,2- a]pyridin-8-ol 138
4-[4-(3,5-dimethyl-2- 17.1 0.262 N.D. oxidopyridazin-4-yl)-3-
methylphenoxy]furo[3,2- c]pyridine and 4-[4-(3,5-
dimethyl-1-oxidopyridazin-4- yl)-3-methylphenoxy]furo[3,2-
c]pyridine 139 4-[4-(4,6-dimethylpyrimidin-5- 119 0.287 N.D.
yl)-2,5- difluorophenoxy]furo[3,2- c]pyridine 140
4-[4-(3,5-dimethylpyridazin-4- .sup. 48.0.sup.d 0.292 N.D.
yl)-3-fluorophenoxy]furo[3,2- c]pyridine 141
4-[4-(4,6-dimethylpyrimidin-5- 69.9 0.298.sup.b N.D. yl)-2,3-
difluorophenoxy]furo[3,2- c]pyridine 142 (-)-4-[4-(3,5- 10.8 0.0772
N.D. dimethylpyridazin-4-yl)-3- methoxyphenoxy]furo[3,2- c]pyridine
143 (+)-4-[4-(3,5- 64.9 0.273 N.D. dimethylpyridazin-4-yl)-3-
methoxyphenoxy]furo[3,2- c]pyridine 144
4-{[7-(4,6-dimethylpyrimidin- 246.sup.d 3.49 N.D.
5-yl)-2-methyl-2H-indazol-4- yl]oxy}furo[3,2-c]pyridine 145
4-[3-methyl-4-(3- 110.sup.d 1.44 N.D. methylpyridazin-4-
yl)phenoxy]furo[3,2-c]pyridine 146 5-[4-(furo[3,2-c]pyridin-4- 49.7
0.324.sup.b N.D. yloxy)-2-methylphenyl]-6- methylimidazo[1,2-
a]pyrimidine 147 5-[4-(furo[3,2-c]pyridin-4- 3.60 0.068.sup.b N.D.
yloxy)-2-methylphenyl]-6- methylimidazo[1,2- a]pyrimidine 148
4-{[7-(4,6-dimethylpyrimidin- 111 0.777 N.D.
5-yl)-1-methyl-1H-indazol-4- yl]oxy}furo[3,2-c]pyridine,
trifluoroacetate salt 149 4-[4-(2-methoxy-4,6- 31.4 0.464.sup.b
N.D. dimethylpyrimidin-5-yl)-3- methylphenoxy]furo[3,2- c]pyridine
150 4-[4-(3,5-dimethylpyridazin-4- 67.0 0.443 N.D.
yl)phenoxy]furo[3,2-c]pyridine 151 4-[4-(furo[3,2-c]pyridin-4- 101
1.12 N.D. yloxy)-2-methylphenyl]-N,N,5- trimethylpyridazin-3-amine,
trifluoroacetate salt 152 5-[4-(furo[3,2-c]pyridin-4- 79.5 0.565
N.D. yloxy)-2-methylphenyl]-4,6- dimethylpyrimidin-2-ol 153
5-(furo[3,2-c]pyridin-4-yloxy)- 5.99 0.0518 N.D.
2-(6-methylimidazo[1,2- a]pyridin-5-yl)phenol 154 4-[3-methyl-4-(5-
402.sup.d 2.16 N.D. methylpyridazin-4-
yl)phenoxy]furo[3,2-c]pyridine 155 4-{[4-(4,6-dimethylpyrimidin-
138.sup.d 1.01 N.D. 5-yl)-3- methylphenyl]sulfanyl}furo[3,2
-c]pyridine 156 4-{[7-(4,6-dimethylpyrimidin- 1820.sup.d >15.1
N.D. 5-yl)-1,3-benzodioxol-4- yl]oxy}furo[3,2-c]pyridine 157
4-[4-(3-ethoxy-5- 354.sup.d 3.52 N.D. methylpyridazin-4-yl)-3-
methylphenoxy]furo[3,2- c]pyridine 158
8-(4,6-dimethylpyrimidin-5-yl)- 280.sup.d 2.69 N.D.
5-(furo[3,2-c]pyridin-4- yloxy)quinoline 159
5-[4-(furo[3,2-c]pyridin-4- 11.6 0.212 N.D.
yloxy)-2-methylphenyl]-2,4,6- trimethylpyridazin-3(2H)-one 160
5-[2-chloro-4-(furo[3,2- 5.24 0.013 N.D.
c]pyridin-4-yloxy)phenyl]-4,6- dimethylpyridazin-3(2H)-one 161
4-[4-(6-methylimidazo[1,2- 8.49 0.0947 0.173 a]pyridin-5-
yl)phenoxy]furo[3,2-c]pyridine 162 5-[4-(furo[3,2-c]pyridin-4- 10.6
0.251 0.446.sup.d yloxy)-2,6-dimethylphenyl]-6-
methylimidazo[1,2-a]pyrazine 163 4-(4-{4-[(3S)-3- 12.8 0.389 N.D.
fluoropyrrolidin-1-yl]-6- methylpyrimidin-5-yl}-3-
methylphenoxy)furo[3,2- c]pyridine, formate salt 164
4-{3-methyl-4-[4-methyl-6-(1- 15.2 0.625 N.D. methyl-4,6-
dihydropyrrolo[3,4-c]pyrazol- 5(1H)-yl)pyrimidin-5-
yl]phenoxy}furo[3,2- c]pyridine, formate salt 165
5-[4-(furo[3,2-c]pyridin-4- 15.6 0.182 N.D.
yloxy)-2-methylphenyl]-N,N,6- trimethylpyrimidin-4-amine,
trifluoroacetate salt 166 6-[4-(furo[3,2-c]pyridin-4- 22.9 0.310
N.D. yloxy)-2-methoxyphenyl]-1- methylpyridin-2(1H)-one 167
4-{4-[4-(2,5-dihydro-1H- 24.4 0.354 N.D.
pyrrol-1-yl)-6-methylpyrimidin- 5-yl]-3- methylphenoxy}furo[3,2-
c]pyridine, trifluoroacetate salt 168 5-[4-(furo[3,2-c]pyridin-4-
28.6 N.D. 0.458.sup.d yloxy)phenyl]-6- methoxyisoquinoline,
trifluoroacetate salt 169 4-[4-(3,5-dimethylpyridazin-4- 29.2
0.150.sup.b N.D. yl)-3- methoxyphenoxy]furo[3,2- c]pyridine 170
5-[2-chloro-4-(furo[3,2- 30.0 0.657 N.D. c]pyridin-4-
yloxy)phenyl]imidazo[1,2- a]pyrazine 171 4-[4-(5-methoxy-3- 31.1
0.487 N.D. methylpyridazin-4-yl)-3- methylphenoxy]furo[3,2-
c]pyridine 172 5-[4-(furo[3,2-c]pyridin-4- 32.7 N.D. 0.408.sup.d
yloxy)phenyl]-6- methylimidazo[1,2-a]pyrazine 173
5-[4-(furo[3,2-c]pyridin-4- 36.8 N.D. 0.564
yloxy)-2-methoxyphenyl]-6- methylimidazo[1,2-a]pyrazine 174
4-[4-(imidazo[1,2-a]pyridin-5- 37.9 N.D. 0.200.sup.d
yl)-3-methylphenoxy]furo[3,2- c]pyridine 175
6-{5-[4-(furo[3,2-c]pyridin-4- 41.4 0.475 N.D.
yloxy)-2-methylphenyl]-6- methylpyrimidin-4-yl}-6,7-
dihydro-5H-pyrrolo[3,4- d]pyrimidine, formate salt 176
3-[4-(furo[3,2-c]pyridin-4- 44.2 N.D. 0.780
yloxy)-2-methylphenyl]-4- methylpyridine-2-carbonitrile 177
5-[4-(furo[3,2-c]pyridin-4- .sup. 46.4.sup.d 2.55 N.D.
yloxy)-2-methylphenyl]-6- methyl-1,2,4-triazin-3(2H)- one 178
4-{3-methyl-4-[4-methyl-6- 46.4 1.16 N.D.
(pyrrolidin-1-yl)pyrimidin-5- yl]phenoxy}furo[3,2- c]pyridine,
trifluoroacetate salt 179 (1-{5-[4-(furo[3,2-c]pyridin-4- 47.2
0.921 N.D. yloxy)-2-methylphenyl]-6- methylpyrimidin-4-
yl}pyrrolidin-3-yl)methanol, formate salt 180
[(2S)-1-{5-[4-(furo[3,2- 52.9 0.812 N.D. c]pyridin-4-yloxy)-2-
methylphenyl]-6- methylpyrimidin-4- yl}pyrrolidin-2-yl]methanol,
formate salt 181 4-[3-methoxy-4-(2- 53.1 0.803 N.D.
methylpyridin-3- yl)phenoxy]furo[3,2-c]pyridine 182
4-{4-(3-methylpyrazin-2-yl)-3- 58.0 N.D. 0.641.sup.d
[(3-propyl-1,2,4-oxadiazol-5- yl)methoxy]phenoxy}furo[3,2-
c]pyridine, formate salt 183 4-{4-[4-(5,7-dihydro-6H- 62.4 1.40
N.D. pyrrolo[3,4-b]pyridin-6-yl)-6- methylpyrimidin-5-yl]-3-
methylphenoxy}furo[3,2- c]pyridine, formate salt 184
4-[4-(2-methylpyridin-3- 63.3 0.881 N.D.
yl)phenoxy]furo[3,2-c]pyridine 185 4-(4-{4-[(3R)-3- 64.2 1.16 N.D.
fluoropyrrolidin-1-yl]-6- methylpyrimidin-5-yl}-3-
methylphenoxy)furo[3,2- c]pyridine, trifluoroacetate salt 186
4-{3-[(3,5-dimethyl-1,2- 64.6 N.D. 1.02.sup.d
oxazol-4-yl)methoxy]-4- (imidazo[1,2-a]pyridin-5-
yl)phenoxy}furo[3,2- c]pyridine, trifluoroacetate salt 187
(1-{5-[4-(furo[3,2-c]pyridin-4- 65.7 0.984 N.D.
yloxy)-2-methylphenyl]-6- methylpyrimidin-4-
yl}pyrrolidin-2-yl)methanol, trifluoroacetate salt 188
4-{3-[(3-cyclopropyl-1,2,4- 72.5 0.464 0.447.sup.d
oxadiazol-5-yl)methoxy]-4-(3- methylpyrazin-2- yl)phenoxy}furo[3,2-
c]pyridine, formate salt 189 5-[4-(furo[3,2-c]pyridin-4- 77.6 N.D.
0.308 yloxy)-2- methylphenyl]imidazo[1,2- a]pyrazine,
trifluoroacetate salt 190 4-[4-(4,6-dimethylpyrimidin-5- .sup.
79.3.sup.d 2.65 N.D. yl)-3-(2- methoxyethoxy)phenoxy]furo[3,2-
c]pyridine 191 5-[4-(furo[3,2-c]pyridin-4- 85.8 1.12 N.D.
yloxy)-2-methoxyphenyl]-6- methylpyridin-2-amine, formate salt 192
4-[4-(4-ethoxy-6- 86.4 0.737 1.50 methylpyrimidin-5-yl)-3-
fluorophenoxy]furo[3,2- c]pyridine 193 6-[2-chloro-4-(furo[3,2-
87.5 0.944 N.D. c]pyridin-4-yloxy)phenyl]-5- methylpyrazin-2-amine
194 4-{4-(2-methylpyridin-3-yl)-3- 88.5 1.68 1.33 [2-(1,2-oxazol-4-
yl)ethoxy]phenoxy}furo[3,2- c]pyridine, formate salt 195
3-[5-(furo[3,2-c]pyridin-4- .sup. 90.4.sup.d N.D. 0.565.sup.d
yloxy)-2-(imidazo[1,2- a]pyridin-5- yl)phenoxy]propan-1-ol,
trifluoroacetate salt 196 4-[3-chloro-4-(3- .sup. 91.7.sup.d 1.40
N.D. methylpyrazin-2- yl)phenoxy]furo[3,2-c]pyridine 197
4-[4-(imidazo[1,2-a]pyridin-5- .sup. 97.0.sup.a 0.801 1.09
yl)phenoxy]furo[3,2-c]pyridine 198 4-{5-[4-(furo[3,2-c]pyridin-4-
.sup. 97.0.sup.d 1.14 N.D. yloxy)-2-methylphenyl]-6-
methylpyrimidin-4-yl}-1- methylpiperazin-2-one, formate salt 199
4-{3-[(3-ethyl-1,2,4-oxadiazol- 104 N.D. 0.782.sup.d
5-yl)methoxy]-4-(3-
methylpyrazin-2- yl)phenoxy}furo[3,2- c]pyridine, formate salt 200
4-[3-methyl-4-(1-methyl-1H- 111 N.D. 1.24.sup.d
indazol-7-yl)phenoxy]furo[3,2- c]pyridine 201
2-[5-(furo[3,2-c]pyridin-4- 113 N.D. 0.889.sup.d
yloxy)-2-(imidazo[1,2- a]pyridin-5-yl)phenoxy]-N-
(propan-2-yl)acetamide, trifluoroacetate salt 202 4-(4-{4-[(3S)-3-
114.sup.d 1.29 N.D. methoxypyrrolidin-1-yl]-6-
methylpyrimidin-5-yl}-3- methylphenoxy)furo[3,2- c]pyridine,
trifluoroacetate salt 203 1-{5-[4-(furo[3,2-c]pyridin-4- 118 0.799
N.D. yloxy)-2-methylphenyl]-6- methylpyrimidin-4-yl}azetidin- 3-ol,
formate salt 204 4-[4-(1-methyl-1H-pyrazol-5-yl)-3- 130.sup.a 1.17
0.627 (trifluoromethyl)phenoxy]furo[3,2- c]pyridine 205
4-[4-(2-methylpyridin-3-yl)-3- 148.sup.d 4.63 3.57
(tetrahydro-2H-pyran-4- yloxy)phenoxy]furo[3,2- c]pyridine, formate
salt 206 4-[4-(4-methoxy-6- 160.sup.d 0.768.sup.b 1.25
methylpyrimidin-5-yl)-3- methylphenoxy]furo[3,2- c]pyridine 207
5-[4-(furo[3,2-c]pyridin-4- 161.sup.d 0.796 N.D.
yloxy)-2-methylphenyl]-6- methylimidazo[1,2-
a]pyrazine-8-carbonitrile 208 4-[4-(furo[3,2-c]pyridin-4- 170 N.D.
1.55 yloxy)phenyl]-8- methoxyquinazoline 209
3-cyclopropyl-4-[4-(4,6- 131 5.62 N.D. dimethylpyrimidin-5-yl)-3-
methylphenoxy]furo[3,2- c]pyridine, trifluoroacetate salt 210
4-[4-(4,6-dimethylpyrimidin-5- 18.8 0.655 N.D.
yl)-3-methylphenoxy]furo[3,2- c]pyridine-3-carbonitrile 211
5-{4-[(3-bromofuro[3,2- 6.86 0.098 N.D.
c]pyridin-4-yl)oxy]phenyl}-4,6- dimethylpyridazin-3(2H)-one 212
4-[4-(3,5-dimethyl-6-oxo-1,6- 18.7 0.119 N.D. dihydropyridazin-4-
yl)phenoxy]furo[3,2- c]pyridine-3-carbonitrile 213
6-{4-[(3-bromofuro[3,2- 64.5 0.694 N.D. c]pyridin-4-yl)oxy]-2-
methylphenyl}-1,5- dimethylpyrazin-2(1H)-one 214
4-[4-(imidazo[1,2-a]pyridin-5- 67.6 N.D. 0.457
yl)phenoxy]thieno[3,2- c]pyridine 215
(-)-6-[4-(furo[3,2-c]pyridin-4- .sup. 1.06.sup.a 0.00139 N.D.
yloxy)-2-methylphenyl]-1,5- dimethylpyrimidine- 2,4(1H,3H)-dione
216 6-[4-(furo[3,2-c]pyridin-4- 4.2 0.00938 N.D. yloxy)phenyl]-1,5-
dimethylpyrimidine- 2,4(1H,3H)-dione, trifluoroacetate salt
.sup.aValue represents the geometric mean of .gtoreq.5
determinations. .sup.bValue represents the geometric mean of 7-15
determinations. .sup.cNot determined. .sup.dValue represents a
single determination
Example CC
D1R Mutant Studies
[0572] Fourteen different potential binding site residue mutations
of the D1R were made to more precisely determine where the D1
agonists of the present invention were binding. Generally, there is
very good agreement between the fold-shift values of the D1
agonists of the present invention when compared to those of known
catechol derivative full (or super) D1 agonists and partial
agonists; however 4 of those 14 residues (Ser188, Ser198, Ser202,
and Asp103) showed statistically significant deviations and
reprentative results are shown herein.
[0573] Human Dopamine D1 receptor agonist activity was measured
using Cisbio Dynamic 3'-5'-cyclic adenosine monophosphate (CAMP)
detection kit (Cisbio International 62AM4PEJ). cAMP was measured
using a homogeneous time-resolved fluorescence (HTRF) competitive
immunoassay between native cAMP and cAMP labeled with the dye
d2.
[0574] A monoclonal anti-cAMP antibody labeled cryptate bound the
labeled cAMP. Europiumcryptate donor was added, and the transfer of
energy to the d2 acceptor was measured. The maximum signal was
achieved if the samples did not contain free cAMP, due to the
proximity of Eu-cryptate donor and d2 acceptor entities. The
signal, therefore, was inversely proportional to the concentration
of native cAMP in the sample. A time resolved and ratiometric
measurement (em 665 nm/em 620 nm) was obtained, which was then
converted to cAMP concentrations using a standard curve. All cAMP
experiments were performed in the presence of 500 nM IBMX to
inhibit phosphodiesterase (PDE) activity.
[0575] The cAMP standard curve was generated using cAMP provided in
the Cisbio cAMP detection kit. Preparation of the standard curve is
as follows. (1) Prepared 2848 nM cAMP stock solution in
D.mu.lbecco's Phosphate Buffered Saline (PBS, from Sigma,
Cat#D8537), this stock solution was aliquoted (40 .mu.l/vial) and
frozen at -20.degree. C. 2) On the day of assay, 40 .mu.l PBS was
added to two column of a 96-well compound plate (Costar, Cat#3357).
2) On the day of assay, 40 .mu.l 2848 nM cAMP stock solution was
transferred to first well and mixed with 40 .mu.l PBS (see the
figure below), and then a 16 pt, 2 fold dilution was made by
transfer 40 .mu.l from higher conc. to lower conc. (3) Manually
transfer 10 .mu.l/well (in triplicate) of cAMP solution to assay
plate.
[0576] Stable HEK293T cells expressing hD1R (wild type or a mutant
thereof) were grown in high glucose DMEM (Invitrogen 11995-065),
10% fetal bovine serum dialyzed (Invitrogen 26400-044), 1.times.
MEM NEAA (Invitrogen 1140), 25 mM HEPES (Invitrogen 15630),
1.times. Penicillin/Streptomycin (Invitrogen 15070-063) and 500
.mu.g/mL Genenticin (Invitrogen 10131-035) at 37 C and 5% CO2. At
72 to 96 hours post seeding, cells were rinsed with phosphate
buffered saline and 0.25% Trypsin-EDTA was added to dislodge the
cells. Media was then added and cells were centrifuged and media
removed. The cell pellets were re-suspended in Cell Culture
Freezing Medium (Invitrogen 12648-056) at a density of 40 million
cells/mL. One mL aliquots of the cells were made in Cryo-vials and
frozen at -80.degree. C. for use in the hD1 (or a mutant thereof)
HTRF cAMP assay.
[0577] Frozen cells were quickly thawed, re-suspended in warm media
and allowed to sit for 5 min prior to centrifugation (1000 rpm) at
room temperature. Media was removed and the cell pellet was
re-suspended in PBS containing 500 nM IBMX. Using a Multidrop Combi
(Thermo Scientific), 5 .mu.L cells/well at a cell density of
approximately 1000 cells/well were added to the assay plate
(Greiner 784085) which contained 5 .mu.L of test compound. The
exact cell density could vary depending on the cAMP concentration
relative to the standard curve. Each plate contained positive
controls of 5 uM dopamine (final concentration) and negative
controls of 0.5% DMSO (final concentration). Cells and compounds
were incubated at room temperature for 30 min. Working solutions of
cAMP-d2 and anti-cAMPcryptate were prepared according to Cisbio
instructions. Using the Multidrop Combi, 5 .mu.L cAMP-d2 working
solution was added to the assay plate containing the test compound
and cells. Using the Multidrop Combi, 5 .mu.L anti-cAMP-cryptate
working solutions was added to assay plate containing test
compound, cells and cAMP-d2. Assay plates were incubated for 1 hour
at room temperature, then read using an Envision plate reader
(Perkin Elmer) using Cisbio recommended settings. A cAMP standard
curve was generated using cAMP stock solution provided in the
Cisbio kit, which was then used to convert the raw ratio data to
cAMP concentrations. EC.sub.50 values were determined using a
logistic 4 parameter fit model. The percent efficacy for each curve
was determined by the maximum asymptote of that fitted curve, and
expressed as a percent of the maximum response produced by the
positive controls (5 .mu.M dopamine) on each plate.
[0578] Wild type 3.times.HA-h D1 expression construct (in
pcDNA3.1+) was obtained from Missouri S&T cDNA Resource Center.
Several mutations were created using mutagenesis methods (e.g.,
Stratagene Quick Change Mutagenesis Kit). All mutations were
confirmed via sequencing. Wild type and mutant(s) expressing HEK293
cells were generated (for cAMP assays) via transient transfection
(48 hrs.) in Freestyle HEK 293F cells (Invitrogen). The number of
cells/paste used per data point was based on relative expression
levels as determined via western blot analysis.
[0579] D1R WT refers to wild type. Several mutants were designed
based upon a computational homology model of D1 and mutant
numbering is consistent with what has been previously published in
the literature. See e.g., N J Pollock, et.al, "Serine mutations in
transmembrane V of the dopamine D1 receptor affect ligand
interactions and receptor activation." J. Biol. Chem. 1992, 267
[25], 17780-17786. Mutants are designated by the number
corresponding to their position in the primary sequence and the
three-letter amino acid code. For example, D103A mutant refers to
the amino acid aspartate (D) at the 103.sup.rd position in the
primary sequence mutated to the amino acid alanine (A); S1881
mutant refers to the amino acid Serine (S) at the 188.sup.th
position in the primary sequence mutated to the amino acid
isoleucine (1); and S198A mutant refers to the amino acid Serine
(S) at the 198.sup.th position in the primary sequence mutated to
the amino acid alanine (A).
[0580] Relative 3.times.HA-hD1 mutant expression levels were
normalized to wild type hD1 levels by western blot analysis.
Soluble RIPA lysates of transiently transfected HEK293F cells were
prepared by lysing cells at 4.degree. C. for 30 minutes in RIPA
Buffer (Sigma) with protease and phosphatase inhibitors (Pierce).
Equivalent amounts of total soluble RIPA lysates (determined by BCA
total protein assay, Pierce) were run on SDS-PAGE, transferred to
nitrocellulose and probed with anti-HA as well as anti-GAPDH
antibodies (Sigma). Total mutant hD1 HA immunoreactivity was
quantitated verses GAPDH immunoreactivity (HA/GAPDH) and finally
normalized to wild type 3.times.HA-hD1 (HA/GAPDH) using
LiCor/Odyssey software. Based on this relative HA/GAPDH ratios as
compared to wild type, the relative amount of cell paste or cell
number/well was adjusted for each mutants' expression levels.
[0581] A first run of cAMP assays was conducted. From the first
run, it was determined that the results were at the upper end of
linear range (for agonists) of the standard curve (the range is
provided by Cisbo), indicating this first run is at a higher
density of cells/well. Typically, a higher density of cells/well
run (within the linear range) is suitable for mutants that are
either lower expressers or have low activity; but not as suitable
for the higher activity/expressing mutants. Table 4 shows EC.sub.50
data in the first run of cAMP assays. A second run of cAMP assays
was conducted. According to a comparison with the standard curve,
this run of assays was at a lower density of cells/well because the
results were at the lower end of linear range (for agonists) of the
standard curve. Typically, assays at a lower density of cells/well
(within the liner range) are more suitable for the higher
activity/expressing mutants, but less suitable for those mutants
with lower expression/activity. Table 5 shows EC.sub.50 data in the
second run of cAMP assays.
TABLE-US-00004 TABLE 4 EC.sub.50 Data (high expression levels of
D1R). EC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 (S188I
(S202A (S198A (D103A D1 WT mutant) mutant) mutant) mutant) Compound
[nM] [nM] [nM] [nM] [nM] Example 27 3 12 5 18 102 Example 25 6 40 7
36 188 Dopamine 58 95 3058 923 >29,900 Dihydrexidine 9 6 189 208
1324 SKF-38393 33 6 119 277 >29,900 SKF-77434 28 7 49 119
>29,900
TABLE-US-00005 TABLE 5 EC.sub.50 Data (lower expression levels of
D1R). EC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 EC.sub.50 D1 WT
(S188I (Ser202A (Ser198A (Asp103A Compound [nM] mutant) mutant)
mutant) mutant) Example 215 0.4 5 1 3 31 Dopamine 51 208 12709 1631
>29,900 Dihydrexidine 7 6 527 349 1264 SKF-38393 51 19 139
>29,900 >29,900 SKF-77434 14 6 20 >29,900 >29,900
[0582] Results from both mutation runs revealed that many of the
mutant receptors have weaker activity (higher EC.sub.50 values)
when compared to the WT D1, reflecting the loss of interaction
between the ligand and the receptor with the mutated side chain. In
an attempt to determine the side-chain contribution to activity,
quantifications of the shift between the mutant receptor and the WT
receptor, i.e., Fold Shift data were calculated according to the
equation; Fold Shift=EC.sub.50 (Mutant)/EC.sub.50 (WT). Fold shift
data are shown in Table 6.
[0583] In general, assays with most of the mutant D1 receptors
provided values in the "kit-defined" linear range with the lower
cell/well variant. However, S198A gave poor results for the lower
cells/well run. A comparison of the average fold shifts for each
tested mutant across both runs revealed that the fold shifts were
more pronounced for the lower activity run by a factor of
.about.2.5. This factor was determined by regressing the average
log(foldshift) values between runs for all mutants:
log(fold-shift_lower)=0.3968+1.023*log(fold-shift_higher).(R
2=0.92)
[0584] The intercept value of 0.3968 reflects the .about.2.5.times.
systematic difference between the runs.
[0585] Dopamine, another catechol-derivative full D1 agonist
(Dihydrexidine), and two other catechol-derivative partial D1
agonist (SKF-38393 and SKF-77434) have fold shift less than about
4.0 with respect to S1881 mutant, indicating that they do not
interact significantly with the Ser188 unit of DIR. In contrast,
Examples 215 and 27 (full D1 agonists) and Example 25 (partial D1
agonist) have fold shift greater than about 7.0 with respect to
S1881 mutant, indicating that they interact significantly with the
Ser188 unit of D1R.
[0586] Dopamine and another catechol-derivative D1 full agonist
(Dihydrexidine) have fold shift greater than about 70 with respect
to S202A mutant, indicating that they interact significantly with
the Ser202 unit of D1R. In contrast, Examples 215 and 27 (full D1
agonists) have fold shift less than about 4.0 with respect to S202A
mutant, indicating that they do not interact significantly with the
Ser202 unit of D1R.
[0587] Dopamine and 3 other catechol-derivative D1 agonists, as
well as Examples 215 and 27 (full D1 agonists) and Example 25
(partial D1 agonist) have fold shift greater than about 7.0 with
respect to D103A mutant, indicating that they interact
significantly with the Asp103 unit of D1R. On average, the fold
shift for the catechol-derivative agonist (greater than 100, 150,
or 180) are much greater than those for Examples 215 and 27 (full
D1 agonists) and Example 25 (partial D1 agonist), indicating the
interactions between D1R and non-catechol derivative Examples 215,
27, and 25 are less strong than those between D1R and the
catechol-derivative agonists.
[0588] Dopamine and 3 other catechol-derivative D1 agonists, as
well as Examples 215 and 27 (full D1 agonists) and Example 25
(partial D1 agonist) have fold shift greater than about 7.0 with
respect to S198A mutant, indicating that they interact
significantly with the Ser198 unit of D1R. However, on average, the
fold shift for the catechol-derivative full agonists (Dopamine and
Dihydrexidine, both are greater than 25, 30, or 35) are greater
than Examples 215 and 27 (full D1 agonists), indicating the
interactions between D1R and non-catechol-derivative full agonist
Examples 215, and 27 are less strong than those between D1R and the
catechol-derivative full agonists.
[0589] The % intrinsic activity of each of the test compounds
[i.e., the maximum percent efficacy (Calculated by maximum cAMP
concentration) in reference to Dopamine] was determined using cAMP
data from a D1 cAMP HTRF assay as in Example BB.
TABLE-US-00006 TABLE 6 Fold-Shift Values and % intrinsic activity
(intrinsic activity data: % activity comparing to Dopamine) Fold
Fold Fold Fold % Shift Shift Shift Shift intrinsic (S188I (S202A
(S198A (D103A Compound activity mutant) mutant) mutant) mutant)
Example 215 101 11.6 2.3 7.0 72 Example 27 109 8.9 .sup.a 3.7
.sup.a 13.4 .sup.a 76 .sup.a Example 25 74 15 .sup.a 2.6 .sup.a
13.4 .sup.a 70 .sup.a Dopamine 100 4.0 249 36 .sup.a >586
Dihydrexidine 108 0.9 75 53 .sup.a 180 SKF-38393 78.5 0.4 2.7 18.9
.sup.a >586 SKF-77434 36.2 0.4 1.4 9.4 .sup.a >2135 .sup.a
These fold shift value have been transformed using the equation:
FoldShift = 2.234*(EC.sub.50--Mutant/EC.sub.50--WT). This
correction was done in order to correct for differences in receptor
density between two assay runs shown in Tables 4 and 5. Any other
FoldShift refers to the shift in functional activity as defined: =
EC.sub.50 (Mutant)/EC.sub.50 (WT).
Example DD
.beta.-Arrestin Membrane Recruitment Assays and TIRF Microscopy
[0590] For all studies of .beta.-arrestin, a stable U2OS cell line
co-expressing human Dopamine D1(D1A) receptors and human
.beta.-arrestin2-green fluorescent fusion protein (GFP) was used.
This cell line was obtained and licensed from Professor Marc G.
Caron, Duke University, Durham, N.C., USA. The stable U2OS cell
line provides a fluorescent biosensor of .beta.-arrestin2-GFP that
can be used to assess GPCR signaling and GPCR-mediated
.beta.-arrestin membrane recruitment using imaging-based methods
such as fluorescence microscopy (U.S. Pat. Nos. 7,572,888 and
7,138,240)(9); this technology is currently marketed as the
Transfluor Assay (Molecular Devices, USA). The U2OS cells were
cultured under antibiotic selection in DMEM (Invitrogen) containing
25 mM glucose and 4 mM L-glutamine supplemented with 10% dialyzed
fetal bovine serum, 200 mg/mL Geneticin, 100 mg/mL Zeocin, and 100
U/mL penicillin/streptomycin (all from Invitrogen) and incubated at
37.degree. C. in 5% carbon dioxide. Cells from passage four through
ten were used in these experiments. Cells were grown in 35 mm glass
bottomed imaging dishes (Mattek Corp). Cells were incubated for 1 h
in serum free media (SFM) and subsequently treated for 10 minutes
at 37.degree. C. with 0.01% DMSO (Control) or 1 .mu.M of all test
compounds dissolved in SFM followed by immediate fixation on ice
with a 4% paraformaldehyde/1.times. phosphate buffered saline
solution.
[0591] Total Internal Reflection Fluorescence Microscopy (TIRFM)
was used. TIRFM is a microscopy technique that enables
visualization of the plasma membrane and a narrow region just
inside the cell, providing a means to visualize proteins at the
plasma membrane of cells such as D1 receptors and recruited
.beta.-arrestin-GFP (see Yudowski G A, von Zastrow M.
"Investigating G protein-coupled receptor endocytosis and
trafficking by TIR-FM"; Methods in Molecular Biology. 2011;
756:325-32.). All images were captured using a Zeiss PS.1 Elyra
Superresoution fluorescence microscope equipped with TIRF module.
Images of cells were obtained using TIRF and a 100.times. oil
immersion objective and dedicated 488 nm excitation laser. Optimal
exposure time and laser power was determined using Dopamine treated
cells which exhibited maximal .beta.-arrestin-GFP membrane signal
and identical acquisition parameters were used for all cells and
conditions. To quantify .beta.-arrestin-GFP membrane recruitment,
individual cells in microscopy images were identified and a polygon
region of interest was traced for each cell using ImageJ, imaging
analysis software (Schneider C A, Rasband W S, Eliceiri K W. "NIH
Image to ImageJ: 25 years of image analysis". Nature Methods. 2012;
9(7):671-5). An intensity-based threshold was established by
evaluating Dopamine treated cells which exhibited the maximal
plasma membrane signal of .beta.-arrestin-GFP. A range of values,
10, 30, 60, 90, etc. were tested and the lowest possible threshold,
in this case 60, capable of identifying the individual
.beta.-arrestin-GFP puncta was selected for continued analysis.
Sub-images were generated for all identified cells, and the total
number of membrane .beta.-arrestin-GFP puncta/cell, integrated
intensity/cell, and total area/cell was established. Individual
objects were filtered based on size. A minimum of 60 cells for each
condition were analyzed across three independent cell preparations
and experiments. The mean membrane .beta.-arrestin-GFP
intensity/cell and puncta area/cell were determined and statistical
differences compared by a one-way ANOVA with Dunnett's post-test
analysis using Graphpad Prism 5.02.
[0592] U2OS cells stably expressing human D1 receptors and human
.beta.-arrestin-GFP proteins were treated for 10 minutes with 0.01%
DMSO in serum free media (Control) or with 1 .mu.M of a test
compound).
[0593] Test compounds include Dopamine, Dihydrexidine, SKF-81297,
SKF-38393, SKF-77434, Example 5 (partial agonist, 70% intrinsic
activity at human D1R v. Dopamine), Example 9 (full agonist, 92%
intrinsic activity at human D1R v. Dopamine), Example 13 (partial
agonist, 58% intrinsic activity at human D1R v. Dopamine), and
Example 25 (full agonist, 88% intrinsic activity at human D1R v.
Dopamine). The % intrinsic activity of each of the test compounds
[i.e., the maximum percent efficacy (Calculated by maximum cAMP
concentration) in reference to Dopamine] was determined using cAMP
data from a D1 cAMP HTRF assay as in Example BB.
[0594] Cells were immediately fixed and .beta.-arrestin-GFP located
at the plasma membrane of cells was determined using Total Internal
Reflection Fluorescence Microscopy (TIRFM).
[0595] Tables 7 and 8 list quantification of .beta.-arrestin-GFP
signal at the plasma membrane of cells using TIRFM to assess total
intensity/cell and total area/cell; non-catechol-derivative D1
receptor agonists (Examples 5, 9, 13 and 25) showed significantly
reduced plasma membrane .beta.-arrestin-GFP total intensity and
total area relative to Dopamine. All results are the
mean.+-.standard error averaged from .gtoreq.60 cells/condition
obtained across three independent experiments (n=3). a, p<0.05
versus control; b, p<0.05 versus Dopamine.
TABLE-US-00007 TABLE 7 Membrane .beta.-arrestin-GFP Total
Intensity/cell Membrane .beta.-arrestin-GFP Total Intensity/cell
Unit % recruitment Control/test (arbitrary fluorescence normalized
to compound units/cell) Dopamine Control 9 .+-. 6 .sup.b 0.13 .+-.
0.08 Dopamine 7072 .+-. 966 .sup.a 100 .+-. 14 Dihydrexidine 8969
.+-. 1130 .sup.a 127 .+-. 16 SKF-81297 7424 .+-. 1203 .sup.a 105
.+-. 17 SKF-38393 241 .+-. 99 .sup.b 3.4 .+-. 1.4 SKF-77434 35 .+-.
12 .sup.b 0.50 .+-. 0.17 Example 5 774 .+-. 205 .sup.b 10.9 .+-.
2.9 Example 9 940 .+-. 198 .sup.b 13.3 .+-. 2.8 Example 25 1801
.+-. 203 .sup.b 25.5 .+-. 2.9 Example 13 499 .+-. 101 .sup.b 7.0
.+-. 1.4
TABLE-US-00008 TABLE 8 Membrane .beta.-arrestin-GFP Total Area/cell
Membrane .beta.-arrestin-GFP % recruitment Control/test Total
Area/cell normalized to compound Unit [.mu.m] Dopamine Control
.+-.0.08 .sup.b 0.13 .+-. 0.10 Dopamine 79 .+-. 11 .sup.a 100 .+-.
14 Dihydrexidine 92 .+-. 11 .sup.a 116.4 .+-. 13.9 SKF-81297 77
.+-. 11 .sup.a 97.5 .+-. 13.9 SKF-38393 6 .+-. 3 .sup.b 7.6 .+-.
3.8 SKF-77434 0.5 .+-. 0.2 .sup.b 0.6 .+-. 0.2 Example 5 10 .+-. 2
.sup.b 12.6 .+-. 2.5 Example 9 12 .+-. 2 .sup.b 15.2 .+-. 2.5
Example 25 24 .+-. 3 .sup.b 30.3 .+-. 3.8 Example 13 7 .+-. 1
.sup.b 8.9 .+-. 1.3
[0596] As shown in Tables 7 and 8, Dopamine and two
catechol-derivative full D1 agonists (Dihydrexidine and SKF-81297)
recruited greater than about 95% .beta.-arrestin-GFP to the plasma
membrane relative to Dopamine (the result can also be observed
qualitatively from representative TIRFM images of cells treated
with these agonists). In contrast, either of Examples 9 and 25
(full non-catechol-derivative D1 agonists) recruited less than 60%
(or 50%, or 40% or 30%) .beta.-arrestin-GFP to the plasma membrane
relative to Dopamine. Each of the partial D1 agonists tested
(SKF-38393, SKF-77434, and Examples 5 and 13) recruited less than
60% (or 50%, or 40% or 30%) .beta.-arrestin-GFP to the plasma
membrane relative to Dopamine.
Example EE
cAMP and Receptor Desensitization Assays
[0597] Primary striatal neurons were obtained from embryonic day 18
(E18) rats by standard neuronal isolation procedures and plated at
a density of 35,000 cells/well in poly-ornithine/laminin coated 96
well plates (BD Falcon). Striatal neurons were chosen because they
express endogenous D1-like receptors and are a physiologically
relevant tissue for examining neurotransmitter receptor
desensitization in vitro. Neurons were cultured in neurobasal media
supplemented with B27, 1.times. Glutamax and
penicillin/streptomycin (100 U/mL) (all from Invitrogen) and
incubated at 37.degree. C. in 5% carbon dioxide for 14-16 days
prior to assay. To assess D1R desensitization, neurons in wells
were pretreated for 120 minutes with 0.1% DMSO in serum free media
(Control/SFM) or 10 .mu.M of a test compound dissolved in serum
free neurobasal media. After the pretreatment, cells were washed
twice at 5 minute intervals with 250.mu.l/well fresh neurobasal
media. The ability of D1-like receptors to signal was then examined
by treating cells for 30 minutes with 1 .mu.M SKF-81297, a catechol
derivative D1-like selective full agonist, in the presence of 500
.mu.M isobutylmethylxanthine. The concentration of cAMP accumulated
in each well was determined using the Cisbio HTRF cAMP dynamic
range assay kit (Cisbio) according to the manufacturers' suggested
protocol. The concentration of cAMP (nM) from treated wells was
interpolated from a cAMP standard curve by non-linear regression
least squares analysis using Graphpad Prism 5.02. The
mean.+-.standard error of the cAMP concentrations were calculated
from results obtained across three independent experiments (n=3)
each assayed in quadruplicate. The % desensitization was calculated
as the percent decrease in cAMP relative to control. Statistical
differences were compared by a one-way ANOVA with Dunnett's
post-test analysis using Graphpad Prism 5.02.
[0598] All results are the mean.+-.standard error from three
independent experiments assayed in quadruplicate (n=3). *,
p<0.05 versus control.
TABLE-US-00009 TABLE 9 cAMP concentration v. Pretreatment of
neurons with test compounds (in addition to Control and untreated
neuron) Untreated/Control/Pretreated cAMP concentration test
compound Unit [nM] Untreated 4 .+-. 0.4 * Control 46 .+-. 4.sup.
Dopamine 20 .+-. 2 * Dihydrexidine 20 .+-. 2 * SKF-81297 25 .+-. 2
* SKF-38393 30 .+-. 3 * SKF-77434 31 .+-. 3 * Example 5 45 .+-.
3.sup. Example 9 39 .+-. 2.sup. Example 25 41 .+-. 2.sup. Example
13 41 .+-. 2.sup.
TABLE-US-00010 TABLE 10 % Desensitization Control/Pretreated test %
Desensitization Unit compound (% decrease in cAMP v. Control)
Control 0 .+-. 8 Dopamine 56 .+-. 4 * Dihydrexidine 56 .+-. 5 *
SKF-81297 46 .+-. 4 * SKF-38393 34 .+-. 7 * SKF-77434 32 .+-. 7 *
Example 5 2 .+-. 6 Example 9 15 .+-. 5.sup. Example 25 10 .+-.
7.sup. Example 13 11 .+-. 4.sup.
[0599] As shown in Table 9, pretreatment of neurons with Dopamine,
two catechol derivative full D1 agonists (Dihydrexidine and
SKF-81297), and two catechol derivative partial D1 agonists
(SKF-38393 and SKF-77434) significantly decreased D1R-mediated cAMP
signaling. In contrast, pretreatments with non-catechol derivative
D1 full agonists (Examples 9 and 25) and non-catechol derivative D1
partial agonists (Examples 5 and 13) did not significantly decrease
D1R-mediated cAMP signaling (Closer to Control).
[0600] As shown in Table 10, Dopamine, two catechol derivative full
D1 agonists (Dihydrexidine and SKF-81297), and two catechol
derivative partial D1 agonists (SKF-38393 and SKF-77434)
significantly desensitized D1R receptors (decreased greater than
about 30%, 40%, or 50% v. Control). In contrast, non-catechol
derivative D1 full agonists (Examples 9 and 25) and non-catechol
derivative D1 partial agonists (Examples 5 and 13) show decreased
desensitization (only decreased less than about 25%, 20%, 18%, or
15% v. Control).
[0601] Various modifications of the invention, in addition to those
described herein, will be apparent to those skilled in the art from
the foregoing description. Such modifications are also intended to
fall within the scope of the appendant claims. Each reference
(including all patents, patent applications, journal articles,
books, and any other publications) cited in the present application
is hereby incorporated by reference in its entirety.
* * * * *