U.S. patent application number 13/653452 was filed with the patent office on 2014-02-06 for amino-heteroaryl-containing prokineticin 1 receptor antagonists.
The applicant listed for this patent is Steven J. Coats, Alexey B. Dyatkin, Wei He, Joseph Lisko, Tamara A. Miskowski, Janet L. Ralbovsky, Mark J. Schulz. Invention is credited to Steven J. Coats, Alexey B. Dyatkin, Wei He, Joseph Lisko, Tamara A. Miskowski, Janet L. Ralbovsky, Mark J. Schulz.
Application Number | 20140038968 13/653452 |
Document ID | / |
Family ID | 40206493 |
Filed Date | 2014-02-06 |
United States Patent
Application |
20140038968 |
Kind Code |
A1 |
Coats; Steven J. ; et
al. |
February 6, 2014 |
AMINO-HETEROARYL-CONTAINING PROKINETICIN 1 RECEPTOR ANTAGONISTS
Abstract
The present invention relates to certain novel compounds of
Formula (I): ##STR00001## and methods for preparing these
compounds, compositions, intermediates and derivatives thereof and
for the treatment of prokineticin 1 or prokinetin 1 receptor
mediated disorders.
Inventors: |
Coats; Steven J.;
(McDonough, GA) ; Dyatkin; Alexey B.; (Maple Glen,
PA) ; He; Wei; (Audubon, PA) ; Lisko;
Joseph; (Alpharetta, GA) ; Miskowski; Tamara A.;
(Chalfont, PA) ; Ralbovsky; Janet L.; (Memphis,
TN) ; Schulz; Mark J.; (Skippack, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Coats; Steven J.
Dyatkin; Alexey B.
He; Wei
Lisko; Joseph
Miskowski; Tamara A.
Ralbovsky; Janet L.
Schulz; Mark J. |
McDonough
Maple Glen
Audubon
Alpharetta
Chalfont
Memphis
Skippack |
GA
PA
PA
GA
PA
TN
PA |
US
US
US
US
US
US
US |
|
|
Family ID: |
40206493 |
Appl. No.: |
13/653452 |
Filed: |
October 17, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12256891 |
Oct 23, 2008 |
8324380 |
|
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13653452 |
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60983638 |
Oct 30, 2007 |
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Current U.S.
Class: |
514/245 ;
514/241; 544/212; 544/220; 544/221 |
Current CPC
Class: |
A61P 1/14 20180101; C07D
403/12 20130101; A61P 1/12 20180101; A61P 29/00 20180101; C07D
401/12 20130101; A61P 35/00 20180101; A61P 1/04 20180101; A61P
43/00 20180101; A61P 1/10 20180101; A61P 1/00 20180101; C07D 405/14
20130101; A61P 1/06 20180101; C07D 251/38 20130101 |
Class at
Publication: |
514/245 ;
544/221; 514/241; 544/212; 544/220 |
International
Class: |
C07D 251/38 20060101
C07D251/38; C07D 403/12 20060101 C07D403/12 |
Claims
1. A compound of Formula (I) ##STR00035## wherein: A.sub.1 is
hydrogen, C.sub.1-4alkoxy, aryl, aryloxy, optionally benzofused
heterocyclyl, or an optionally benzofused heteroaryl; and aryl,
aryloxy, heteroaryl, heterocyclyl, the benzo portion of benzofused
heterocyclyl, and benzofused heteroaryl are optionally substituted
with a substituent selected from the group consisting of
C.sub.1-6alkyl, hydroxy(C.sub.1-6)alkyl, C.sub.1-6alkoxy, halogen,
nitro, halogenated C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy,
C.sub.1-6alkylthio, C.sub.1-6alkoxycarbonyl, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, cyano, hydroxy,
aminocarbonyl, C.sub.1-6alkylaminocarbonyl,
di(C.sub.1-6alkyl)aminocarbonyl, C.sub.1-6alkoxycarbonylamino,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkylthiocarbonyl, formyl,
C.sub.1-6alkylsulfonyl, C.sub.1-6alkylsulfonylamino, aminosulfonyl,
C.sub.1-6alkylaminosulfonyl, and di(C.sub.1-6alkyl)aminosulfonyl;
and wherein aryl, aryloxy, heteroaryl, heterocyclyl, the benzo
portion of benzofused heterocyclyl, and benzofused heteroaryl are
optionally further substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, halogen, and hydroxy; provided that A.sub.1 is
other than 3,5-di-t-butyl-phenyl; L.sub.1 is --(CH.sub.2).sub.r--,
--CH.sub.2C.sub.2-4alkenyl-, or
--CH.sub.2CH.sub.2X(CH.sub.2).sub.s--, wherein L.sub.1 is
optionally substituted with one to two substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, and halogen; and, r is an
integer of 1 to 5; such that r is greater than or equal to 4 when
A.sub.1 is C.sub.1-4alkoxy; s is an integer of 1 to 3; X is O or S;
D is --P-A.sub.2; wherein P is --(CH.sub.2).sub.1-2-- or
--CH.sub.2CH.dbd.CH-- when A.sub.2 is phenyl, optionally benzofused
heterocyclyl, optionally benzofused heteroaryl, or
C.sub.3-8cycloalkyl; alternatively, P is --(CH.sub.2).sub.3-6--,
when A.sub.2 is hydrogen, C.sub.1-4alkoxy, or
C.sub.1-4alkoxycarbonyl; and wherein P is optionally substituted
with one to two substituents independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
and halogen; A.sub.2 is hydrogen; dihydrobenzofuranyl; heteroaryl
other than unsubstituted pyridin-2-yl; C.sub.3-8cycloalkyl; or
phenyl optionally substituted at the meta and para positions with
one to three substituents independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, halogenated
C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy, aryl(C.sub.1-6)alkoxy,
phenyl, C.sub.1-6alkylthio, C.sub.1-6alkoxycarbonyl, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, cyano, hydroxy,
nitro, C.sub.1-6alkylcarbonyl, C.sub.1-6alkylthiocarbonyl,
aminocarbonyl, C.sub.1-6alkylaminocarbonyl,
di(C.sub.1-6alkyl)aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a
non fused C.sub.3-6cycloalkyloxy; wherein dihydrobenzofuranyl,
heteroaryl, and C.sub.3-8cycloalkyl are optionally substituted with
one to three substituents independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, halogenated
C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy, aryl(C.sub.1-6)alkoxy,
phenyl, C.sub.1-6alkylthio, C.sub.1-6alkoxycarbonyl, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, cyano, hydroxy,
nitro, C.sub.1-6alkylcarbonyl, C.sub.1-6alkylthiocarbonyl,
aminocarbonyl, C.sub.1-6alkylaminocarbonyl,
di(C.sub.1-6alkyl)aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a
non fused C.sub.3-6cycloalkyloxy; provided that no more than two
substituents on A.sub.2 are aryl(C.sub.1-6)alkoxy, phenyl, or a non
fused C.sub.3-6cycloalkyloxy; such that both A.sub.1 and A.sub.2
are not 4-fluoro-phenyl when L.sub.1 and L.sub.2 are both
--CH.sub.2-- and Q is a substituent of formula Q.sub.1; W is
C(R.sub.W); wherein R.sub.W is H or C.sub.1-2alkyl; L.sub.2 is a
bivalent radical selected from the group consisting of pyrrolidinyl
or piperidinyl attached to the W-containing ring of Formula (I) via
its nitrogen atom, wherein said pyrrolidinyl or piperidinyl is
substituted on a carbon atom with --(CH.sub.2).sub.0-2--;
--NH--C.sub.5-7cycloalkyl(CH.sub.2).sub.0-2--; such that when
C.sub.5-7cycloalkyl is cyclohexyl, Q is attached at either the 2-
or cis-4-position relative to the position of NH--;
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5--; and
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; R.sup.x, R.sup.y,
and R.sup.z are independently H or C.sub.1-4alkyl; and provided
that L.sub.2 in any instance does not exceed 7 atoms in length;
such that Q is selected from the group consisting of Q.sub.1,
Q.sub.2, Q.sub.4, and Q.sub.6 when L.sub.2 is other than
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; Q is ##STR00036##
wherein the benzo portion of Q.sub.1, Q.sub.2, Q.sub.4 and Q.sub.6
is optionally substituted with R.sub.1; R.sub.1 is one to two
substituents independently selected from the group consisting of
hydrogen, C.sub.1-4alkyl, C.sub.1-4alkoxy, hydroxy, halogen,
trifluoromethyl, and C.sub.1-4alkylsulfonyl; R.sub.a and R.sub.b
are independently hydrogen, trifluoromethylcarbonyl,
C.sub.1-4alkylcarbonyl, and methyl; and enantiomers, diastereomers,
solvates, and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 wherein A.sub.1 is phenyl,
2,3-dihydro-benzofuranyl wherein the point of attachment to L.sub.1
is at the benzo ring, or 1-methyl-benzotriazol-5-yl; wherein phenyl
is optionally substituted with a substituent selected from the
group consisting of C.sub.1-2alkyl, C.sub.1-2alkoxy, fluoro,
chloro, and C.sub.1-2alkylthio; and wherein phenyl is optionally
further substituted with a fluoro or chloro substituent.
3. The compound of claim 1 wherein A.sub.1 is 4-ethyl-phenyl,
3,4-dichloro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl,
4-methylthio-phenyl, 2,3-dihydro-benzofuran-5-yl, or
1-methyl-benzotriazol-5-yl.
4. The compound of claim 1 wherein L.sub.1 is (CH.sub.2).sub.r--
optionally substituted with a substituent selected from the group
consisting of methyl and allyl, provided that r is 1 to 3 when
A.sub.1 is other than hydrogen.
5. The compound of claim 1 wherein L.sub.1 is --CH.sub.2--.
6. The compound of claim 1 wherein P is --CH.sub.2--.
7. The compound of claim 1 wherein A.sub.2 is hydrogen, a
heteroaryl other than unsubstituted pyridin-2-yl,
dihydrobenzofuranyl, or phenyl optionally substituted at the meta
and para positions with one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, halogen, halogenated C.sub.1-6alkyl, halogenated
C.sub.1-6alkoxy, aryl(C.sub.1-6)alkoxy, phenyl, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; wherein heteroaryl other than unsubstituted
pyridin-2-yl and dihydrobenzofuranyl are optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen,
halogenated C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy,
aryl(C.sub.1-6)alkoxy, phenyl, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; provided that no more than two substituents
on A.sub.2 are aryl(C.sub.1-6)alkoxy, phenyl, or a non fused
C.sub.3-6cycloalkyloxy.
8. The compound of claim 1 wherein A.sub.2 is furanyl,
pyridin-3-yl, pyridin-4-yl, or phenyl optionally substituted at the
meta and para positions with one to three substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, halogen, halogenated C.sub.1-3alkoxy,
C.sub.1-3alkylthio, hydroxy, amino, aminocarbonyl,
C.sub.1-3alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; and wherein furanyl, pyridin-3-yl, and
pyridin-4-yl are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, halogenated
C.sub.1-3alkoxy, C.sub.1-3alkylthio, hydroxy, amino, aminocarbonyl,
C.sub.1-3alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; provided that no more than two substituents
on A.sub.2 are non fused C.sub.3-6cycloalkyloxy.
9. The compound of claim 1 wherein A.sub.2 is pyridin-3-yl,
Pyridin-4-yl, or phenyl optionally substituted at the meta and para
positions with one to two substituents independently selected from
the group consisting of methyl, ethyl, methoxy, ethoxy,
isopropyloxy, trifluoromethoxy, difluoromethoxy, hydroxy,
aminocarbonyl, and methylcarbonylamino; wherein pyridin-3-yl and
pyridin-4-yl are optionally substituted with one to two
substituents independently selected from the group consisting of
methyl, ethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy,
difluoromethoxy, hydroxy, aminocarbonyl, and
methylcarbonylamino.
10. The compound of claim 1 wherein A.sub.2 is phenyl substituted
at the para position with a substituent selected from the group
consisting of methoxy, ethoxy, isopropyloxy, difluoromethoxy,
hydroxy, and aminocarbonyl; or A.sub.2 is pyridin-3-yl or
pyridin-4-yl substituted with methoxy.
11. The compound of claim 1 wherein W is C(R.sub.w) wherein R.sub.w
is H.
12. (canceled)
13. The compound of claim 1 wherein L.sub.2 is a bivalent radical
selected form the group consisting of
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5-- and
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; wherein R.sup.x,
R.sup.y, and R.sup.z are independently H or C.sub.1-4alkyl; and
provided that L.sub.2 in any instance does not exceed 7 atoms in
length; such that Q is selected from the group consisting of
Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.6 when L.sub.2 is other than
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--.
14. The compound of claim 1 wherein L.sub.2 is a bivalent radical
selected form the group consisting of --NH--CH.sub.2CH.sub.2--;
wherein R.sup.x, R.sup.y, and R.sup.z are each H.
15. The compound of claim 1 wherein Q is ##STR00037## wherein
R.sub.a and R.sub.b are each hydrogen.
16. The compound of claim 1 wherein R.sub.1 is one to two
substituents independently selected from the group consisting of
hydrogen, methyl, methoxy, fluoro, chloro, and trifluoromethyl.
17. The compound of claim 1 wherein R.sub.1 is a substituent
selected from hydrogen, fluoro, or chloro.
18. The compound of claim 1 wherein R.sub.a and R.sub.b are each
hydrogen.
19. The compound of claim 1 wherein A.sub.1 is phenyl, benzofused
heterocyclyl wherein the point of attachment to L.sub.1 is at benzo
ring, or benzofused heteroaryl; wherein phenyl, the benzo portion
of benzofused heterocyclyl, and benzofused heteroaryl are
optionally substituted with a substituent selected from the group
consisting of C.sub.1-4alkyl, hydroxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy, fluoro, chloro, halogenated C.sub.1-4alkyl,
halogenated C.sub.1-4alkoxy, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, cyano, hydroxy, aminocarbonyl,
C.sub.1-4alkylaminocarbonyl, di(C.sub.1-4alkyl)aminocarbonyl,
C.sub.1-4alkoxycarbonylamino, C.sub.1-4alkylcarbonyl,
C.sub.1-4alkylthiocarbonyl, formyl, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonylamino, aminosulfonyl,
C.sub.1-4alkylaminosulfonyl, and di(C.sub.1-4alkyl)aminosulfonyl;
and wherein phenyl, the benzo portion of benzofused heterocyclyl,
and benzofused heteroaryl are optionally further substituted with
one to two substituents independently selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy, fluoro, chloro, and
hydroxy; provided that A.sub.1 is other than 3,5-di-t-butyl-phenyl;
L.sub.1 is --(CH.sub.2).sub.r--, optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, and halogen;
provided that when A.sub.1 is hydrogen, r is greater than or equal
to 4; D is --P-- A.sub.2; P is --CH.sub.2-- or
--CH.sub.2CH.dbd.CH--; A.sub.2 is hydrogen, heteroaryl other than
unsubstituted pyridin-2-yl, dihydrobenzofuranyl, or phenyl
optionally substituted at the meta and para positions with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, halogenated
C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy, aryl(C.sub.1-6)alkoxy,
phenyl, C.sub.1-6alkylthio, C.sub.1-6alkoxycarbonyl, amino, cyano,
hydroxy, nitro, aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a
non fused C.sub.3-6cycloalkyloxy; wherein heteroaryl other than
unsubstituted pyridin-2-yl and C.sub.3-8cycloalkyl are optionally
substituted with one to three substituents independently selected
from the group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy,
halogen, halogenated C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy,
aryl(C.sub.1-6)alkoxy, phenyl, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; provided that no more than two substituents
on A.sub.2 are aryl(C.sub.1-6)alkoxy, phenyl, or a non fused
C.sub.3-6cycloalkyloxy; W is C(R.sub.w) wherein R.sub.w is H;
L.sub.2 is a bivalent radical selected form the group consisting of
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-6 and
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; wherein R.sup.x,
R.sup.y, and R.sup.z are independently H or C.sub.1-4alkyl; such
that Q is selected from the group consisting of Q.sub.1, Q.sub.2,
Q.sub.4, and Q.sub.6 when L.sub.2 is other than
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; and provided that
L.sub.2 in any instance does not exceed 7 atoms in length; Q is
##STR00038## R.sub.1 is one to two substituents independently
selected from the group consisting of hydrogen, methyl, methoxy,
fluoro, chloro, and trifluoromethyl; R.sub.a is hydrogen,
trifluoromethylcarbonyl, methylcarbonyl, or t-butylcarbonyl; and
R.sub.b is hydrogen; and enantiomers, diastereomers, solvates, and
pharmaceutically acceptable salts thereof.
20. (canceled)
21. (canceled)
22. A compound of Formula (Ia) (wherein L.sub.1 is CH.sub.2)
##STR00039## selected from the group consisting of a compound of
Formula (Ia) wherein A.sub.1 is 4-methoxy-phenyl, D is
4-methoxy-phenylmethyl, W is CH, L.sub.2 is
--C(O)NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl;
and enantiomers, diastereomers, solvates, and pharmaceutically
acceptable salts thereof.
23. A pharmaceutical composition comprising a compound, salt or
solvate according to claim 1 admixed with a pharmaceutically
acceptable carrier, excipient, or diluent.
24. A pharmaceutical composition comprising a compound, salt, or
solvate according to claim 22 admixed with a pharmaceutically
acceptable carrier, excipient, or diluent.
25. A method of treating or preventing a disease or condition in a
mammal in which the disease or condition selected from the group
consisting of gastrointestinal (GI) diseases, GERD and secretory
diarrhea, cancers of the GI tract and reproductive organs, and
pain.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of application Ser. No.
12/256,891, filed Oct. 23, 2008, currently allowed, which in turn
claims priority to U.S. Provisional Patent Application No.
60/983,638, filed Oct. 30, 2007, now abandoned, which are hereby
incorporated by reference in their entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] The research and development of the invention described
below was not federally sponsored.
BACKGROUND OF THE INVENTION
[0003] Functional bowel disorders involve abnormal motility and
secretion within organs of the gastrointestinal (GI) tract, and are
characterized by abdominal discomfort/pain. The criteria for these
disorders are summarized by gastroenterologists in the `Rome II
criteria`. Based on these criteria the disorders are common and
include, but are not limited to, functional dyspepsia, irritable
bowel syndrome (IBS), gastroesophageal reflux disease (GERD) and
non-erosive reflux disease (NERD), and chronic constipation
(including colonic inertia, idiopathic pseudoobstruction). GERD is
extremely prevalent, is usually associated with non-cardiac chest
pain and may be treated with acid-suppressing agents and prokinetic
agents. IBS is characterized by the presence of reoccurring
constipation and/or diarrhea, which can be associated with gaseous
distention/bloating and abdominal discomfort/pain (Thompson, W. G.
and Heaton, K. W. Gastroenterology 1980, 79, 283-288). The onset of
the pain of IBS is associated with a change in the frequency and/or
form of stool and can be relieved by defecation. IBS is an
extremely prevalent condition that occurs to varying severity in
10-15% of the population (Saito, Y. A.; Schoenfeld, P.; and Locke,
G. R. Am. J. Gastroenterol. 2002, 97, 1910-1915). The pain may be
treated with smooth muscle relaxants and antidepressants (Jackson,
J. L.; O'Malley, P. G.; Tomkins, G.; Balden, E.; Santoro, J.; and
Kroenke, K.; Am. J. Med. 2000, 108, 65-72; Jailwala, J.; Imperiale,
T. F.; and Kroenke, K.; Ann. Intern. Med. 2000, 133:136-147;
Akehurst, R. and Kaltenthaler, E. Gut 2001, 48, 272-282; Poynard,
T.; Regimbeau, C.; and Benhamou, Y.; Aliment Pharmacol. Ther. 2001,
15, 355-361). Severe diarrhea predominant IBS is treated by
alosetron, whereas constipation predominant IBS is treated by
tegaserod. Functional dyspepsia is a disorder of the upper GI tract
with symptoms exacerbated by a meal and associated with early
satiety, nausea and vomiting. Although its etiology is unknown,
prokinetic agents may relieve the symptoms of IBS. In some patients
there is overlap in symptoms between GERD/NERD, functional
dyspepsia and IBS. Treatments for functional bowel disorders, such
as IBS, have low efficacy and are associated with adverse effects.
For example, alosetron is approved by the FDA on a risk management
program because it is associated with an increase in a serious
adverse event, ischemic colitis. No treatments effectively
alleviate pain in functional bowel disorders.
[0004] In addition to functional disorders, inflammatory bowel
diseases (IBD) are common and include ulcerative colitis (UC) and
Crohn's disease (CD). Although there may be a genetic component to
CD, the etiology of both CD and UC is unknown.
[0005] UC is a diffuse mucosal disease of the colon, characterized
by inflammation and ulceration, which is associated with diarrhea
and abdominal cramping. The mucosal inflammation progresses from
the rectal area to eventually extend through the large bowel. CD is
a transmural inflammation that most frequently involves the distal
small bowel and colon. The inflammation can result in ulcers of
varying involvement and in severe cases result in transmural
scarring and chronic inflammation. Both infectious and dysregulated
immune functions may contribute to disease onset. Therapies for IBD
include corticosteroids, immunosuppressives (azathioprine,
mercaptopurine, and methotrexate) and aminosalicylates (5-ASA).
These therapies involve suppression of the immune system by
mimicking corticoids, or unknown mechanisms of action. Oral
corticosteroid use is associated with serious adverse effects,
whereas immunosuppressives and aminosalicylates are only moderately
effective. Infliximab (a chimeric monoclonal anti-tumor necrosis
factor antibody) is effective in CD, however, its use is associated
with the presence of antibodies, which reduce its efficacy. There
are no treatments that target the motility and secretory
abnormalities or painful sensation that are associated with gut
inflammation.
[0006] The cysteine rich proteins known as Prokineticin 1 (PK1) and
Prokineticin 2 (PK2), as well as variants, fragments and molecules
having PK activity, have been identified. These have been shown to
contract gastrointestinal smooth muscle (Li, M.; Bullock, C. M.;
Knauer, D. J.; Ehlert, F. J.; and Zhou, Q. Y., Mol. Pharmacol.
2001, 59, 692-698), and suppress feeding (Negri, L.; Lattanzi, R.;
Giannini, E.; De Felice, M.; Colucci, A. and Melchiorri, P. Brit.
J. Pharmacol. 2004, 142, 181-191). PK1 and PK2 act on both PK1 and
PK2 receptors, and limited structural changes of C-terminal
cysteine-rich regions of these related PKs are tolerated. For
example, chimeric PKs, where the cysteine-rich domains of PK 1 and
PK 2 were exchanged between the two; and a splice variant of PK2
that included a 21 residue insertion in its C-terminal domain
retained activity (Bullock, C M; Li J. D.; Zhou, Q. Y.; Mol.
Pharmacol. 2004, 65(3), 582-8). A PK variant binds to receptors of
primary sensory neurons, and results in an intense sensitization of
peripheral nociceptors to thermal and mechanical stimuli (Mollay,
C.; Weschelberger, C.; Mignogna, G.; Negri, L.; Melchiorri, P.;
Barra, D.; Kreil, G.; Eur. J. Pharmacol. 1999, 374, 189-196; Negri,
L.; Lattanzi, R.; Giannini, E.; Metere, A.; Colucci, M.; Barra, D.;
Kreil, G.; Melchiorri, P.; Brit. J. Pharmacol. 2002, 137(8),
1147-54).
[0007] Patent application PCT/US2004/087054 A2 provides methods of
modulating gastric acid or pepsinogen secretion by administering an
amount of a prokineticin receptor antagonist effective to alter one
or more indicia of gastric acid secretion.
[0008] PK1 induces proliferation, migration and fenestration in
capillary endothelial cells derived from endocrine glands. The
expression of PK mRNA is restricted to the steroidogenic glands,
ovary, testis, adrenal and placenta (LeCouter, J.; Kowalski, J.;
Foster, J.; Hass, P., Zhang, Z.; Dillard-Telm, L., Frantz, G.,
Rangell, L.; DeGuzman, L.; Keller, G. A.; Peale, F.; Gurney, A.;
Hillan, K. J.; Ferrara, N. Nature 2001, 412 (6850), 877-84). In
2002 the identification of the PK1 receptor provided a novel
molecular basis for the regulation of angiogenesis in endocrine
glands (Masuda, Y.; Takatsu, Y.; Terao, Y.; Kumano, S.; Ishibashi,
Y.; Suenaga, M.; Abe, M.; Fukusumi, S.; Watanabe, T.; Shintani, Y.;
Yamada, T.; Hinuma, S.; Inatomi, N.; Ohtaki, T.; Onda, H.; Fujino,
M.; Biochem. Biophys. Res. Commun. 2002, 293(1), 396-402; LeCouter,
J.; Lin, R.; Ferrara, N.; Cold Spring Harb Symp Quant Biol. 2002,
67, 217-21). For example, adenoviral delivery of PK1 to the mouse
testis results in a potent angiogenic response (LeCouter, J.; Lin,
R.; Tejada, M.; Frantz, G.; Peale, F.; Hillan, K. J.; Ferrara, N.
Proc. Natl. Acad. Sci. USA. 2003, 100, 2685-90). Recently, it was
shown that PK1 mRNA is not normally expressed in colorectal normal
mucosa but is detected in colorectal cancer cells (Goi, T.;
Fujioka, M.; Satoh, Y.; Tabata, S.; Koneri, K.; Nagano, H.; Hirono,
Y.; Katayama, K.; Hirose, K. and Yamaguchi., Cancer Res. 2004, 64,
1906-1910).
[0009] Prokineticin 1 receptor antagonists are useful in the
treatment and prevention of various mammalian disease states, for
example, visceral pain that is associated with IBS and IBD.
Additionally, PK1 receptor antagonists are useful for the treatment
of GERD or other forms of secretory diarrhea. Additionally, PK1
receptor antagonists are useful in treating cancer-specific
angiogenesis factor in the large intestine and reproductive
organs.
[0010] It is an object of the present invention to provide
prokineticin 1 receptor antagonists. It is also an object of the
invention to provide a method of treating or ameliorating a
condition mediated by prokineticin 1 receptor. And, it is an object
of the invention to provide a useful pharmaceutical composition
comprising a compound of the present invention useful as a
prokineticin 1 receptor antagonist.
SUMMARY OF THE INVENTION
[0011] The present invention is directed to a compound of Formula
(I):
##STR00002## [0012] A.sub.1 is hydrogen, C.sub.1-4alkoxy, aryl,
aryloxy, optionally benzofused heterocyclyl, or an optionally
benzofused heteroaryl; [0013] and aryl, aryloxy, heteroaryl,
heterocyclyl, the benzo portion of benzofused heterocyclyl, and
benzofused heteroaryl are optionally substituted with a substituent
selected from the group consisting of C.sub.1-6alkyl,
hydroxy(C.sub.1-6)alkyl, C.sub.1-6alkoxy, halogen, nitro,
halogenated C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, amino, C.sub.1-6alkylamino,
di(C.sub.1-6alkyl)amino, cyano, hydroxy, aminocarbonyl,
C.sub.1-6alkylaminocarbonyl, C.sub.1-6alkyl)aminocarbonyl,
C.sub.1-6alkoxycarbonylamino, C.sub.1-6alkylcarbonyl,
C.sub.1-6alkylthiocarbonyl, formyl, C.sub.1-6alkylsulfonyl,
C.sub.1-6alkylsulfonylamino, aminosulfonyl,
C.sub.1-6alkylaminosulfonyl, and di(C.sub.1-6alkyl)aminosulfonyl;
[0014] and wherein aryl, aryloxy, heteroaryl, heterocyclyl, the
benzo portion of benzofused heterocyclyl, and benzofused heteroaryl
are optionally further substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, halogen, and hydroxy; provided that A.sub.1 is
other than 3,5-di-t-butyl-phenyl; [0015] L.sub.1 is
--(CH.sub.2).sub.r--, --CH.sub.2C.sub.2-4alkenyl-, or
--CH.sub.2CH.sub.2X(CH.sub.2).sub.s--, wherein L.sub.1 is
optionally substituted with one to two substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, and halogen; and, r is an
integer of 1 to 5; such that r is greater than or equal to 4 when
A.sub.1 is C.sub.1-4alkoxy; [0016] s is an integer of 1 to 3;
[0017] X is O or S; [0018] D is --P-A.sub.2; [0019] wherein P is
--(CH.sub.2).sub.1-2-- or --CH.sub.2CH.dbd.CH-- when A.sub.2 is
phenyl, optionally benzofused heterocyclyl, optionally benzofused
heteroaryl, or C.sub.3-8cycloalkyl; alternatively, P is
--(CH.sub.2).sub.3-6-- when A.sub.2 is hydrogen, C.sub.1-4alkoxy,
or C.sub.1-4alkoxycarbonyl; and wherein P is optionally substituted
with one to two substituents independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
and halogen; [0020] A.sub.2 is hydrogen; dihydrobenzofuranyl;
heteroaryl other than unsubstituted pyridin-2-yl;
C.sub.3-8cycloalkyl; or phenyl optionally substituted at the meta
and para positions with one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, halogen, halogenated C.sub.1-6alkyl, halogenated
C.sub.1-6alkoxy, aryl(C.sub.1-6)alkoxy, phenyl, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, C.sub.1-6alkylamino,
di(C.sub.1-6alkyl)amino, cyano, hydroxy, nitro,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkylthiocarbonyl, aminocarbonyl,
C.sub.1-6alkylaminocarbonyl, di(C.sub.1-6alkyl)aminocarbonyl,
C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; wherein dihydrobenzofuranyl, heteroaryl,
and C.sub.3-8cycloalkyl are optionally substituted with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, halogenated
C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy, aryl(C.sub.1-6)alkoxy,
phenyl, C.sub.1-6alkylthio, C.sub.1-6alkoxycarbonyl, amino,
C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, cyano, hydroxy,
nitro, C.sub.1-6alkylcarbonyl, C.sub.1-6alkylthiocarbonyl,
aminocarbonyl, C.sub.1-6alkylaminocarbonyl,
di(C.sub.1-6alkyl)aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a
non fused C.sub.3-6cycloalkyloxy; [0021] provided that no more than
two substituents on A.sub.2 are aryl(C.sub.1-6)alkoxy, phenyl, or a
non fused C.sub.3-6cycloalkyloxy; [0022] such that both A.sub.1 and
A.sub.2 are not 4-fluoro-phenyl when L.sub.1 and L.sub.2 are both
--CH.sub.2-- and Q is a substituent of formula Q.sub.1; [0023] W is
N or C(R.sub.W); wherein R.sub.W is H or C.sub.1-2alkyl; [0024]
L.sub.2 is a bivalent radical selected from the group consisting of
pyrrolidinyl or piperidinyl attached to the W-containing ring of
Formula (I) via its nitrogen atom, wherein said pyrrolidinyl or
piperidinyl is substituted on a carbon atom with
(CH.sub.2).sub.0-2--; [0025]
--NH--C.sub.5-7cycloalkyl(CH.sub.2).sub.0-2--; such that when
C.sub.5-7cycloalkyl is cyclohexyl, Q is attached at either the 2-
or cis-4-position relative to the position of NH--; [0026]
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5--; [0027] and [0028]
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; [0029] Rx, Ry, and
R.sup.z are independently H or C.sub.1-4alkyl; [0030] and provided
that L.sub.2 in any instance does not exceed 7 atoms in length;
[0031] such that Q is selected from the group consisting of
Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.6 when L.sub.2 is other than
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; [0032] Q is
[0032] ##STR00003## [0033] wherein the benzo portion of Q.sub.1,
Q.sub.2, Q.sub.4 and Q.sub.6 is optionally substituted with
R.sub.1; [0034] R.sub.1 is one to two substituents independently
selected from the group consisting of hydrogen, C.sub.1-4alkyl,
C.sub.1-4alkoxy, hydroxy, halogen, trifluoromethyl, and
C.sub.1-4alkylsulfonyl; [0035] R.sub.a and R.sub.b, are
independently hydrogen, trifluoromethylcarbonyl,
C.sub.1-4alkylcarbonyl, and methyl; [0036] and enantiomers,
diastereomers, solvates, and pharmaceutically acceptable salts
thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] FIG. 1 shows a MALDI-TOF ANALYSIS of a Prokineticin-1 ligand
preparation mixture. The mixture includes a four C-terminal residue
truncated product (MW=9172), and a full-length prokineticin-1
ligand (MW=9668).
[0038] FIG. 2 shows a cumulative concentration-response curve
evoked in the short-circuit current (lsc) response to PK1 peptide
in PK1 exposed rat ileal tissues mounted in Ussing-type ion flux
chambers.
[0039] FIG. 3 is a graphical representation that shows that
Compound 3 of the present invention suppresses the PK1-evoked
stimulation of gut secretion in rat ileum, without inhibiting the
stimulatory action of an unrelated secretagogue.
[0040] FIG. 4 is a graphical representation that shows that
Compound 3 of the present invention suppresses the Cholera
toxin-evoked stimulation of gut secretion in rat ileum, without
inhibiting the stimulatory action of an unrelated secretagogue.
[0041] FIG. 5 shows that Compound 3 of the present invention
suppresses Vibrio cholera toxin induced increased in baseline lsc
of muscle-stripped rat ileum mucosa.
DETAILED DESCRIPTION OF THE INVENTION
[0042] As used herein, the following terms are intended to have the
following meanings:
[0043] "C.sub.a-b" (where a and b are integers) refers to a radical
containing from a to b carbon atoms inclusive. For example,
C.sub.1-3 denotes a radical containing 1, 2 or 3 carbon atoms.
[0044] With reference to substituents, the term "independently"
means that when more than one of such substituent is possible, such
substituents may be the same or different from each other.
Therefore, designated numbers of carbon atoms (e.g. C.sub.1-8)
shall refer independently to the number of carbon atoms in an alkyl
or cycloalkyl moiety or to the alkyl portion of a larger
substituent in which alkyl appears as its prefix root.
[0045] As used herein, unless otherwise noted, "alkyl" whether used
alone or as part of a substituent group refers to straight and
branched carbon chains having 1 to 8 carbon atoms or any number
within this range. The term "alkoxy" refers to an --Oalkyl
substituent group, wherein alkyl is as defined supra. Similarly,
the terms "alkenyl" and "alkynyl" refer to straight and branched
carbon chains having 2 to 8 carbon atoms or any number within this
range, wherein an alkenyl chain has at least one double bond in the
chain and an alkynyl chain has at least one triple bond in the
chain. An alkyl and alkoxy chain may be substituted on a carbon
atom. In substituent groups with multiple alkyl groups such as
(C.sub.1-6alkyl).sub.2amino--the C.sub.1-8alkyl groups of the
dialkylamino may be the same or different.
[0046] "Halogenated alkyl" refers to a saturated branched or
straight chain alkyl radical derived by removal of 1 hydrogen atom
from the parent alkyl; the parent alkyl chain contains from 1 to 8
carbon atoms with 1 or more hydrogen atoms substituted with halogen
atoms up to and including substitution of all hydrogen atoms with
halogen. Preferred halogenated alkyl groups include include
trifluoromethyl substituted alkyls and perfluorinated alkyls; more
preferred fluorinated alkyls include trifluoromethyl and
difluoromethyl.
[0047] "Halogenated alkoxy" refers to a radical derived from a
halogenated alkyl, radical attached to an oxygen atom with the
oxygen atom having one open valence for attachment to a parent
structure.
[0048] The term "cycloalkyl" refers to saturated or partially
unsaturated, moncyclic or polycyclic hydrocarbon rings of from 3 to
20 carbon atom members (preferably from 3 to 14 carbon atom
members). Examples of such rings include, and are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
adamantyl. The term cycloalkyl includes a cycloalkyl ring fused to
a benzene ring (benzo fused cycloalkyl), a 5 or 6 membered
heteroaryl ring (containing one of O, S or N and, optionally, one
additional nitrogen) to form a heteroaryl fused cycloalkyl.
[0049] The term "heterocyclyl" refers to a nonaromatic cyclic ring
of 5 to 10 members in which 1 to 4 members are nitrogen or a
nonaromatic cyclic ring of 5 to 10 members in which zero, one or
two members are nitrogen and up to two members is oxygen or sulfur;
wherein, optionally, the ring contains zero, one or two unsaturated
bonds. The term heterocyclyl includes a heterocyclyl ring fused to
a benzene ring (benzo fused heterocyclyl), a 5 or 6 membered
heteroaryl ring (containing one of O, S or N and, optionally, one
additional nitrogen), a 5 to 7 membered cycloalkyl or cycloalkenyl
ring, a 5 to 7 membered heterocyclyl ring (of the same definition
as above but absent the option of a further fused ring) or fused
with the carbon of attachment of a cycloalkyl, cycloalkenyl or
heterocyclyl ring to form a spiro moiety. For instant compounds of
the invention, the carbon atom ring members that form the
heterocyclyl ring are fully saturated. Other compounds of the
invention may have a partially saturated heterocyclyl ring.
Additionally, heterocyclyl includes a heterocyclic ring bridged to
form bicyclic rings. Preferred partially saturated heterocyclyl
rings may have from one to two double bonds. Such compounds are not
considered to be fully aromatic and are not referred to as
heteroaryl compounds. Examples of heterocyclyl groups include, and
are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl
or 3-pyrrolinyl), pyrrolidinyl, 2-imidazolinyl, imidazolidinyl,
2-pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl and piperazinyl.
[0050] The term "aryl" refers to an unsaturated, aromatic
monocyclic ring of 6 carbon members or to an unsaturated, aromatic
polycyclic ring of from 10 to 14 carbon members. Examples of such
aryl rings include, and are not limited to, phenyl, naphthalenyl or
anthracenyl. Preferred aryl groups for the practice of this
invention are phenyl and naphthalenyl.
[0051] The term "heteroaryl" refers to an aromatic ring of 5 or 6
members wherein the ring consists of carbon atoms and has at least
one heteroatom member. Suitable heteroatoms include nitrogen,
oxygen or sulfur. In the case of 5 membered rings, the heteroaryl
ring contains one member of nitrogen, oxygen or sulfur and, in
addition, may contain up to three additional nitrogens. In the case
of 6 membered rings, the heteroaryl ring may contain from one to
three nitrogen atoms. For the case wherein the 6 membered ring has
three nitrogens, at most two nitrogen atoms are adjacent. The term
heteroaryl includes a heteroaryl ring fused to a benzene ring
(benzofused heteroaryl), a 5 or 6 membered heteroaryl ring
(containing one of O, S or N and, optionally, one additional
nitrogen), a 5 to 7 membered cycloalkyl ring or a 5 to 7 membered
heterocyclic ring (as defined supra but absent the option of a
further fused ring). Examples of heteroaryl groups include, and are
not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or
pyrazinyl; fused heteroaryl groups include indolyl, isoindolyl,
indolinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl,
benzthiazolyl, benzoxazolyl, benzisoxazolyl, benzothiadiazolyl,
benzotriazolyl, quinolizinyl, quinolinyl, isoquinolinyl or
quinazolinyl.
[0052] The term "arylalkyl" means an alkyl group substituted with
an aryl group (e.g., benzyl, phenethyl). Similarly, the term
"arylalkoxy" indicates an alkoxy group substituted with an aryl
group (e.g., benzyloxy).
[0053] The term "halogen" refers to fluorine, chlorine, bromine and
iodine. Substituents that are substituted with multiple halogens
are substituted in a manner that provides compounds, which are
stable.
[0054] The term "oxo" whether used alone or as part of a
substituent group refers to an O=to either a carbon or a sulfur
atom. For example, phthalimide and saccharin are examples of
compounds with oxo substituents.
[0055] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., arylalkyl,
alkylamino) it shall be interpreted as including those limitations
given above for "alkyl" and "aryl." Designated numbers of carbon
atoms (e.g., C.sub.1-C.sub.6) shall refer independently to the
number of carbon atoms in an alkyl moiety or to the alkyl portion
of a larger substituent in which alkyl appears as its prefix root.
For alkyl, and alkoxy substituents the designated number of carbon
atoms includes all of the independent member included in the range
specified individually and all the combination of ranges within in
the range specified. For example C.sub.1-6 alkyl would include
methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well
as sub-combinations thereof (e.g. C.sub.1-2, C.sub.1-3, C.sub.1-4,
C.sub.1-5, C.sub.2-6, C.sub.3-6, C.sub.4-6, C.sub.5-6, C.sub.2-5,
etc.).
[0056] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment.
[0057] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated.
[0058] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0059] As used herein, the term "acyl" refers to alkylcarbonyl
substituents.
[0060] Throughout this disclosure, the terminal portion of the
designated side chain is described first, followed by the adjacent
functionality toward the point of attachment. Thus, for example, a
"phenyl(C.sub.1-6)alkylaminocarbonyl(C.sub.1-6)alkyl" substituent
refers to a group of the formula
##STR00004##
[0061] Embodiments of the present invention include compounds of
Formula (I) wherein: [0062] a) A.sub.1 is phenyl, benzofused
heterocyclyl wherein the point of attachment to L.sub.1 is at the
benzo ring, or benzofused heteroaryl; wherein phenyl, the benzo
portion of benzofused heterocyclyl, and benzofused heteroaryl are
optionally substituted with a substituent selected from the group
consisting of C.sub.1-4alkyl, hydroxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy, fluoro, chloro, halogenated C.sub.1-4alkyl,
halogenated C.sub.1-4alkoxy, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, cyano, hydroxy, aminocarbonyl,
C.sub.1-4alkylaminocarbonyl, di(C.sub.1-4alkyl)aminocarbonyl,
C.sub.1-4alkoxycarbonylamino, C.sub.1-4alkylcarbonyl,
C.sub.1-4alkylthiocarbonyl, formyl, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonylamino, aminosulfonyl,
C.sub.1-4alkylaminosulfonyl, and di(C.sub.1-4alkyl)aminosulfonyl;
and wherein phenyl, the benzo portion of benzofused heterocyclyl,
and benzofused heteroaryl are optionally further substituted with
one to two substituents independently selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy, fluoro, chloro, and
hydroxy; provided that A.sub.1 is other than 3,5-di-t-butyl-phenyl;
[0063] b) A.sub.1 is phenyl, benzofused heterocyclyl wherein the
point of attachment to L.sub.1 is at the benzo ring, or benzofused
heteroaryl; wherein phenyl, the benzo portion of benzofused
heterocyclyl, and benzofused heteroaryl are optionally substituted
with a substituent selected from the group consisting of
C.sub.1-4alkyl, hydroxy(C.sub.1-4)alkyl, C.sub.1-4alkoxy, fluoro,
chloro, trifluoromethyl, trifluoromethoxy, C.sub.1-4alkylthio, and
hydroxy; and wherein phenyl, the benzo portion of benzofused
heterocyclyl, and benzofused heteroaryl are optionally further
substituted with one to two substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
fluoro, chloro, and hydroxy; and wherein phenyl, the benzo portion
of benzofused heterocyclyl, and benzofused heteroaryl are
optionally further substituted with a fluoro or chloro substituent;
provided that A.sub.1 is other than 3,5-di-t-butyl-phenyl; [0064]
c) A.sub.1 is phenyl, benzofused heterocyclyl wherein the point of
attachment to L.sub.1 is at the benzo ring, or benzofused
heteroaryl; wherein phenyl, the benzo portion of benzofused
heterocyclyl, and benzofused heteroaryl are optionally substituted
with a substituent selected from the group consisting of
C.sub.1-4alkyl, hydroxy(C.sub.1-4)alkyl, C.sub.1-4alkoxy, fluoro,
chloro, trifluoromethyl, trifluoromethoxy, C.sub.1-4alkylthio, and
hydroxy; and wherein phenyl, the benzo portion of benzofused
heterocyclyl, and benzofused heteroaryl are optionally further
substituted with a fluoro or chloro substituent; [0065] d) A.sub.1
is phenyl, 2,3-dihydro-benzofuranyl wherein the point of attachment
to L.sub.1 is at the benzo ring, or 1-methyl-benzotriazol-5-yl;
wherein phenyl is optionally substituted with a substituent
selected from the group consisting of C.sub.1-2alkyl,
C.sub.1-2alkoxy, fluoro, chloro, and C.sub.1-2alkylthio; and
wherein phenyl is optionally further substituted with a fluoro or
chloro substituent; [0066] e) A.sub.1 is 4-ethyl-phenyl,
3,4-dichloro-phenyl, 4-fluoro-phenyl, 4-chloro-phenyl,
4-methylthio-phenyl, 2,3-dihydro-benzofuran-5-yl, or
1-methyl-benzotriazol-5-yl; [0067] f) L.sub.1 is (CH.sub.2).sub.r,
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, and halogen; provided that when
A.sub.1 is hydrogen, r is greater than or equal to 4; [0068] g)
L.sub.1 is (CH.sub.2).sub.r--, optionally substituted with a
substituent selected from the group consisting of C.sub.1-4alkyl,
C.sub.2-4alkenyl, and C.sub.2-4alkynyl, provided that r is 1 to 3
when A.sub.1 is other than hydrogen; or r is greater than or equal
to 4 when A.sub.1 is hydrogen; [0069] h) L.sub.1 is
(CH.sub.2).sub.r-- optionally substituted with a substituent
selected from the group consisting of methyl and allyl, provided
that r is 1 to 3 when A.sub.1 is other than hydrogen; [0070] i)
L.sub.1 is CH.sub.2--; [0071] j) P is --CH.sub.2-- or
CH.sub.2CH.dbd.CH; [0072] k) P is --CH.sub.2--; [0073] l) A.sub.2
is hydrogen, heteroaryl other than unsubstituted pyridin-2-yl,
dihydrobenzofuranyl, or phenyl optionally substituted at the meta
and para positions with one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, halogen, halogenated C.sub.1-6alkyl, halogenated
C.sub.1-6alkoxy, aryl(C.sub.1-6)alkoxy, phenyl, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; wherein heteroaryl other than unsubstituted
pyridin-2-yl and dihydrobenzofuranyl are optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen,
halogenated C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy,
aryl(C.sub.1-6)alkoxy, phenyl, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; provided that no more than two substituents
on A.sub.2 are aryl(C.sub.1-6)alkoxy, phenyl, or a non fused
C.sub.3-6cycloalkyloxy; [0074] m) A.sub.2 is heteroaryl other than
unsubstituted pyridin-2-yl, dihydrobenzofuranyl, or phenyl
optionally substituted at the meta and para positions with one to
three substituents independently selected from the group consisting
of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen, halogenated
C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, hydroxy, nitro, aminocarbonyl,
C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; wherein heteroaryl other than unsubstituted
pyridin-2-yl and dihydrobenzofuranyl are optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen,
halogenated C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy,
C.sub.1-6alkylthio, C.sub.1-6alkoxycarbonyl, amino, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; provided that no more than two substituents
on A.sub.2 are non fused C.sub.3-6cycloalkyloxy; [0075] n) A.sub.2
is furanyl, pyridin-3-yl, pyridin-4-yl, or phenyl optionally
substituted at the meta and para positions with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, halogenated
C.sub.1-3alkoxy, C.sub.1-3alkylthio, hydroxy, amino, aminocarbonyl,
C.sub.1-3alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; and wherein furanyl, pyridin-3-yl, and
pyridin-4-yl are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, halogenated
C.sub.1-3alkoxy, C.sub.1-3alkylthio, hydroxy, amino, aminocarbonyl,
C.sub.1-3alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; [0076] provided that no more than two
substituents on A.sub.2 are non fused C.sub.3-6cycloalkyloxy;
[0077] o) A.sub.2 is pyridin-3-yl pyridin-4-yl, or phenyl
optionally substituted at the meta and para positions with one to
two substituents independently selected from the group consisting
of methyl, ethyl, methoxy, ethoxy, isopropyloxy, trifluoromethoxy,
difluoromethoxy, hydroxy, aminocarbonyl, and methylcarbonylamino;
wherein pyridin-3-yl and pyridin-4-yl are optionally substituted
with one to two substituents independently selected from the group
consisting of methyl, ethyl, methoxy, ethoxy, isopropyloxy,
trifluoromethoxy, difluoromethoxy, hydroxy, aminocarbonyl, and
methylcarbonylamino; [0078] p) A.sub.2 is phenyl substituted at the
para position with a substituent selected from the group consisting
of methoxy, ethoxy, isopropyloxy, difluoromethoxy, hydroxy, and
aminocarbonyl; or A.sub.2 is pyridin-3-yl or pyridin-4-yl
substituted with methoxy; [0079] q) W is N or C(R.sub.w) wherein
R.sub.w is H; [0080] r) W is N; [0081] s) L.sub.2 is a bivalent
radical selected form the group consisting of
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5 and
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5 wherein R.sup.x,
R.sup.y, and R.sup.z are independently H or C.sub.1-4alkyl; and
provided that L.sub.2 in any instance does not exceed 7 atoms in
length; such that Q is selected from the group consisting of
Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.6 when L.sub.2 is other than
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; [0082] t) L.sub.2
is a bivalent radical selected form the group consisting of
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5 wherein R.sup.x,
R.sup.y, and R.sup.z are independently H or C.sub.1-4alkyl; and
provided that L.sub.2 in any instance does not exceed 7 atoms in
length; [0083] u) L.sub.2 is a bivalent radical selected form the
group consisting of --NH--CH(R.sup.x)--(CR.sup.yR.sup.z)--; [0084]
wherein R.sup.x, R.sup.y, and R.sup.z are independently H or
C.sub.1-4alkyl; [0085] v) L.sub.2 is a bivalent radical selected
form the group consisting of --NH--CH.sub.2CH.sub.2--; wherein
R.sup.x, R.sup.y, and R.sup.z are each H; [0086] w) Q is
[0086] ##STR00005## [0087] x) Q is
[0087] ##STR00006## [0088] wherein R.sub.a and R.sub.b are each
hydrogen; [0089] y) R.sub.1 is one to two substituents
independently selected from the group consisting of hydrogen,
methyl, methoxy, fluoro, chloro, and trifluoromethyl; [0090] z)
R.sub.1 is one to two substituents wherein one substituent is
selected from the group consisting of hydrogen, methyl, methoxy,
fluoro, chloro, and trifluoromethyl; and the second substituent is
hydrogen, fluoro, or chloro; [0091] aa) R.sub.1 is a substituent
selected from hydrogen, fluoro, or chloro; [0092] bb)R.sub.a is
hydrogen, trifluoromethylcarbonyl, methylcarbonyl, or
t-butylcarbonyl; and R.sub.b is hydrogen; [0093] cc) R.sub.a and
R.sub.b are each hydrogen; and any combination of embodiments a)
through cc) above, provided that it is understood that combinations
in which different embodiments of the same substituent would be
combined are excluded.
[0094] An embodiment of the present invention is directed to a
compound of Formula (I) wherein: [0095] A.sub.1 is phenyl,
benzofused heterocyclyl wherein the point of attachment to L.sub.1
is at benzo ring, or benzofused heteroaryl; wherein phenyl, the
benzo portion of benzofused heterocyclyl, and benzofused heteroaryl
are optionally substituted with a substituent selected from the
group consisting of C.sub.1-4alkyl, hydroxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy, fluoro, chloro, halogenated C.sub.1-4alkyl,
halogenated C.sub.1-4alkoxy, C.sub.1-4alkylthio,
C.sub.1-4alkoxycarbonyl, amino, C.sub.1-4alkylamino,
di(C.sub.1-4alkyl)amino, cyano, hydroxy, aminocarbonyl,
C.sub.1-4alkylaminocarbonyl, di(C.sub.1-4alkyl)aminocarbonyl,
C.sub.1-4alkoxycarbonylamino, C.sub.1-4alkylcarbonyl,
C.sub.1-4alkylthiocarbonyl, formyl, C.sub.1-4alkylsulfonyl,
C.sub.1-4alkylsulfonylamino, aminosulfonyl,
C.sub.1-4alkylaminosulfonyl, and di(C.sub.1-4alkyl)aminosulfonyl;
and wherein phenyl, the benzo portion of benzofused heterocyclyl,
and benzofused heteroaryl are optionally further substituted with
one to two substituents independently selected from the group
consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy, fluoro, chloro, and
hydroxy; provided that A.sub.1 is other than 3,5-di-t-butyl-phenyl;
[0096] L.sub.1 is (CH.sub.2).sub.r, optionally substituted with one
to three substituents independently selected from the group
consisting of C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl,
and halogen; provided that when A.sub.1 is hydrogen, r is greater
than or equal to 4; [0097] D is --P-A.sub.2; [0098] P is
--CH.sub.2-- or --CH.sub.2CH.dbd.CH--; [0099] A.sub.2 is hydrogen,
heteroaryl other than unsubstituted pyridin-2-yl,
dihydrobenzofuranyl, or phenyl optionally substituted at the meta
and para positions with one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, halogen, halogenated C.sub.1-6alkyl, halogenated
C.sub.1-6alkoxy, aryl(C.sub.1-6)alkoxy, phenyl, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; wherein heteroaryl other than unsubstituted
pyridin-2-yl and dihydrobenzofuranyl are optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen,
halogenated C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy,
aryl(C.sub.1-6)alkoxy, phenyl, C.sub.1-6alkylthio,
C.sub.1-6alkoxycarbonyl, amino, cyano, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; [0100] provided that no more than two
substituents on A.sub.2 are aryl(C.sub.1-6)alkoxy, phenyl, or a non
fused C.sub.3-6cycloalkyloxy; [0101] W is N or C(R.sub.w) wherein
R.sub.w is H; [0102] L.sub.2 is a bivalent radical selected form
the group consisting of --C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5 and
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; [0103] wherein
R.sup.x, R.sup.y, and R.sup.z are independently H or
C.sub.1-4alkyl; such that Q is selected from the group consisting
of Q.sub.1, Q.sub.2, Q.sub.4, and Q.sub.6 when L.sub.2 is other
than --NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; [0104] and
provided that L.sub.2 in any instance does not exceed 7 atoms in
length; [0105] Q is
[0105] ##STR00007## [0106] R.sub.1 is one to two substituents
independently selected from the group consisting of hydrogen,
methyl, methoxy, fluoro, chloro, and trifluoromethyl; [0107]
R.sub.a is hydrogen, trifluoromethylcarbonyl, methylcarbonyl, or
t-butylcarbonyl; and R.sub.b is hydrogen; [0108] and enantiomers,
diastereomers, solvates, and pharmaceutically acceptable salts
thereof.
[0109] A further embodiment of the present invention is directed to
a compound of Formula (I) wherein: [0110] A.sub.1 is phenyl,
benzofused heterocyclyl wherein the point of attachment to L.sub.1
is at the benzo ring, or benzofused heteroaryl; wherein phenyl, the
benzo portion of benzofused heterocyclyl, and benzofused heteroaryl
are optionally substituted with a substituent selected from the
group consisting of C.sub.1-4alkyl, hydroxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy,
C.sub.1-4alkylthio, and hydroxy; and wherein phenyl, the benzo
portion of benzofused heterocyclyl, and benzofused heteroaryl are
optionally further substituted with one to two substituents
independently selected from the group consisting of C.sub.1-4alkyl,
C.sub.1-4alkoxy, fluoro, chloro, and hydroxy; and wherein phenyl,
the benzo portion of benzofused heterocyclyl, and benzofused
heteroaryl are optionally further substituted with a fluoro or
chloro substituent; provided that A.sub.1 is other than
3,5-di-t-butyl-phenyl; [0111] L.sub.1 is --(CH.sub.2).sub.r--,
optionally substituted with one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.2-6alkynyl, and halogen; provided that when
A.sub.1 is hydrogen, r is greater than or equal to 4; [0112] D is
--P-A.sub.2; [0113] P is --CH.sub.2-- or --CH.sub.2CH.dbd.CH--;
[0114] A.sub.2 is heteroaryl other than unsubstituted pyridin-2-yl,
dihydrobenzofuranyl, or phenyl optionally substituted at the meta
and para positions with one to three substituents independently
selected from the group consisting of C.sub.1-6alkyl,
C.sub.1-6alkoxy, halogen, halogenated C.sub.1-6alkyl, halogenated
C.sub.1-6alkoxy, C.sub.1-6alkoxycarbonyl, amino, hydroxy, nitro,
aminocarbonyl, C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; wherein heteroaryl other than unsubstituted
pyridin-2-yl and dihydrobenzofuranyl are optionally substituted
with one to three substituents independently selected from the
group consisting of C.sub.1-6alkyl, C.sub.1-6alkoxy, halogen,
halogenated C.sub.1-6alkyl, halogenated C.sub.1-6alkoxy,
C.sub.1-6alkoxycarbonyl, amino, hydroxy, nitro, aminocarbonyl,
C.sub.1-6alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; provided that no more than two substituents
on A.sub.2 are non fused C.sub.3-6cycloalkyloxy; [0115] W is N or
C(R.sub.W) wherein R.sub.W is H; [0116] L.sub.2 is a bivalent
radical selected form the group consisting of
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5 and
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; [0117] wherein
R.sup.x, R.sup.y, and R.sup.z are independently H or
C.sub.1-4alkyl; [0118] and provided that L.sub.2 in any instance
does not exceed 7 atoms in length; [0119] Q is
[0119] ##STR00008## [0120] R.sub.1 is one to two substituents
independently selected from the group consisting of hydrogen,
methyl, methoxy, fluoro, chloro, and trifluoromethyl; [0121]
R.sub.a is hydrogen, trifluoromethylcarbonyl, methylcarbonyl, or
t-butylcarbonyl; and R.sub.b is hydrogen; [0122] and enantiomers,
diastereomers, solvates, and pharmaceutically acceptable salts
thereof.
[0123] A further embodiment of the present invention is directed to
a compound of Formula (I) wherein: [0124] A.sub.1 is phenyl,
benzofused heterocyclyl wherein the point of attachment to L.sub.1
is at the benzo ring, or benzofused heteroaryl; wherein phenyl, the
benzo portion of benzofused heterocyclyl, and benzofused heteroaryl
are optionally substituted with a substituent selected from the
group consisting of C.sub.1-4alkyl, hydroxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy,
C.sub.1-4alkylthio, and hydroxy; and wherein phenyl, the benzo
portion of benzofused heterocyclyl, and benzofused heteroaryl are
optionally further substituted with a fluoro or chloro substituent;
[0125] L.sub.1 is (CH.sub.2).sub.r--, optionally substituted with a
substituent selected from the group consisting of C.sub.1-4alkyl,
C.sub.2-4alkenyl, and C.sub.2-4alkynyl, provided that r is 1 to 3
when A.sub.1 is other than hydrogen; or r is greater than or equal
to 4 when A.sub.1 is hydrogen; [0126] D is --P-A.sub.2; [0127] P is
--CH.sub.2--; [0128] A.sub.2 is furanyl, pyridin-3-yl,
pyridin-4-yl, or phenyl optionally substituted at the meta and para
positions with one to three substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
halogen, halogenated C.sub.1-3alkoxy, hydroxy, amino,
aminocarbonyl, C.sub.1-3alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; and wherein furanyl, pyridin-3-yl, and
pyridin-4-yl are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, halogenated
C.sub.1-3alkoxy, hydroxy, amino, aminocarbonyl,
C.sub.1-3alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; [0129] provided that no more than two
substituents on A.sub.2 are non fused C.sub.3-6cycloalkyloxy;
[0130] W is N; [0131] L.sub.2 is a bivalent radical selected form
the group consisting of [0132]
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--; [0133] wherein
R.sup.x, R.sup.y, and R.sup.z are independently H or
C.sub.1-4alkyl; [0134] and provided that L.sub.2 in any instance
does not exceed 7 atoms in length; [0135] Q is
[0135] ##STR00009## [0136] wherein R.sub.a and R.sub.ic, are each
hydrogen; [0137] R.sub.1 is one to two substituents wherein one
substituent is selected from the group consisting of hydrogen,
methyl, methoxy, fluoro, chloro, and trifluoromethyl; and the
second substituent is hydrogen, fluoro, or chloro; and enantiomers,
diastereomers, solvates, and pharmaceutically acceptable salts
thereof.
[0138] A further embodiment of the present invention is directed to
a compound of Formula (I) wherein: [0139] A.sub.1 is phenyl,
benzofused heterocyclyl wherein the point of attachment to L.sub.1
is at the benzo ring, or benzofused heteroaryl; wherein phenyl, the
benzo portion of benzofused heterocyclyl, and benzofused heteroaryl
are optionally substituted with a substituent selected from the
group consisting of C.sub.1-4alkyl, hydroxy(C.sub.1-4)alkyl,
C.sub.1-4alkoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy,
C.sub.1-4alkylthio, and hydroxy; and wherein phenyl, the benzo
portion of benzofused heterocyclyl, and benzofused heteroaryl are
optionally further substituted with a fluoro or chloro substituent;
[0140] L.sub.1 is (CH.sub.2).sub.r--, optionally substituted with a
substituent selected from the group consisting of C.sub.1-4alkyl,
C.sub.2-4alkenyl, and C.sub.2-4alkynyl, provided that r is 1 to 3
when A.sub.1 is other than hydrogen; or r is greater than or equal
to 4 when A.sub.1 is hydrogen; [0141] D is --P-A.sub.2; [0142] P is
--CH.sub.2--; [0143] A.sub.2 is furanyl, pyridin-3-yl,
pyridin-4-yl, or phenyl optionally substituted at the meta and para
positions with one to three substituents independently selected
from the group consisting of C.sub.1-4alkyl, C.sub.1-4alkoxy,
halogen, halogenated C.sub.1-3alkoxy, C.sub.1-3alkylthio, hydroxy,
amino, aminocarbonyl, C.sub.1-3alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; and wherein furanyl, pyridin-3-yl, and
pyridin-4-yl are optionally substituted with one to three
substituents independently selected from the group consisting of
C.sub.1-4alkyl, C.sub.1-4alkoxy, halogen, halogenated
C.sub.1-3alkoxy, hydroxy, amino, aminocarbonyl,
C.sub.1-3alkylcarbonylamino, and a non fused
C.sub.3-6cycloalkyloxy; [0144] provided that no more than two
substituents on A.sub.2 are non fused C.sub.3-6cycloalkyloxy;
[0145] W is N; [0146] L.sub.2 is a bivalent radical selected form
the group consisting of --NH--CH(R.sup.x)--(CR.sup.yR.sup.z)--;
[0147] wherein R.sup.x, R.sup.y, and R.sup.z are independently H or
C.sub.1-4alkyl; [0148] Q is
[0148] ##STR00010## [0149] wherein R.sub.a and R.sub.b are each
hydrogen; [0150] R.sub.1 is one to two substituents wherein one
substituent is selected from the group consisting of hydrogen,
methyl, methoxy, fluoro, chloro, and trifluoromethyl; and the
second substituent is hydrogen, fluoro, or chloro; and enantiomers,
diastereomers, solvates, and pharmaceutically acceptable salts
thereof.
[0151] A further embodiment of the present invention is directed to
a compound of Formula (I) wherein: [0152] A.sub.1 is phenyl,
2,3-dihydro-benzofuranyl wherein the point of attachment to L.sub.1
is at the benzo ring, or 1-methyl-benzotriazol-5-yl; wherein phenyl
is optionally substituted with a substituent selected from the
group consisting of C.sub.1-2alkyl, C.sub.1-2alkoxy, fluoro,
chloro, and C.sub.1-2alkylthio; and wherein phenyl is optionally
further substituted with a fluoro or chloro substituent; [0153]
L.sub.1 is (CH.sub.2).sub.r-- optionally substituted with a
substituent selected from the group consisting of methyl and allyl,
provided that r is 1 to 3 when A.sub.1 is other than hydrogen;
[0154] D is --P-A.sub.2; [0155] P is --CH.sub.2--; [0156] A.sub.2
is pyridin-3-yl pyridin-4-yl, or phenyl optionally substituted at
the meta and para positions with one to two substituents
independently selected from the group consisting of methyl, ethyl,
methoxy, ethoxy, isopropyloxy, trifluoromethoxy, difluoromethoxy,
hydroxy, aminocarbonyl, and methylcarbonylamino; wherein
pyridin-3-yl and pyridin-4-yl are optionally substituted with one
to two substituents independently selected from the group
consisting of methyl, ethyl, methoxy, ethoxy, isopropyloxy,
trifluoromethoxy, difluoromethoxy, hydroxy, aminocarbonyl, and
methylcarbonylamino; [0157] W is N; [0158] L.sub.2 is a bivalent
radical selected form the group consisting of
--NH--CH.sub.2CH.sub.2--; wherein R.sup.x, R.sup.y, and R.sup.z are
each H; [0159] Q is
[0159] ##STR00011## [0160] wherein R.sub.a and R.sub.ic, are each
hydrogen; [0161] R.sub.1 is a substituent selected from hydrogen,
fluoro, or chloro; and enantiomers, diastereomers, solvates, and
pharmaceutically acceptable salts thereof.
[0162] A further embodiment of the present invention is directed to
a compound of Formula (I) wherein: [0163] A.sub.1 is
4-ethyl-phenyl, 3,4-dichloro-phenyl, 4-fluoro-phenyl,
4-chloro-phenyl, 4-methylthio-phenyl, 2,3-dihydro-benzofuran-5-yl,
or 1-methyl-benzotriazol-5-yl; [0164] L.sub.1 is CH.sub.2--; [0165]
D is --P-A.sub.2; [0166] P is --CH.sub.2--; [0167] A.sub.2 is
phenyl substituted at the para position with a substituent selected
from the group consisting of methoxy, ethoxy, isopropyloxy,
difluoromethoxy, hydroxy, and aminocarbonyl; or A.sub.2 is
pyridin-3-yl or pyridin-4-yl substituted with methoxy; [0168] W is
N; [0169] L.sub.2 is a bivalent radical selected form the group
consisting of --NH--CH.sub.2CH.sub.2--; wherein R.sup.x, R.sup.y,
and R.sup.z are each H; [0170] Q is
[0170] ##STR00012## [0171] wherein R.sub.a and R.sub.ic, are each
hydrogen; [0172] R.sub.1 is a substituent selected from hydrogen,
fluoro, or chloro; [0173] and enantiomers, diastereomers, solvates,
and pharmaceutically acceptable salts thereof.
[0174] A further embodiment of the present invention is directed to
a pharmaceutical composition comprising of Formula (Ia) (wherein
L.sub.1 is CH.sub.2)
##STR00013##
selected from the group consisting of [0175] a compound of Formula
(Ia) wherein A.sub.1 is 3,4-dichloro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 1H-benzoimidazol-2-ylamino; [0176] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-imidazol-1-yl; [0177] a compound of Formula (Ia)
wherein A.sub.1 is 4-fluoro-phenyl, D is 4-methoxy-phenylmethyl, W
is N, L.sub.2 is --NH(CH.sub.2).sub.2--, and Q is
2-amino-benzoimidazol-1-yl; [0178] a compound of Formula (Ia)
wherein A.sub.1 is 4-fluoro-phenyl, D is 4-methoxy-phenylmethyl, W
is N, L.sub.2 is NH(CH.sub.2).sub.2--, and Q is
2-amino-3H-imidazol-4-yl; [0179] a compound of Formula (Ia) wherein
A.sub.1 is 4-fluoro-phenyl, D is 4-methoxy-phenylmethyl, W is N,
L.sub.2 is --NH(CH.sub.2).sub.2--, and Q is
2-amino-5-fluoro-benzoimidazol-1-yl; [0180] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NHCH.sub.2--, and Q is
2-amino-1H-imidazol-4-yl; [0181] a compound of Formula (Ia) wherein
A.sub.1 is 4-fluoro-phenyl, D is 4-methoxy-phenylmethyl, W is N,
L.sub.2 is --NH(CH.sub.2).sub.2--, and Q is
2-amino-6-methyl-benzoimidazol-1-yl; [0182] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-5-trifluoromethyl-benzoimidazol-1-yl; [0183] a
compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-5-methanesulfonyl-benzoimidazol-1-yl; [0184] a
compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-6-chloro-benzoimidazol-1-yl; [0185] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-4-fluoro-benzoimidazol-1-yl; [0186] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-4H-quinazolin-3-yl; [0187] a compound of Formula
(Ia) wherein A.sub.1 is 4-methoxy-phenyl, D is
4-methoxy-phenylmethyl, W is CH, L.sub.2 is
--C(O)NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl;
[0188] a compound of Formula (Ia) wherein A.sub.1 is
4-chloro-phenyl, D is 4-methoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0189]
a compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-t-butylcarbonylamino-benzoimidazol-1-yl; [0190] a
compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is a mixture of 2-methylamino-benzoimidazol-1-yl and
2-dimethylamino-benzoimidazol-1-yl; [0191] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-trifluoromethylcarbonylamino-benzoimidazol-1-yl; [0192]
a compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-t-butylcarbonylamino-imidazol-1-yl; [0193] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0194]
a compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0195]
a compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-fluoro-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-imidazol-1-yl; [0196] a compound of Formula (Ia)
wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-imidazol-1-yl; [0197] a
compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-imidazol-1-yl; [0198] a
compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-methylcarbonylamino-benzoimidazol-1-yl; [0199] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-fluoro-benzoimidazol-1-yl; [0200] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
5-fluoro-2-amino-benzoimidazol-1-yl; [0201] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-5-trifluoromethyl-benzoimidazol-1-yl; [0202] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-4,6-difluoro-benzoimidazol-1-yl; [0203] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6,7-difluoro-benzoimidazol-1-yl; [0204] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-chloro-benzoimidazol-1-yl; [0205] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-4-fluoro-benzoimidazol-1-yl; [0206] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-7-fluoro-benzoimidazol-1-yl; [0207] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-fluoro-benzoimidazol-1-yl; [0208] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-5-fluoro-benzoimidazol-1-yl; [0209] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--,
2-amino-5-trifluoromethyl-benzoimidazol-1-yl; [0210] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-4,6-difluoro-benzoimidazol-1-yl; [0211] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6,7-difluoro-benzoimidazol-1-yl; [0212] a compound of
Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-chloro-benzoimidazol-1-yl; [0213] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-4-fluoro-benzoimidazol-1-yl; [0214] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-7-fluoro-benzoimidazol-1-yl; [0215] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-4H-quinazolin-3-yl; [0216]
a compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-5-chloro-4H-quinazolin-3-yl; [0217] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-chloro-4H-quinazolin-3-yl; [0218] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-7-chloro-4H-quinazolin-3-yl; [0219] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-fluoro-4H-quinazolin-3-yl; [0220] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-7-fluoro-4H-quinazolin-3-yl; [0221] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-4H-quinazolin-3-yl; [0222]
a compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-5-chloro-4H-quinazolin-3-yl; [0223] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-chloro-4H-quinazolin-3-yl; [0224] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-7-chloro-4H-quinazolin-3-yl; [0225] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-fluoro-4H-quinazolin-3-yl; [0226] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-7-fluoro-4H-quinazolin-3-yl; [0227] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0228] a
compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-trifluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0229] a
compound of Formula (Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-4-methoxy-benzoimidazol-1-yl; [0230] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-6-hydroxy-4H-quinazolin-3-yl; [0231] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is
2-amino-7-methoxy-4H-quinazolin-3-yl; [0232] a compound of Formula
(Ia) wherein A.sub.1 is 4-fluoro-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-4H-quinazolin-1-yl; [0233]
a compound of Formula (Ia) wherein A.sub.1 is 3,4-dichloro-phenyl,
D is 4-methoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0234] a
compound of Formula (Ia) wherein A.sub.1 is 4-ethyl-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-3H-imidazol-4-yl; [0235] a compound of Formula
(Ia) wherein A.sub.1 is 4-methylthio-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-3H-imidazol-4-yl; [0236] a compound of Formula
(Ia) wherein A.sub.1 is 2,3-dihydro-benzofuran-5-yl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-3H-imidazol-4-yl; [0237] a compound of Formula
(Ia) wherein A.sub.1 is 3,4-dichloro-phenyl, D is
2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0238] a
compound of Formula (Ia) wherein A.sub.1 is 4-methylthio-phenyl, D
is 2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0239] a
compound of Formula (Ia) wherein A.sub.1 is 4-ethyl-phenyl, D is
2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0240] a
compound of Formula (Ia) wherein A.sub.1 is
2,3-dihydro-benzofuran-5-yl, D is
2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0241] a
compound of Formula (Ia) wherein A.sub.1 is
1-methyl-1H-benzotriazol-5-yl, D is 4-methoxy-phenylmethyl, W is N,
L.sub.2 is --NH(CH.sub.2).sub.2--, and Q is
2-amino-3H-imidazol-4-yl; [0242] a compound of Formula (Ia) wherein
A.sub.1 is 1-methyl-1H-benzotriazol-5-yl, D is
2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0243] a
compound of Formula (Ia) wherein A.sub.1 is 3,4-dichloro-phenyl, D
is 4-methoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0244]
a compound of Formula (Ia) wherein A.sub.1 is 4-methylthio-phenyl,
D is 4-methoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzimidazol-1-yl; [0245]
a compound of Formula (Ia) wherein A.sub.1 is 4-ethyl-phenyl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-benzoimidazol-1-yl; [0246] a compound of Formula
(Ia) wherein A.sub.1 is 2,3-dihydro-benzofuran-5-yl, D is
4-methoxy-phenylmethyl, W is N, L.sub.2 is --NH(CH.sub.2).sub.2--,
and Q is 2-amino-benzoimidazol-1-yl; [0247] a compound of Formula
(Ia) wherein A.sub.1 is 3,4-dichloro-phenyl, D is
2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0248]
a compound of Formula (Ia) wherein A.sub.1 is 4-methylthio-phenyl,
D is 2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0249]
a compound of Formula (Ia) wherein A.sub.1 is 4-ethyl-phenyl, D is
2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0250]
a compound of Formula (Ia) wherein A.sub.1 is
2,3-dihydro-benzofuran-5-yl, D is
2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0251]
a compound of Formula (Ia) wherein A.sub.1 is
1-methyl-1H-benzotriazol-5-yl, D is 4-methoxy-phenylmethyl, W is N,
L.sub.2 is --NH(CH.sub.2).sub.2--, and Q is
2-amino-benzoimidazol-1-yl; [0252] a compound of Formula (Ia)
wherein A.sub.1 is 1-methyl-1H-benzotriazol-5-yl, D is
2,3-dihydro-benzofuran-5-ylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl;
[0253] a compound of Formula (Ia) wherein A.sub.1 is
3,4-dichloro-phenyl, D is 4-difluoromethoxy-phenylmethyl, W is N,
L.sub.2 is --NH(CH.sub.2).sub.2--, and Q is
2-amino-3H-imidazol-4-yl; [0254] a compound of Formula (Ia) wherein
A.sub.1 is 4-methylthio-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0255] a
compound of Formula (Ia) wherein A.sub.1 is 4-ethyl-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0256] a
compound of Formula (Ia) wherein A.sub.1 is
2,3-dihydro-benzofuran-5-yl, D is 4-difluoromethoxy-phenylmethyl, W
is N, L.sub.2 is --NH(CH.sub.2).sub.2--, and Q is
2-amino-3H-imidazol-4-yl; [0257] a compound of Formula (Ia) wherein
A.sub.1 is 1-methyl-1H-benzotriazol-5-yl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-3H-imidazol-4-yl; [0258] a
compound of Formula (Ia) wherein A.sub.1 is 3,4-dichloro-phenyl, D
is 4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0259]
a compound of Formula (Ia) wherein A.sub.1 is 4-methylthio-phenyl,
D is 4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0260]
a compound of Formula (Ia) wherein A.sub.1 is 4-ethyl-phenyl, D is
4-difluoromethoxy-phenylmethyl, W is N, L.sub.2 is
--NH(CH.sub.2).sub.2--, and Q is 2-amino-benzoimidazol-1-yl; [0261]
and [0262] a compound of Formula (Ia) wherein A.sub.1 is
2,3-dihydro-benzofuran-5-yl, D is 4-difluoromethoxy-phenylmethyl, W
is N, L.sub.2 is --NH(CH.sub.2).sub.2--, and Q is
2-amino-benzoimidazol-1-yl [0263] and enantiomers, diastereomers,
solvates, and pharmaceutically acceptable salts thereof.
[0264] Additional embodiments of the present invention include
those compounds wherein the substituents selected from one or more
of the variables defined herein (i.e. A.sub.1, L.sub.1, s, X, P,
A.sub.2, W, L.sub.2, and Q) are independently selected to be any
individual substituent or any subset of substituents selected from
the complete list as defined herein.
[0265] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicine, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts" (Ref. International
J. Pharm., 1986, 33, 201-217; J. Pharm. Sci., 1997 (January), 66,
1, 1). Other salts well known to those in the art may, however, be
useful in the preparation of compounds according to this invention
or of their pharmaceutically acceptable salts. Representative
organic or inorganic acids include, but are not limited to,
hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric,
nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic,
maleic, fumaric, malic, tartaric, citric, benzoic, mandelic,
methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic,
pamoic, 2-naphthalenesulfonic, p-toluenesulfonic,
cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic
acid. Representative organic or inorganic bases include, but are
not limited to, basic or cationic salts such as benzathine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
meglumine, procaine, aluminum, calcium, lithium, magnesium,
potassium, sodium and zinc.
[0266] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds that are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0267] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are
intended to be encompassed within the scope of this invention.
[0268] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography. The compounds may be prepared in
racemic form, or individual enantiomers may be prepared either by
enantiospecific synthesis or by resolution. The compounds may, for
example, be resolved into their component enantiomers by standard
techniques, such as the formation of diastereomeric pairs by salt
formation with an optically active acid, such as
(-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric
acid followed by fractional crystallization and regeneration of the
free base. The compounds may also be resolved by formation of
diastereomeric esters or amides, followed by chromatographic
separation and removal of the chiral auxiliary. Alternatively, the
compounds may be resolved using a chiral HPLC column.
[0269] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the
art.
[0270] Even though the compounds of the present invention
(including their pharmaceutically acceptable salts and
pharmaceutically acceptable solvates) can be administered alone,
they will generally be administered in admixture with a
pharmaceutical carrier, excipient, or diluent selected with regard
to the intended route of administration and standard pharmaceutical
or veterinary practice. Thus, the present invention is directed to
pharmaceutical and veterinary compositions comprising compounds of
Formula (I) and one or more pharmaceutically acceptable carriers,
excipients or diluents.
[0271] By way of example, in the pharmaceutical and veterinary
compositions of the present invention, the compounds of the present
invention may be admixed with any suitable binder(s), lubricant(s),
suspending agent(s), coating agent(s), and/or solubilising
agent(s).
[0272] Tablets or capsules of the compounds may be administered
singly or two or more at a time, as appropriate. It is also
possible to administer the compounds in sustained release
formulations.
[0273] Alternatively, the compounds of the general Formula (I) can
be administered by inhalation or in the form of a suppository or
pessary, or they may be applied topically in the form of a lotion,
solution, cream, ointment or dusting powder. An alternative means
of transdermal administration is by use of a skin patch. For
example, they can be incorporated into a cream consisting of an
aqueous emulsion of polyethylene glycols or liquid paraffin. They
can also be incorporated, at a concentration of between 1 and 10%
by weight, into an ointment consisting of a white wax or white soft
paraffin base together with such stabilisers and preservatives as
may be required.
[0274] For some applications, preferably the compositions are
administered orally in the form of tablets containing excipients
such as starch or lactose, or in capsules or ovules either alone or
in admixture with excipients, or in the form of elixirs, solutions
or suspensions containing flavouring or coloring agents.
[0275] The compositions (as well as the compounds alone) can also
be injected parenterally, for example intracavernosally,
intravenously, intramuscularly or subcutaneously. In this case, the
compositions will comprise a suitable carrier or diluent.
[0276] For parenteral administration, the compositions are best
used in the form of a sterile aqueous solution which may contain
other substances, for example enough salts or monosaccharides to
make the solution isotonic with blood.
[0277] For buccal or sublingual administration the compositions may
be administered in the form of tablets or lozenges which can be
formulated in a conventional manner.
[0278] By way of further example, pharmaceutical and veterinary
compositions containing one or more of the compounds of the
invention described herein as the active ingredient can be prepared
by intimately mixing the compound or compounds with a
pharmaceutical carrier according to conventional pharmaceutical
compounding techniques. The carrier may take a wide variety of
forms depending upon the desired route of administration (e.g.,
oral, parenteral). Thus for liquid oral preparations such as
suspensions, elixirs and solutions, suitable carriers and additives
include water, glycols, oils, alcohols, flavoring agents,
preservatives, stabilizers, coloring agents and the like; for solid
oral preparations, such as powders, capsules and tablets, suitable
carriers and additives include starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like. Solid oral preparations may also be coated with
substances such as sugars or be enteric-coated so as to modulate
the major site of absorption. For parenteral administration, the
carrier will usually consist of sterile water and other ingredients
may be added to increase solubility or preservation. Injectable
suspensions or solutions may also be prepared utilizing aqueous
carriers along with appropriate additives.
[0279] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those skilled in that art. To be administered in the form of a
transdermal delivery system, the dosage administration will, of
course, be continuous rather than intermittent throughout the
dosage regimen.
[0280] The instant pharmaceutical composition will generally
contain a per dosage unit (e.g., tablet, capsule, powder,
injection, teaspoonful and the like) from about 0.001 to about 50
mg/kg. In one embodiment, the instant pharmaceutical composition
contains a per dosage unit of from about 0.01 to about 20 mg/kg of
compound, and preferably from about 0.05 to about 10 mg/kg. Methods
are known in the art for determining therapeutically effective
doses for the instant pharmaceutical composition. The
therapeutically effective amount for administering the
pharmaceutical composition to a human, for example, can be
determined mathematically from the results of animal studies.
[0281] A therapeutically effective amount for use of the instant
compounds or a pharmaceutical composition thereof comprises a dose
range from about 0.1 mg to about 3000 mg, in particular from about
1 mg to about 1000 mg or, more particularly from about 10 mg to
about 500 mg of active ingredient in a regimen of about 1 to 4
times per day for an average (70 kg) human; although, it is
apparent to one skilled in the art that the therapeutically
effective amount for active compounds of the invention will vary as
will the conditions being treated.
[0282] For oral administration, a pharmaceutical composition is
preferably provided in the form of tablets containing, 0.01, 0.05,
0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250
and 500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the subject to be treated.
[0283] It is also apparent to one skilled in the art that the
therapeutically effective dose for active compounds of the
invention or a pharmaceutical composition thereof will vary
according to the desired effect. Therefore, optimal dosages to be
administered may be readily determined and will vary with the
particular compound used, the mode of administration, the strength
of the preparation, and the advancement of the disease condition.
In addition, factors associated with the particular subject being
treated, including subject age, weight, diet and time of
administration, will result in the need to adjust the dose to an
appropriate therapeutic level. The above dosages are thus exemplary
of the average case. There can, of course, be individual instances
where higher or lower dosage ranges are merited, and such are
within the scope of this invention.
[0284] Compounds of this invention may be administered in any of
the foregoing compositions and dosage regimens or by means of those
compositions and dosage regimens established in the art whenever
use of the compounds of the invention as prokineticin receptor
antagonists is required for a subject in need thereof.
[0285] The invention also provides a pharmaceutical or veterinary
pack or kit comprising one or more containers filled with one or
more of the ingredients of the pharmaceutical and veterinary
compositions of the invention.
[0286] As antagonists of a Prokineticin 1 receptor, the compounds
of Formula (I) are useful in methods for treating or preventing a
disease or condition in a mammal which disease or condition is
affected by the antagonistic activity of one or more Prokineticin 1
receptors. Such methods comprise administering to a mammal in need
of such treatment or prevention a therapeutically effective amount
of a compound, salt or solvate of Formula (I). The compounds of
Formula (I) are useful in methods for preventing or treating
gastrointestinal (GI) diseases, cancers of the GI tract and
reproductive organs, and pain. Examples of GI diseases to be within
the scope of the present invention include, but are not limited to:
irritable bowel syndrome (IBS, including diarrhea-predominant, as
well as alternating diarrhea/constipation forms of IBS),
inflammatory bowel disease (IBD, including ulcerative colitis, and
Crohn's disease), and GERD and secretory bowel disorders induced by
pathogens. Examples of cancers within the scope of the present
invention include, but are not limited to, testicular cancer,
ovarian cancer, Leydig cell carcinoma, and cancers of the small or
large bowel. An example of pain to be covered within the scope of
the present invention, is, but not restricted to, visceral
hyperalgesia often associated with IBS and IBD.
[0287] While the present invention comprises compositions
comprising one or more of the compounds of Formula (I) the present
invention also comprises compositions comprising intermediates used
in the manufacture of compounds of Formula (I).
[0288] Representative IUPAC names for the compounds of the present
invention were derived using the ACD/LABS SOFTWARE.TM. Index Name
Pro Version 4.5 nomenclature software program provided by Advanced
Chemistry Development, Inc., Toronto, Ontario, Canada.
[0289] Abbreviations used in the instant specification,
particularly the Schemes and Examples, are as follows:
Boc=tert-butoxycarbonyl BuLi=n-butyllithium Cpd or Cmpd=compound
d=day/days DCM=dichloromethane DIAD=diisopropyl azodicarboxylate
DIPEA or DIEA=diisopropylethylamine
DMEM=Dulbecco's Modified Eagle Medium
DMF=N,N-dimethylformamide
[0290] DMSO=dimethylsulfoxide EtOAc=ethyl acetate EtOH=ethanol
h=hour/hours LDA=lithium diisopropylamide M=molar MeCN=acetonitrile
MeOH=methanol min=minute(s) NaOMe=sodium methoxide rt/RT=room
temperature THF=tetrahydrofuran TFA=trifluoroacetic acid
General Schemes
[0291] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and are illustrated in the schemes that follows.
The starting materials and reagents used in the schemes that follow
are understood to be either commercially available or prepared by
methods known to those skilled in the art. Since the schemes are an
illustration, the invention should not be construed as being
limited by the chemical reactions and conditions expressed.
[0292] Scheme A illustrates the general synthesis of certain
intermediates of the present invention wherein W is N and L.sub.2
is other than --C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5--.
##STR00014##
[0293] A compound of formula A1 may be methylated with a
methylating agent such as methyl iodide in a polar solvent such as
methanol to give a compound of formula A2. A compound of formula A2
may be condensed with an appropriately substituted isocyanate such
as N-chlorocarbonyl isocyanate in the presence of excess tertiary
amine such as diisopropylethylamine to give a triazine of formula
A3. A compound of formula A3 may be alkylated with a compound of
formula A4, wherein LG.sub.1 is a leaving group, using conventional
chemistry known to one versed in the art. For instance, when
LG.sub.1 is a hydroxy group, compound A4 may be coupled with
compound A3 with the aid of a coupling agent such as DIAD in the
presence of triphenylphosphine in a non-alcoholic polar solvent
such as THF or methylene chloride. Alternatively, LG.sub.1 may be a
halide, tosylate, or the like such that LG.sub.1 is displaced by
the amino portion of a compound of A3 to give a compound of formula
A5.
[0294] Scheme B describes the synthesis of certain -L.sub.2-Q
intermediates of the present invention wherein W is N, L.sub.2 is
--NH--CH(R.sup.x)--(CR.sup.yR.sup.z).sub.1-5--, and Q is of formula
Q.sub.3.
##STR00015##
[0295] The commercially available compound of formula B1 may be
treated with sodium nitrite to form a diazonium salt of formula B2.
Reaction of a compound of formula B3 (wherein PG is a conventional
amino protecting group) with a compound of formula B2 affords the
diazo-compound of formula B4. Hydrogenation of a compound of
formula B4 in the presence of a transition metal catalyst such as
platinum (I) oxide affords an amino-substituted imidazole of
formula B5. Subsequent removal of the amino protecting group (PG)
provides a compound of formula B6, which may be used as a
nucleophile in reaction with a compound of formula A5 to provide a
compound of Formula (I)-B.
[0296] Scheme C describes the synthesis of certain compounds of the
present invention wherein W is N, L.sub.2 is other than
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5-- and Q is of formula
Q.sub.2 wherein R.sub.a is H.
##STR00016##
[0297] A compound of formula A5 may be treated with a diamine of
formula C1 to give a compound of formula C2. One versed in the art
will recognize that when L.sub.2 is asymmetrical, a
nitrogen-protecting group may be necessary to avoid competing
reactions between the amino groups. The terminal amine of a
compound of formula C2 may be alkylated with an aldehyde of formula
C3 in the presence of a hydride source, such as sodium
triacetoxyborohydride, to give a compound of formula C4. Reaction
with zinc metal in the presence of acetic acid, followed by
treatment with cyanogen bromide affords compounds of Formula
(I)-C.
[0298] Scheme D illustrates the synthesis of certain compounds of
the present invention wherein W is N, L.sub.2 is other than
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5-- and Q is of formula
Q.sub.1 wherein R.sub.a is H.
##STR00017##
A compound of formula C2 may undergo an aromatic nucleophilic
displacement with a compound of formula D1 to give a compound of
formula D2. Reaction of with zinc metal in the presence of acetic
acid, followed by treatment with cyanogens bromide affords a
Q.sub.1-substituted compound of Formula (I)-D.
[0299] Scheme E illustrates the synthesis of certain compounds of
the present invention wherein W is N, L.sub.2 is other than
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5-- and Q is of formula
Q.sub.5.
##STR00018##
[0300] A compound of formula E1 may be treated with a base and then
alkylated with a compound of formula E2 to provide a compound of
formula E3. The compound of formula E3 may be used in an
nucleophilic displacement reaction with a compound of formula A5 to
provide compounds of formula (I)-E of the present invention.
[0301] Scheme F illustrates the general synthesis of compounds of
the present invention wherein W is C(R.sub.w), and L.sub.2 is other
than --C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5--.
##STR00019##
A compound of formula F1 may be condensed with a compound of
formula F2 with heating, (wherein LG.sub.2 is C.sub.1-4alkoxy,
choro, or the like) to form a compound of formula F3. A compound of
formula F3 may then be treated with phosphorus oxychloride,
phosphorus pentachloride, or the like and heat to afford a compound
of formula F4. Alternatively, the bromo analog may be used in this
synthetic sequence, which is prepared from F3 using phosphorus
oxybromide in place of phosphorus oxychloride. A compound of
formula F5 may be used to install --P-A.sub.2 via conventional
alkylation procedures. A compound of formula F6 may be elaborated
via a nucleophilic displacement of the chloride or bromide with an
amino compound of formula B6, C1, E4, or the like to afford a
compound of Formula (I)-F. For illustrative purposes only, Scheme F
shows a compound of formula E4 as the nucleophile in reaction with
a compound of formula F6.
[0302] Scheme G illustrates the general synthesis of compounds of
the present invention in which W is N and L.sub.2 is
--C(.dbd.O)NH(CR.sup.yR.sup.z).sub.2-5--.
##STR00020## ##STR00021##
[0303] A compound of formula G1 (either commercially available or
prepared by known methods described in the scientific literature)
may be treated with a base followed by alkylation with a compound
of formula A4 to afford a compound of formula G2. Treatment of a
compound of formula G2 with an aqueous base such as sodium
hydroxide gives a compound of formula G3, which upon treatment with
ammonia or its equivalent provides a compound of formula G4. The
compound of formula G4 may then be condensed with a compound of
formula G5 to form a triazine compound of formula G6. A compound of
Formula G6 may be treated with a methylating agent such as
trimethylsilyl diazomethane to give a methyl ester of formula G7.
Under Mitsunobu-type coupling conditions (in the presence of a
coupling agent, activating agent), an alcohol of formula G8 may be
coupled with a secondary amine of formula G7 to afford a compound
of formula G9. Standard base hydrolysis of the methyl ester gives
the corresponding carboxylic acid of formula G10, which may be
coupled with an amine of formula G11 (which includes a
Q-substituent or a precursor to a Q-substituent) to afford a
compound of Formula (I)-G.
[0304] Scheme H illustrates the general synthesis of compounds of
the present invention wherein W is CH and L.sub.2 is
--C(.dbd.O)NEI(CR.sup.yR.sup.z).sub.2-5--.
##STR00022## ##STR00023##
A compound of formula H1 may be condensed with an O-alkylated
isourea to afford a cyclic compound of formula H2. The amine may be
deprotonated with an organometallic base and subsequently treated
with a compound of formula A4 to install the -L.sub.1A.sub.1
substituent of Formula (I). O-demethylation of an alkylated
compound of H2 affords a compound of formula H3. Using conventional
oxidation chemistry, the methyl substituent of H3 may be converted
to its corresponding aldehyde, affording a compound of formula H4.
A compound of formula H4 may be treated under Mitsunobu-type
coupling conditions (in the presence of a coupling agent and
activating agent), with an alcohol of formula G8 to afford a
compound of formula H5. Oxidation of the aldehyde group using an
appropriate oxidizing agent gives a compound of formula H6, wherein
the corresponding carboxylic acid may be coupled with an amine of
formula H7 (PG is an appropriate amino protecting group) to afford
a compound of formula H8. The conventional removal of the amino
protecting group, PG, yields the primary amine of formula H9, which
may be converted to a Q-group according to the methods described
herein to yield a compound of Formula (I)-H. Similarly, a compound
of formula H6 may be coupled with a Q-containing amine of formula
G11 to give a compound of Formula (I)-H.
SPECIFIC EXAMPLES
[0305] Specific compounds which are representative of this
invention were prepared as per the following examples and reaction
sequences; the examples and the diagrams depicting the reaction
sequences are offered by way of illustration, to aid in the
understanding of the invention and should not be construed to limit
in any way the invention set forth in the claims which follow
thereafter. The instant compounds may also be used as intermediates
in subsequent examples to produce additional compounds of the
present invention. No attempt has been made to optimize the yields
obtained in any of the reactions. One skilled in the art would know
how to increase such yields through routine variations in reaction
times, temperatures, solvents and/or reagents.
[0306] Reagents were purchased from commercial sources. Nuclear
magnetic resonance (NMR) spectra for hydrogen atoms were measured
in the indicated solvent with (TMS) as the internal standard on a
BrukerBiospin Inc. DRX 500 (500 MHz) or DPX 300 (300 MHz)
spectrometer. The values are expressed in parts per million
downfield from TMS. The mass spectra (MS) were determined on a
Micromass Platform LC spectrometer, an Agilent LC spectrometer or a
Micromass LCT spectrometer using electrospray techniques. Microwave
accelerated reactions were performed using a CEM Discover microwave
instrument, and were contained in a sealed pressure vessel unless
otherwise noted. Stereoisomeric compounds may be characterized as
racemic mixtures or as separate diastereomers and enantiomers
thereof using X-ray crystallography and other methods known to one
skilled in the art. Unless otherwise noted, the materials used in
the examples were obtained from readily available commercial
suppliers or synthesized by standard methods known to one skilled
in the art of chemical synthesis. The substituent groups, which
vary between examples, are hydrogen unless otherwise noted.
Example 1
3-(4-Fluoro-benzyl)-6-methylsulfanyl-1-(4-trifluoromethoxy-benzyl)-1H-[1,3-
,5]triazine-2,4-dione (Cpd 1f)
##STR00024##
[0307] A. N-Methylcarbonyl-5-methylisothiourea (Cpd 1a)
[0308] A stirred suspension of S-methylisothiourea sulfate (46 g,
0.17 mol) in water (60 mL.) was heated to 60.degree. C. and then
cooled quickly to 0.degree. C. using an ice-salt bath. The aqueous
mixture was treated over 1 h with cold aqueous NaOH (60 mL
containing 13.2 g; 0.33 mol) while the internal temperature was
maintained at 5.degree. C. The thick pale green slurry obtained was
stirred 30 min at 5.degree. C., cooled to 0.degree. C., and treated
with cold methyl chloroformate (15.6 g, 0.17 mol) over 1 h while
maintaining the reaction temperature at 0-5.degree. C. Stirring was
continued for another 15 min at 0-5.degree. C. then the ice-salt
bath was removed and the mixture warmed to rt. The mixture was then
transferred to a separatory funnel and extracted with ethyl acetate
(2.times.60 mL). The aqueous layer was transferred to the reaction
flask, cooled to 0-5.degree. C., treated with cold aqueous NaOH (40
mL containing 19.8 g; 0.17 mol), and the resulting mixture was
stirred at 5.degree. C. for 30 min. After cooling to 0.degree. C.,
the mixture was treated with methyl chloroformate (7.8 g, 0.08 mol)
over 1 hr while maintaining the temperature at 0-5.degree. C. After
stirring for an additional 15 min, the mixture was extracted with
ethyl acetate (2.times.30 mL) and the extract was combined with the
previous one. The combined extracts were washed once with cold
brine (15 mL) and dried over Na.sub.2SO.sub.4. The solvent was
removed under reduced pressure and the resulting residue was
purified by a flash column on silica gel (10%-60% EtOAc in heptane)
to afford compound 1a as a white powder. .sup.1H-NMR (CDCl.sub.3)
.delta. 2.47 (s, 3H), 3.75 (s, 3H) and 7.28-8.35 (bs, 2H).
B.
3-(4-Fluoro-benzyl)-6-methylsulfanyl-1-(4-trifluoromethoxy-benzyl)-1H-[-
1,3,5]triazine-2,4-dione (Cpd 1b)
[0309] 4-Fluorobenzyl isocyanate (2.1 mL, 16.2 mmol) was added
dropwise over 3 min to a 5.degree. C. solution of 1a (2 g, 13.5
mmol) and Cs.sub.2CO.sub.3 (14.1 g, 43.2 mmol) in DMSO (20 mL). The
cooling bath was removed and the reaction was stirred toward rt. At
50 min, LC/MS analysis showed approximately 10% of compound 1a
remaining. An additional portion of 4-fluorobenzyl isocyanate (0.21
mL, 1.6 mmol) was added and after stirring for 20 min the reaction
was judged complete by LC/MS analysis. To the stirred rt mixture
was added 4-trifluoromethoxybenzyl bromide (5.2 mL, 32.5 mmol).
After stirring for 1 h, water (20 mL) was added, and the resulting
solution was loaded on a 100 mL SLE cartridge. Elution with DCM
(500 mL) was followed by concentration under vacuum to a
DMSO-containing residue. The residue was stored for 24 h at <0.5
mm Hg to remove most of the DMSO, then purified on a silica gel
flash column (20% EtOAc 75% EtOAc in heptane), to give compound 1b
as a white powder.
Example 2
6-[2-(2-Amino-3H-imidazol-4-yl)-ethylamino]-3-(4-fluoro-benzyl)-1-(4-trifl-
uoromethoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd 54)
##STR00025##
[0310] A.
N-{2-[2-(4-Bromo-phenylazo)-3H-imidazol-4-yl]-ethyl}acetamide (Cpd
2d)
[0311] A solution of sodium nitrite (2.3 g, 0.033 mol) in 32 mL of
water was cooled to 0.degree. C. and was added gradually to a
stirred, ice-cold solution of compound 1a (5.4 g, 0.031 mol) in 160
mL of 2.3 N hydrochloric acid. The solution of diazonium salt (2b)
was stored at approximately 0.degree. C. for 40 min and was then
added gradually to a stirred, ice-cold solution of 5.0 g (0.032
mol) of compound 2c) in 320 mL of 0.2 M sodium carbonate. The
mixture was stirred at ice temperature for 2 h before adjusting the
pH to about 10 with 3N NaOH.sub.(aq). The resulting yellow-orange
precipitate was collected and dried. A solution of the crude
product in the minimum volume of 20% methanol/chloroform was
applied to a column of flash grade silica gel which had been
previously equilibrated with 50% EtOAc/hexanes. The column was
eluted with a gradient, increasing to 20% methanol/EtOAc. The crude
mixture was purified to give compound 2d of sufficient purity for
use in the subsequent step.
B. N-[2-(2-Amino-3H-imidazol-4-yl)-ethyl]acetamide (Cpd 2e)
[0312] To a nitrogen-degassed/blanketed suspension of compound 2d
(3.2 g, 0.0096 mol) in 130 mL of absolute ethanol was added
platinum oxide (0.32 g, 0.0014 mol). The resulting slurry was
subjected to catalytic hydrogenation at ambient temperature at an
initial hydrogen pressure of 55 psi (Parr shaker). A hydrogen
pressure of >45 psi was maintained throughout the reduction
process. After the reaction mixture had been shaken for 23 h, the
catalyst was removed by filtration over Celite and the resulting
solution was concentrated. The residual mixture of compound 2e and
p-bromoaniline was used in the subsequent step without further
purification.
C. 5-(2-Amino-ethyl)-1H-imidazol-2-ylamine (Cpd 2f)
[0313] A solution of compound 2e (0.5 g) in 10 ml of 6 N
hydrochloric acid was heated at 100.degree. C. for 16 hr. The
solvent was removed in vacuo and the resulting residue was stored
at <1 mm Hg for 24 h. The resulting mixture of 2f and
p-bromoaniline were used without further purification.
D.
6-[2-(2-Amino-3H-imidazol-4-yl)-ethylamino]-3-(4-fluoro-benzyl)-1-(4-tr-
ifluoromethoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd 54)
[0314] To a solution of compound 2f (0.050 g, 0.12 mmol) in ethanol
(0.75 mL) was added compound 1b (72 mg, 0.36 mmol) and DIEA (0.084
mL, 0.48 mmol). The mixture was heated at 95.degree. C. for 17 h,
concentrated, and the resulting residue was purified by
reverse-phase liquid chromatography using a gradient of 90:10
(water:acetonitrile, with 0.1% TFA) to 90:10 (water:acetonitrile,
with 0.1% TFA) to give the title compound 54. HRMS calcd. for
C.sub.23H.sub.22F.sub.4N.sub.7O.sub.3 m/z 520.1720 (M+H). found:
520.1744.
[0315] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the general procedure of
Example 2, the following compounds were prepared:
TABLE-US-00001 MS obs Cpd MS obs MS calc Cpd (ES+) MS calc 6 452.13
451.18 65 488.19 487.23 53 502.00 501.17 66 502.21 501.21 59 516.16
515.12 67 503.17 502.22 60 476.22 475.23 68 515.19 514.22 61 494.14
493.19 79 552.02 551.11 62 490.19 489.21 80 530.10 529.17 63 528.14
527.12 81 512.14 511.21 64 506.14 505.19 82 526.14 525.19 83 539.15
538.20
Example 3
6-[2-(2-Amino-4H-quinazolin-3-yl)-ethylamino]-3-(4-fluoro-benzyl)-1-(4-met-
hoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd 12)
##STR00026## ##STR00027##
[0316] A. ((4-Fluorobenzyl)amino)carbonyl)carbamimidothioic acid
methyl ester (Cpd 3a)
[0317] S-methylisothiouronium sulfate (10.0 g, 35.9 mmol) was
dissolved in 8:2:1 MeOH/H.sub.2O/THF and the mixture was treated
with 3 N NaOH (12 mL, 35.9 mmol). The solution was then cooled to
0.degree. C. and 4-fluorobenzyl isocyanate (5.43 g, 35.9 mmol) was
added dropwise over 30 min. The reaction was stirred overnight and
gradually warmed to room temperature. The mixture was then washed
with saturated aqueous NH.sub.4Cl and extracted with
dichloromethane. The combined organic phases were dried over
Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure.
The resultant residue was purified on an Isco flash column (20%
EtOAc 100% EtOAc in heptanes), to give compound 3a (4.1 g) as a
white powder.
B.
5-(Methylthio)-3,7-dioxo-1-(4-fluorobenzyl)-2-oxa-4,6,8-triazanon-4-en--
9-oic acid methyl ester (Cpd 3b)
[0318] A solution of compound 3a (4.1 g, 17.0 mmol) in
dichloromethane was treated with triethylamine (3.08 mL, 22.1 mmol)
and the mixture was cooled to 10.degree. C. Methyl chloroformate
(2.62 mL, 34.0 mmol) was added dropwise via an addition funnel over
15 min and the reaction was allowed to stir for 4 h while gradually
warming to room temperature. The solution was then washed with
saturated aqueous NH.sub.4Cl and extracted with dichloromethane.
The combined organic phases were dried over Na.sub.2SO.sub.4,
filtered and concentrated. The resultant residue was purified on an
Isco flash column (5% MeOH) to afford compound 3b (3.63 g) as a
white solid.
C.
3-(4-Fluoro-benzyl)-6-methylsulfanyl-1H-[1,3,5]triazine-2,4-dione
(Cpd 3c)
[0319] Compound 3b (3.63 g, 12.1 mmol) was dissolved in MeOH (100
mL) and the solution was treated with NaOMe in MeOH (4.6 M, 2.90
mL, 13.3 mmol) and the reaction was allowed to stir at room
temperature for 1 h. A white precipitate formed upon addition of
the NaOMe. The reaction mixture was diluted with 1N HCl (50 mL) and
the resultant precipitate was collected by filtration. The solid
was dried under reduced pressure at 160.degree. C. over xylenes to
afford compound 3c (3.6 g) as its HCl salt.
D.
3-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-6-methylsulfanyl-1H-[1,3,5]tri-
azine-2,4-dione (Cpd 3d)
[0320] Compound 3c (500 mg, 1.65 mmol) was dissolved in THF and was
treated with 4-methoxybenzyl alcohol (227 mg, 1.65 mmol),
triphenylphospine (866 mg, 3.30 mmol), and diisopropyl
azodicarboxylate (334 mg, 1.65 mmol). The reaction was allowed to
stir overnight at room temperature. After monitoring the reaction
via HPLC, the solution was partitioned between water and ethyl
acetate. The combined organic layers were dried over anhydrous
sodium sulfate, filtered and reduced. The crude mixture was
purified via Isco flash column (20% ethyl acetate-100% ethyl
acetate in heptane, 40 min) to afford compound 3d as a white solid.
.sup.1H NMR (DMSO, d.sub.6). .delta. 3.29 (s, 3H), 3.74 (s, 3H),
4.93 (s, 2H), 5.03 (s, 2H), 6.89-6.92 (d, 2H, J=8.62), 7.12-7.36
(m, 4H), 7.38-7.41 (m, 2H).
E.
4-[3-(3,4-Dichloro-benzyl)-6-methylsulfanyl-2,4-dioxo-3,4-dihydro-2H-[1-
,3,5]triazin-1-ylmethyl]-benzamide (Alternative route to Cpd
3d)
[0321] Compound 3c (dichlorobenzyl) (200 mg, 0.56 mmol) was
dissolved in MeCN and was treated with diisopropylethylamine (0.196
mL, 1.13 mmol) and 4-chloromethyl benzyl chloride (96 mg, 0.56
mmol). The reaction mixture was heated to 80.degree. C. and was
allowed to stir overnight. The reaction mixture was washed with
saturated aqueous NH.sub.4Cl and extracted with ethyl acetate. The
combined organic extracts were dried over Na.sub.2SO.sub.4,
filtered and concentrated. The resultant crude mixture was purified
by Isco flash column (20% 100% EtOAc in heptanes, 40 min) to afford
compound 3d as a white powder.
F.
6-(2-Amino-ethylamino)-3-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-1H-[1,3-
,5]triazine-2,4-dione (Cpd 3e)
[0322] A solution of compound 3d (390 mg, 1.01 mmol) in toluene (8
mL) and was treated with ethylenediamine (302 mg, 5.03 mmol). The
reaction was heated to 90.degree. C. and was allowed to stir
overnight. The mixture was then partitioned between water and ethyl
acetate. The combined organic layers were dried over
Na.sub.2SO.sub.4, filtered and reduced to provide compound 3e as a
crude mixture. The crude compound was used in subsequent steps
without additional purification.
G.
3-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-6-[2-(2-nitro-benzylamino)-eth-
ylamino]-1H-[1,3,5]triazine-2,4-dione (Cpd 3f)
[0323] To a flask containing compound 3e (0.050 g, 0.13 mmol) in
DCE (0.5 mL) was added 2-nitrobenzaldehyde (0.022 g, 0.14 mmol).
After stirring at room temperature for 30 min, Na(OAc).sub.3BH
(0.055 g, 0.26 mmol) was added, and the reaction mixture was
stirred at room temperature for 18 h. The reaction mixture was
quenched with MeOH (0.1 mL)/isopropyl alcohol (0.5 mL),
concentrated to a residue, and stored at <1 mm Hg for 15
minutes. The resulting residue containing compound 3f and
approximately 30% of a dialkylated by-product was used in the
following step without further purification. HRMS calcd. for
C.sub.27H.sub.28FN.sub.6O.sub.5 m/z 535.2105 (M+H). found:
535.2123.
H.
6-[2-(2-Amino-4H-quinazolin-3-yl)-ethylamino]-3-(4-fluoro-benzyl)-1-(4--
methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd??)
[0324] To the above residue of compound 3f was added isopropyl
alcohol (0.5 mL), acetic acid (0.1 mL, 1.7 mmol), and Zn (0.051 g,
0.78 mmol). The reaction slurry was heated with stirring at
50.degree. C. for 20 min. After cooling to rt, the reaction mixture
was quenched with 50% aqueous NaOH (0.05 mL), stirred for 5
minutes, and loaded on a 1 g silica SPE cartridge. After 5 min the
organic products were eluted with a solution of 94%
CH.sub.2Cl.sub.2/5% MeOH/1% Et.sub.3N, (13 mL). The resulting
solution was concentrated and stored at <1 mm Hg for 18 h. The
resulting residue was used in the following step without further
purification. HRMS calcd. for C.sub.27H.sub.30FN.sub.6O.sub.3 m/z
505.2363 (M+H). found: 505.2374.
[0325] The above residue was dissolved in EtOH (0.5 mL),
CH.sub.2Cl.sub.2 (0.1 mL), and cyanogen bromide (0.065 mL, 0.195
mmol, 3M in CH.sub.2Cl.sub.2) was added. The resulting solution was
stirred for 6.5 h at room temperature. The reaction mixture was
quenched with 50% NaOH (0.05 mL), stirred for 5 minutes, and loaded
on a 1 g silica SPE cartridge. After 5 minutes the organics were
eluted with a solution of 94% CH.sub.2Cl.sub.2/5% MeOH/1%
Et.sub.3N, (13 mL). The resulting solution was concentrated and
stored at <1 mm Hg for 18 h. The resulting residue was purified
by preparative reverse phase HPLC to yield the title compound 12.
.sup.1H NMR (CDCl.sub.3) .delta. 3.45-3.82 (4H, m), 3.68 (3H, s),
4.41 (2H, s), 4.88 (2H, s), 5.05 (2H, s), 6.71-6.52 (12H, m), 7.62
(1H, bs), 8.39 (2H, bs). HRMS calcd. for
C.sub.28H.sub.29FN.sub.7O.sub.3 m/z 530.2316 (M+H). found:
530.2316.
[0326] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the general procedure of
Example 3, the following compounds were prepared:
TABLE-US-00002 MS obs Cpd (ES+) MS calc 41 566.23 565.20 42 600.14
599.17 43 600.17 599.17 44 600.18 599.17 45 584.23 583.20 46 584.20
583.20 48 618.16 617.16 49 618.22 617.16 50 618.22 617.16 51 602.19
601.19 52 602.19 601.19 56 582.21 581.20 57 596.22 595.22 58 566.23
565.20
Example 4
6-[2-(2-Amino-6-methyl-benzoimidazol-1-yl)-ethylamino]-3-(4-fluoro-benzyl)-
-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd 3)
##STR00028##
[0327] A.
3-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-6-[2-(5-methyl-2-nitro--
phenylamino)-ethylamino]-1H-[1,3,5]triazine-2,4-dione (Cpd 4a). To
a flask containing compound 3e (0.025 g, 0.063 mmol) in DMF (0.3
mL) was added 2-fluoro-4-methyl-nitrobenzene (0.011 g, 0.069 mmol).
The reaction was sealed and the mixture heated to 60.degree. C.
with stirring for 17 h. The mixture was cooled to rt and used in
the following step without further purification. HRMS calcd. for
C.sub.27H.sub.28FN.sub.6O.sub.5 m/z 535.2105 (M+H). found:
535.2117.
B.
6-[2-(2-Amino-6-methyl-benzoimidazol-1-yl)-ethylamino]-3-(4-fluoro-benz-
yl)-1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd 3)
[0328] To a solution of crude compound 4a was added isopropyl
alcohol (0.3 mL), acetic acid (0.050 mL, 0.85 mmol), and Zn (0.026
g, 0.39 mmol). The reaction slurry was heated with stirring at
65.degree. C. for 30 min. After cooling to rt, the reaction mixture
was quenched with 50% NaOH (0.05 mL), stirred for 5 minutes, and
loaded on a 1 g silica SPE cartridge. After 5 min the organics were
eluted with a solution of 94% CH.sub.2Cl.sub.2/5% MeOH/1%
Et.sub.3N, (13 mL). The resulting solution was concentrated and
stored at <1 mm Hg for 18 h. The resulting residue was used in
the following step without further purification. HRMS calcd. for
C.sub.27H.sub.30FN.sub.6O.sub.3 m/z 505.2363 (M+H). found:
505.2360.
[0329] The above residue was dissolved in EtOH (0.5 mL) and
cyanogen bromide (0.035 mL, 0.095 mmol, 3M in CH.sub.2Cl.sub.2) was
added. The resulting solution was stirred for 6.5 h at room
temperature. The reaction mixture was quenched with 50% NaOH (0.05
mL), stirred for 5 min, and loaded on a 1 g silica SPE cartridge.
After 5 minutes the organics were eluted with a solution of 94%
CH.sub.2Cl.sub.2/5% MeOH/1% Et.sub.3N, (13 mL). The resulting
solution was concentrated and stored at <1 mm Hg for 18 h. The
resulting residue was purified by preparative reverse phase HPLC to
yield the title compound 3. .sup.1H NMR (CDCl.sub.3) .delta. 2.32
(3H, s), 3.63 (3H, s), 3.67-3.81 (2H, m), 4.13-4.28 (2H, m), 4.87
(2H, s), 5.00 (2H, s), 6.70 (2H, J=8.59 Hz, d), 6.86-7.01 (4H, m),
7.05-7.16 (3H, m), 7.33 (2H, dd, J=8.72 and 3.16 Hz), 7.71 (1H,
bs), 8.73 (2H, bs). HRMS calcd. for C.sub.28H.sub.29FN.sub.7O.sub.3
m/z 530.2316 (M+H). found: 530.2316.
[0330] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the general procedure of
Example 4, the following compounds were prepared:
TABLE-US-00003 MS obs Cpd (ES+) MS calc 5 534.05 533.20 7 530.19
529.22 8 584.03 583.20 9 594.16 593.19 10 550.14 549.17 11 534.17
533.20 14 532.20 531.18 15 599.30 599.27 17 611.19 20 552.16 551.19
24 593.20 25 570.12 569.18 26 570.13 569.18 27 620.15 619.18 28
588.16 587.17 29 588.13 587.17 30 586.14 585.15 31 570.14 569.18 32
570.14 569.18 33 588.13 587.17 34 588.13 587.17 35 638.12 637.17 36
606.11 605.16 37 606.11 605.16 38 604.14 603.14 39 588.12 587.17 40
588.12 587.17 55 582.21 581.20 69 566.15 565.14 70 544.14 543.21 71
526.20 525.25 72 540.23 539.23 73 578.11 577.14 74 556.16 555.21 75
538.19 537.25 76 552.20 551.23 77 553.23 552.23 78 565.25 564.23 84
601.89 601.12 85 579.96 579.19 86 562.00 561.23 87 576.01
575.21
Example 5
6-[2-(2-Amino-imidazol-1-yl)-ethylamino]-3-(4-fluoro-benzyl)-1-(4-methoxy--
benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd 2)
##STR00029##
[0331] A. [2-(2-Amino-imidazol-1-yl)-ethyl]-carbamic acid
tert-butyl ester (Cpd 5b)
[0332] To a flask containing 2-aminoimidazole sulfate 5a (1 g, 3.8
mmol) in DMF (20 mL) was added sodium hydride (0.65 g, 16.3 mmol)
in small portions with stirring. The temperature was maintained
below 30.degree. C. during the addition by means of an ice bath.
After stirring for 30 minutes at 25-30.degree. C., the solution was
cooled to 0.degree. C. and (2-bromo-ethyl)-carbamic acid tert-butyl
ester (1.7 g, 7.6 mmol) in DMF (1 mL) was added. After stirring for
1 min the cooling bath was removed and the solution was stirred
toward rt for 16 h. The reaction was carefully quenched with water
(10 mL), extracted with EtOAc (4.times.10 mL), dried over sodium
sulfate, filtered, and concentrated to a residue. The residue was
stored at <0.5 mm Hg for 24 h to remove residual DMF, then
purified by normal phase chromatography to give compound 5b (0.29
g) as a brown glass. HRMS calcd. for C.sub.10H.sub.19N.sub.4O.sub.2
m/z 227.1508 (M+H). found: 227.1518.
B. 1-(2-Amino-ethyl)-1H-imidazol-2-ylamine xTFA (Cpd 5c)
[0333] To a flask containing 5b (0.059 g, 0.26 mmol) in DCM (2 mL)
at rt was added TFA (2 mL). The resulting solution was stirred at
rt for 1 h then concentrated to a residue, stored at <0.5 mm Hg
for 1 h, and used directly without further purification.
C.
6-[2-(2-Amino-3H-imidazol-4-yl)-ethylamino]-3-(4-fluoro-benzyl)-1-(4-tr-
ifluoromethoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd 2)
[0334] To a solution of compound 3d (0.050 g, 0.13 mmol) in ethanol
(0.75 mL) was added crude 5c (0.26 mmol) and DIEA (0.068 mL, 0.39
mmol). The mixture was heated at 95.degree. C. for 17 h,
concentrated, and the resulting residue was purified by
reverse-phase liquid chromatography using a gradient of 90:10
(water:acetonitrile, with 0.1% TFA) to 90:10 (water:acetonitrile,
with 0.1% TFA) to give the title compound 2. .sup.1H NMR
(CDCl.sub.3) 6, 3.60-3.71 (2H, m), 3.74 (3H, s), 3.88-3.97 (2H, m),
4.97 (2H, s), 5.07 (2H, s), 6.03 (1H, s), 6.31 (1H, s), 6.79 (2H,
d, J=8.77 Hz), 6.96 (2H, at, J=8.74 Hz), 7.15 (2H, d, J=8.18 Hz),
7.37 (1H, d, J=7.37 Hz), 7.39 (1H, d, J=8.23 Hz), 7.81 (2H, bs),
12.67 (1H, bs). HRMS calcd. for C.sub.23H.sub.25FN.sub.7O.sub.3 m/z
466.2003 (M+H). found: 466.2008.
[0335] Other compounds of the present invention may be prepared by
those skilled in the art by varying the starting materials,
reagent(s) and conditions used. Using the general procedure of
Example 5, the following compounds were prepared:
TABLE-US-00004 MS obs Cpd (ES+) MS calc 2 466.19 465.19 18 549.6
549.25 19 570.19 569.18 21 454.09 453.17 22 520.04 519.16 23 502.15
501.17
Example 6
6-[2-(1H-Benzoimidazol-2-ylamino)-ethylamino]-3-(3,4-dichloro-benzyl)-1-(4-
-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione (Cpd 1)
##STR00030##
[0337] A. To compound 6a (5 g, 25.5 mmol) suspended in methanol (50
mL) was added methyl iodide (4.8 mL, 0.076 mmol) and the reaction
was heated to 50.degree. C. for 15 min. The reaction was
concentrated to a residue to give compound 6b. Compound 6b was used
without further purification for the next reaction.
[0338] B. To compound 6b (25.5 mmol) dissolved in dry THF (50 mL)
was added cesium carbonate (25 g, 76 mmol) and the reaction was
cooled to -78.degree. C. A solution of chlorocarbonyl-isocyanate
(2.2 mL) in 10 mL THF was added to compound 6b and the reaction was
stirred toward rt for 3 h at which time phenyl isocyanatoformate (2
mL) was added. Stirring was continued for 2 h. The residue was
taken up in DMSO (50 mL) and 3,4-dichlorobenzyl bromide (7.3 g, 31
mmol) was added to the reaction. After 30 min of stirring, water
(50 mL) was added to the reaction mixture and the aqueous phase was
extracted with 4.times.50 mL ethyl ether. The combined ether
extracts were dried, filtered, and concentrated under reduced
pressure. The resulting residue was purified by normal phase column
chromatography (10-75% EtOAc in heptane) to elute compound 6c.
[0339] C. To compound 6c (0.5 g, 1.1 mmol) in toluene (4 mL) in a
microwave vessel was added ethylene diamine (382 L, 5.7 mL) and the
mixture was heated at 160.degree. C. for 10 min. At that time,
xylenes were added (10 mL) and the mixture was concentrated and
stored under reduced pressure for approximately 16 h. Compound 6d
was used in subsequent reactions without further purification.
[0340] D. To compound 6d (0.050 g, 0.11 mmol) in ethanol in a
microwave vessel was added compound 6e (0.017 mg, 0.11 mmol) and
Et.sub.3N (25 L, 0.14 mmol) and the mixture was heated at
180.degree. C. for 25 min. At that time, the mixture was
concentrated, and the resulting residue was purified by
reverse-phase liquid chromatography using a gradient of 90:10
(water:acetonitrile, with 0.1% TFA) to 90:10 (water:acetonitrile,
with 0.1% TFA) to give the title compound 1.
C.sub.27E1.sub.26Cl.sub.2N.sub.7O.sub.3 calc=566.15.
found=566.16.
Example 7
Cpd 16: A mixture of
3-(4-Fluoro-benzyl)-1-(4-methoxy-benzyl)-6-[2-(2-methylamino-benzoimidazo-
l-1-yl)-ethylamino]-1H-[1,3,5]triazine-2,4-dione and
6-[2-(2-Dimethylamino-benzoimidazol-1-yl)-ethylamino]-3-(4-fluoro-benzyl)--
1-(4-methoxy-benzyl)-1H-[1,3,5]triazine-2,4-dione
##STR00031##
[0342] To the tri-hydrochloride salt of compound 3 (0.028 g, 0.045
mmol) in DCM (5 mL) was added methyl iodide (3.1 L, 0.05 mmol) and
DIEA (30 L, 0.27 mmol), and the reaction was allowed to stir at rt.
After 4 h, an additional 10 L of DIEA was added, and stirring at rt
was continued. After approximately 12 h, an additional 3.1 L of
methyl iodide and 10 L of DIEA was added. After 4 more hours, an
additional 3.1 L of methyl iodide was added. After approximately 12
h, an additional 3.1 L of methyl iodide and 10 L of DIEA was added.
Finally, 10 L of methyl iodide and 20 L of DIEA was added to
completion of the reaction. Over 6 d, a total of 42.4 L of methyl
iodide and 95 L of DIEA was added. The reaction was concentrated
and purified by reverse-phase liquid chromatography to afford 60%
of the mono-methylated product and 40% of the dimethylated product
as a mixture.
Example 8
##STR00032##
[0344] A. Compound 8c was prepared according to the methods
described in Example 4, Steps A and B, substituting compound 8a for
compound 3e, and substituting 2-fluoro-nitrobenzene for
2-fluoro-4-methyl-nitrobenzene in Step A. In Step B, compound 8b
was substituted for compound 4a.
[0345] B. To compound 8c was added a 1:1 mixture of TFA and
methylene chloride, and the mixture was stirred at rt for 24 hrs.
At this time, the mixture was washed sequentially with water and
saturated aqueous sodium bicarbonate, and the organic phase was
concentrated to a residue of compound 8d, which was used in
subsequent steps without further purification.
Example 9
1,3-Bis-(4-methoxy-benzyl)-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carbo-
xylic acid [2-(2-amino-benzoimidazol-1-yl)-ethyl]-amide (Cpd
13)
##STR00033##
[0347] A. To compound 9a (1.00 g, 4.7 mmol) in THF (50 mL) was
added triphenyl phosphine (5.0 g) and 4-methoxybenzyl alcohol (2.00
g, 14.1 mmol) at rt. To the mixture was added DIAD (3.80 g) in one
portion and the reaction was stirred overnight at rt. The mixture
was then diluted with water, extracted with EtOAc, dried, filtered,
and concentrated to a residue under reduced pressure. The residue
was purified by normal phase chromatography (heptane: EtOAc, 9:1 to
3:1) to give compound 9b.
[0348] B. Compound 9b was taken up in MeOH/H.sub.2O (60 mL, 5:1)
and lithium hydroxide monohydrate (0.5 g) was added to the mixture.
The reaction was stirred for 48 h at rt. The mixture was then
concentrated and purified by reverse-phase liquid chromatography to
give compound 9c.
[0349] C. Compound 9c (0.075 g) was dissolved in DCM (3 mL) and one
drop of DMF. To this mixture was added oxalyl chloride and the
reaction was stirred at rt for 2 h to give compound 9d which was
used without further purification.
[0350] D. To the reaction mixture of compound 9d dissolved in
dichloromethane and DIEA was added amine 8d (1.2 equiv). Upon
completion, the reaction was diluted with water and extracted with
DCM. The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced pressure
to afford compound 13.
[0351] Using the methods described in the schemes and specific
examples, and adaptations thereof, compounds 1 to 87 of Table 1
were prepared.
TABLE-US-00005 Formula (Ia) ##STR00034## Cpd No. A.sub.1 D W
L.sub.2 Q 1 3,4- 4-methoxy- N --NH(CH.sub.2).sub.2-- 1H-benzo-
dichloro- phenylmethyl imidazol-2-ylamino phenyl 2 4-fluoro-
4-methoxy- N --NH(CH.sub.2).sub.2-- 2-amino-imidazol-1-yl phenyl
phenylmethyl 3 4-fluoro- 4-methoxy- N --NH(CH.sub.2).sub.2--
2-amino- phenyl phenylmethyl benzoimidazol-1-yl 4 4-fluoro-
4-methoxy- N --NH(CH.sub.2).sub.2-- 2-amino-3H-imidazol-4- phenyl
phenylmethyl yl 5 4-fluoro- 4-methoxy- N --NH(CH.sub.2).sub.2--
2-amino-5-fluoro- phenyl phenylmethyl benzoimidazol-1-yl 6
4-fluoro- 4-methoxy- N --NHCH.sub.2-- 2-amino-1H-imidazol-4- phenyl
phenylmethyl yl 7 4-fluoro- 4-methoxy- N --NH(CH.sub.2).sub.2--
2-amino-6-methyl- phenyl phenylmethyl benzoimidazol-1-yl 8
4-fluoro- 4-methoxy- N --NH(CH.sub.2).sub.2-- 2-amino-5- phenyl
phenylmethyl trifluoromethyl- benzoimidazol-1-yl 9 4-fluoro-
4-methoxy- N --NH(CH.sub.2).sub.2-- 2-amino-5- phenyl phenylmethyl
methanesulfonyl- benzoimidazol-1-yl 10 4-fluoro- 4-methoxy- N
--NH(CH.sub.2).sub.2-- 2-amino-6-chloro- phenyl phenylmethyl
benzoimidazol-1-yl 11 4-fluoro- 4-methoxy- N --NH(CH.sub.2).sub.2--
2-amino-4-fluoro- phenyl phenylmethyl benzoimidazol-1-yl 12
4-fluoro- 4-methoxy- N --NH(CH.sub.2).sub.2-- 2-amino-4H- phenyl
phenylmethyl quinazolin-3-yl 13 4-methoxy- 4-methoxy- CH
--C(O)NH(CH.sub.2).sub.2-- 2-amino- phenyl phenylmethyl
benzoimidazol-1-yl 14 4-chloro- 4-methoxy- N --NH(CH.sub.2).sub.2--
2-amino- phenyl phenylmethyl benzoimidazol-1-yl 15 4-fluoro-
4-methoxy- N --NH(CH.sub.2).sub.2-- 2-t-butylcarbonylamino- phenyl
phenylmethyl benzoimidazol-1-yl 16 4-fluoro- 4-methoxy- N
--NH(CH.sub.2).sub.2-- a mixture of phenyl phenylmethyl
2-methylamino- benzoimidazol-1-yl and 2-dimethylamino-
benzoimidazol-1-yl 17 4-fluoro- 4-methoxy- N --NH(CH.sub.2).sub.2--
2- phenyl phenylmethyl trifluoromethylcarbonyl- amino-
benzoimidazol-1-yl 18 4-fluoro- 4-methoxy- N --NH(CH.sub.2).sub.2--
2-t-butylcarbonylamino- phenyl phenylmethyl imidazol-1-yl 19
4-fluoro- 4- N --NH(CH.sub.2).sub.2-- 2-amino- phenyl
trifluoromethoxy- benzoimidazol-1-yl phenylmethyl 20 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino- phenyl difluoromethoxy-
benzoimidazol-1-yl phenylmethyl 21 4-fluoro- 4-fluoro- N
--NH(CH.sub.2).sub.2-- 2-amino-imidazol-1-yl phenyl phenylmethyl 22
4-fluoro- 4- N --NH(CH.sub.2).sub.2-- 2-amino-imidazol-1-yl phenyl
trifluoromethoxy- phenylmethyl 23 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-imidazol-1-yl phenyl
difluoromethoxy- phenylmethyl 24 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-methylcarbonylamino- phenyl
difluoromethoxy- benzoimidazol-1-yl phenylmethyl 25 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-fluoro- phenyl difluoromethoxy-
benzoimidazol-1-yl phenylmethyl 26 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 5-fluoro-2-amino- phenyl difluoromethoxy-
benzoimidazol-1-yl phenylmethyl 27 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-5- phenyl difluoromethoxy-
trifluoromethyl- phenylmethyl benzoimidazol-1-yl 28 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-4,6-difluoro- phenyl
difluoromethoxy- benzoimidazol-1-yl phenylmethyl 29 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6,7-difluoro- phenyl
difluoromethoxy- benzoimidazol-1-yl phenylmethyl 30 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-chloro- phenyl difluoromethoxy-
benzoimidazol-1-yl phenylmethyl 31 4-fluoro- 4- N
--NH(CH.sub.2).sub.3-- 2-amino-4-fluoro- phenyl difluoromethoxy-
benzoimidazol-1-yl phenylmethyl 32 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-7-fluoro- phenyl difluoromethoxy-
benzoimidazol-1-yl phenylmethyl 33 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-fluoro- phenyl trifluoromethoxy-
benzoimidazol-1-yl phenylmethyl 34 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-5-fluoro- phenyl trifluoromethoxy-
benzoimidazol-1-yl phenylmethyl 35 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-5- phenyl trifluoromethoxy-
trifluoromethyl- phenylmethyl benzoimidazol-1-yl 36 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-4,6-difluoro- phenyl
trifluoromethoxy- benzoimidazol-1-yl phenylmethyl 37 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6,7-difluoro- phenyl
trifluoromethoxy- benzoimidazol-1-yl phenylmethyl 38 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-chloro- phenyl trifluoromethoxy-
benzoimidazol-1-yl phenylmethyl 39 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-4-fluoro- phenyl trifluoromethoxy-
benzoimidazol-1-yl phenylmethyl 40 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-7-fluoro- phenyl trifluoromethoxy-
benzoimidazol-1-yl phenylmethyl 41 4-fluoro- 4- N
--NH(CH.sub.2).sub.4-- 2-amino-4H- phenyl difluoromethoxy-
quinazolin-3-yl phenylmethyl 42 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-5-chloro-4H- phenyl difluoromethoxy-
quinazolin-3-yl phenylmethyl 43 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-chloro-4H- phenyl difluoromethoxy-
quinazolin-3-yl phenylmethyl 44 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-7-chloro-4H- phenyl difluoromethoxy-
quinazolin-3-yl phenylmethyl 45 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-fluoro-4H- phenyl difluoromethoxy-
quinazolin-3-yl phenylmethyl 46 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-7-fluoro-4H- phenyl difluoromethoxy-
quinazolin-3-yl phenylmethyl 47 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-4H- phenyl trifluoromethoxy-
quinazolin-3-yl phenylmethyl 48 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-5-chloro-4H- phenyl
trifluoromethoxy- quinazolin-3-yl phenylmethyl 49 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-chloro-4H- phenyl
trifluoromethoxy- quinazolin-3-yl phenylmethyl 50 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-7-chloro-4H- phenyl
trifluoromethoxy- quinazolin-3-yl phenylmethyl 51 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-fluoro-4H- phenyl
trifluoromethoxy- quinazolin-3-yl phenylmethyl 52 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-7-fluoro-4H- phenyl
trifluoromethoxy- quinazolin-3-yl phenylmethyl 53 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- phenyl difluoromethoxy-
imidazol-4-yl phenylmethyl 54 4-fluoro- 4- N --NH(CH.sub.2).sub.2--
2-amino-3H- phenyl trifluoromethoxy- imidazol-4-yl phenylmethyl 55
4-fluoro- 4- N --NH(CH.sub.2).sub.2-- 2-amino-4-methoxy- phenyl
difluoromethoxy- benzoimidazol-1-yl phenylmethyl 56 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-6-hydroxy-4H- phenyl
difluoromethoxy- quinazolin-3-yl phenylmethyl 57 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-7-methoxy-4H- phenyl
difluoromethoxy- quinazolin-3-yl phenylmethyl 58 4-fluoro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-4H- phenyl difluoromethoxy-
quinazolin-1-yl phenylmethyl 59 3,4- 4-methoxy- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- dichloro- phenylmethyl
imidazol-4-yl phenyl 60 4-ethyl- 4-methoxy- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- phenyl phenylmethyl
imidazol-4-yl 61 4- 4-methoxy- N --NH(CH.sub.2).sub.2-- 2-amino-3H-
methylthio- phenylmethyl imidazol-4-yl phenyl 62 2,3-dihydro-
4-methoxy- N --NH(CH.sub.2).sub.2-- 2-amino-3H- benzofuran-
phenylmethyl imidazol-4-yl 5-yl 63 3,4- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- dichloro- benzofuran-5-
imidazol-4-yl phenyl ylmethyl 64 4- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- methylthio- benzofuran-5-yl-
imidazol-4-yl phenyl methyl 65 4-ethyl- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- phenyl benzofuran-5-
imidazol-4-yl ylmethyl 66 2,3-dihydro- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- benzofuran- benzofuran-5-yl-
imidazol-4-yl 5-yl methyl 67 1-methyl- 4-methoxy- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- 1H- phenylmethyl imidazol-4-yl
benzotriazol- 5-yl 68 1-methyl- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- 1H- benzofuran-5-yl-
imidazol-4-yl benzotriazol- methyl 5-yl 69 3,4- 4-methoxy- N
--NH(CH.sub.2).sub.2-- 2-amino- dichloro- phenylmethyl
benzoimidazol-1-yl phenyl 70 4- 4-methoxy- N --NH(CH.sub.2).sub.2--
2-amino- methylthio- phenylmethyl benzimidazol-1-yl phenyl 71
4-ethyl- 4-methoxy- N --NH(CH.sub.2).sub.2-- 2-amino- phenyl
phenylmethyl benzoimidazol-1-yl 72 2,3-dihydro- 4-methoxy- N
--NH(CH.sub.2).sub.2-- 2-amino- benzofuran- phenylmethyl
benzoimidazol-1-yl 5-yl 73 3,4- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino- dichloro- benzofuran-5-yl-
benzoimidazol-1-yl phenyl methyl 74 4- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino- methylthio- benzofuran-5-yl-
benzoimidazol-1-yl phenyl methyl 75 4-ethyl- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino- phenyl benzofuran-5-yl-
benzoimidazol-1-yl methyl 76 2,3-dihydro- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino- benzofuran- benzofuran-5-yl-
benzoimidazol-1-yl 5-yl methyl 77 1-methyl- 4-methoxy- N
--NH(CH.sub.2).sub.2-- 2-amino- 1H- phenylmethyl benzoimidazol-1-yl
benzotriazol- 5-yl 78 1-methyl- 2,3-dihydro- N
--NH(CH.sub.2).sub.2-- 2-amino- 1H- benzofuran-5-
benzoimidazol-1-yl benzotriazol- ylmethyl 5-yl 79 3,4- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- dichloro- difluoromethoxy-
imidazol-4-yl phenyl phenylmethyl 80 4- 4- N --NH(CH.sub.2).sub.2--
2-amino-3H- methylthio- difluoromethoxy- imidazol-4-yl phenyl
phenylmethyl 81 4-ethyl- 4- N --NH(CH.sub.2).sub.2-- 2-amino-3H-
phenyl difluoromethoxy- imidazol-4-yl phenylmethyl 82 2,3-dihydro-
4- N --NH(CH.sub.2).sub.2-- 2-amino-3H- benzofuran-
difluoromethoxy- imidazol-4-yl 5-yl phenylmethyl 83 1-methyl- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-3H- 1H- difluoromethoxy-
imidazol-4-yl benzotriazol- phenylmethyl 5-yl 84 3,4- 4- N
--NH(CH.sub.2).sub.2-- 2-amino-
dichloro- difluoromethoxy- benzoimidazol-1-yl phenyl phenylmethyl
85 4- 4- N --NH(CH.sub.2).sub.2-- 2-amino- methylthio-
difluoromethoxy- benzoimidazol-1-yl phenyl phenylmethyl 86 4-ethyl-
4- N --NH(CH.sub.2).sub.2-- 2-amino- phenyl difluoromethoxy-
benzoimidazol-1-yl phenylmethyl 87 2,3-dihydro- 4- N
--NH(CH.sub.2).sub.2-- 2-amino- benzofuran- difluoromethoxy-
benzoimidazol-1-yl 5-yl phenylmethyl
BIOLOGICAL EXAMPLES
Biological Example 1
Expression, Isolation, and Purification of Prokineticin-1
[0352] Recombinant N-terminal FLAG-tagged human prokineticin-1
(sequence-MRGATRVSIMLLLVTVSDCDYKDDDDKAVITGACERDVQCGAGTCCAISLWL
RGLRMCTPLGREGEECHPGSHKVPFFRKRKHHTCPCLPNLLCSRFPDGRYR CSMDLKNINF) was
expressed in stably transfected HEK 293 cells.
[0353] HEK 293 cells were grown to 100% confluence in DMEM
selective high-glucose media (Invitrogen, Carlsbad, Calif.)
containing 10% FBS, 20 mM HEPES, sodium pyruvate, penicillin and
streptomycin (50 g/ml each), and G418 (400 mg/L). The DMEM media
used to culture the HEK 293 cells was replenished every other day
with fresh media over a two-week period of time. Culture media
containing the PK-1 peptide was collected, and filtered in 500 mL
0.2 m pore size filters (Corning Incorporated, Corning, N.Y.). The
filtrate was stored in a filtrate bottle at 4.degree. C. The PK-1
peptide containing media was purified by gravity flow passage of
media over M2 agarose columns (Sigma Chemical, St. Louis, Mo.) at
4.degree. C. Following media passage, the agarose columns were
washed with sterile 1.times.PBS (pH 7.4) until protein could no
longer be detected by OD 280 nm. Columns were then eluted with a
0.1 M glycine-HCl solution at pH 2.8. The eluted material was
immediately neutralized, by collecting into tubes containing 1M
Tris pH 8. Peak fractions were identified by OD 280 and pooled. The
pooled fractions were subjected to Enterokinase cleavage of Flag
epitope 4 units/mL overnight at room temperature. Enterokinase was
removed, and sample aliquot was stored at 80.degree. C.
Results of Mass Spectral Analysis of Prokineticin 1 Ligand from
above Purification
[0354] The samples were analyzed using Maldi TOF-MS and
LC-Electrospray-Mass Spectral Analysis.
Desired Protein Sequence:
TABLE-US-00006 [0355]
AVITGACERDVQCGAGTCCAISLWLRGLRMCTPLGREGEECHPGSHKVPF
FRKRKHHTCPCLPNLLCSRFPDGRYRCSMDLKNINF
Calculated Avg. Molecular Mass=9667.4.
MALDI-TOF Analysis
Sample Preparation
[0356] The protein sample solution (10 L) was desalted using a C4
Zip Tip according to the User Guide for Reversed-Phase ZipTip, 2002
Millipore Corporation.
Mass Spectrometry
[0357] A Micromass TOF Spec E mass spectrometer was used to
determine molecular mass. MassLynx software 3.4 was used for the
system control and data acquisition. MALDI positive ion mass
spectra were acquired over a mass range of 0-80,000 Da. The raw MS
data were baseline subtracted and smoothed using Masslynx software
and compared to the masses obtained from a reference standard.
[0358] Masses of eluting components were calculated using the
Agilent deconvolution software.
[0359] The mass spectral data shows the presence of the desired
protein (molecular mass=9667) and an additional related component
with a measured molecular mass of 9172 in about the same abundance
based on mass spectral response. This mass agrees, within
measurement error, with a possible truncation product missing the
last four C-terminal residues indicated below.
Proposed Additional Protein Component Sequence
TABLE-US-00007 [0360]
AVITGACERDVQCGAGTCCAISLWLRGLRMCTPLGREGEECHPGSHK
VPFFRKRKHHTCPCLPNLLCSRFPDGRYRCSMDLK
Calculated Avg. Molecular Mass=9178.8.
[0361] No other related protenaceous components were detected. The
mass accuracy for all measurements is approximately 0.1%.
Biological Example 2
Functional Assay
Screening Procedure for PK1 Antagonists on the Fluorometric Imaging
Plate Reader (FLIPR)
[0362] At a time of 24 h prior to running the assay, in cell
culture media (DMEM containing high Glucose and L-glutamine, 10%
FBS, 1% Pen/Streptomycin, 1% Sodium Pyruvate, 20 mM HEPES, Zeocin
200 mg/L), 100 L of 1.3*10.sup.6/ml HEK 293 GPR73 (prokineticin 1
receptor) expressing cells were plated in a 96 well poly-d-lysine
coated plate (Costar), and incubated at 37.degree. C. and 5%
CO.sub.2. On the day in which the assay was run, the media was
removed and 200 L of 5.times. Calcium Plus Dye (Molecular Devices)
which was previously resuspended with 200 mL of assay buffer [HBSS
w/ Ca.sup.2+ and Mg.sup.2+ w/o phenol red, 20 mM HEPES, 0.1% BSA,
10 mL probenecid (710 mg probenecid in 5 mL of 1N NaOH, to which
was then added 5 mL HBSS containing 20 mM HEPES)] was added to each
well of the 96-well plate. The plate was incubated at 37.degree. C.
and 5% CO.sub.2 for 30 min in dark. The plate was removed and
allowed to reach RT for 15 min in the dark. The assay was then run
on the FLIPR. In Brief: base line read for 1 min, compound added
(25 L) and incubated for 4 min, 15 seconds, PK1 ligand preparation
added (25 L) for a final concentration of a previously determined
EC.sub.50 and fluorescence was counted for 1 min, 45 seconds.
Baseline is described as the amount of relative fluorescence read
when buffer alone is added to cells. Baseline was subtracted from
all wells.
Percent of control was calculated as follows:
(Baseline subtracted well value is divided by baseline subtracted
max value)*100. Percent inhibition is 100 minus the percent of
control value.
[0363] The IC.sub.50 is defined as the amount of a given compound
required to inhibit 50% of the maximum signal that is generated by
the concentration of PK1 preparation used in our assay. IC.sub.50
values were calculated using GraphPad Prism.
[0364] Table 2 includes data generated from the PK1 functional
assay described in Example 2.
Biological Data
TABLE-US-00008 [0365] TABLE 2 Ca.sup.2+ Ca.sup.2+ Ca.sup.2+
Mobilization Mobilization Ca.sup.2+ Mobilization Mobilization Cpd
IC50 (M) IC50 (M) % Inh @10 M % Inh @10 M 1 >10 40.4 2 0.019
0.005 97 97 2 0.497 98 3 0.008 0.029 96 94 4 0.048 0.042 97 96 5
0.069 102 6 0.322 91 7 0.123 93 8 0.163 95 9 2.29 67 10 0.155 90 11
0.146 89 12 0.028 94 13 7.39 51 14 0.077 95 15 0.797 93 16* >10
42 17 0.419 96 18 0.106 99 19 0.104 0.212 102 100 20 0.053 0.052
103 101 21 >10 37 22 0.061 100 23 0.028 0.057 100 97 24 7.91 47
25 0.17 87 26 0.081 0.015 92 88 27 0.31 85 28 >10 39 29 0.406 83
30 0.252 86 31 1.28 67 32 0.132 94 33 0.323 93 34 0.363 87 35 5.01
59 36 8.24 50 37 2.2 72 38 0.67 84 39 0.38 80 40 0.969 91 41 0.129
101 42 0.063 101 43 0.111 101 44 0.118 103 45 0.092 101 46 0.061
101 47 0.123 100 48 0.116 101 49 0.233 103 50 0.332 99 51 0.996 99
52 0.359 104 53 0.036 0.015 93 100 54 0.027 0.097 96 95 54 0.183 91
55 0.233 91 56 0.161 100 57 0.144 95 58 0.171 96 59 0.049 96 60
0.295 85 61 0.021 0.019 101 102 62 0.241 97 63 2.01 54 64 0.17 93
65 >10 35 66 2.42 69 67 0.171 93 68 1.41 78 69 0.066 102 70
0.022 103 71 0.09 101 72 0.058 102 73 0.186 90 74 0.034 102 75
0.507 83 76 0.225 97 77 0.055 99 78 0.066 0.13 102 104 79 0.102 96
80 0.032 98 81 0.502 90 82 0.202 96 83 0.224 98 84 0.345 97 85
0.157 99 86 0.337 94 87 0.223 102 *Compound 16 was tested as a
mixture of two compounds, as described in Table 1, hereinabove.
Biological Example 3
Effect of P1<1 on Secretion and Gut Mucosal Ion Transport in
Mammals
[0366] Methodology.
[0367] Segments of ileum starting at a point 2 cm proximal to the
ileocecal junction and extending 10 cm proximally were freshly
excised, placed into Krebs-Ringer bicarbonate (KRB) solution, and
emptied of their contents as a plastic rod was gently inserted into
the intact segment. Ileal segments were scored with the back-edge
of scalpel blade along the entire mesenteric border, and the intact
muscular layers including the myenteric plexus were carefully
removed with flat-head forceps. Three rectangular tissue sheets
approximately 1.5 cm in length were prepared from the remaining
muscle-stripped, mucosa-submucosa tissues and cut with care taken
to avoid Peyer's patches. Each tissue sheet containing intact
submucosal ganglia was pinned over a rectangular portal (total
cross-sectional area of exposed mucosa=0.50 cm.sup.2) between
halves of an acrylic mounting cassette that was inserted between
the tissue-bathing reservoirs of a modified Ussing-type flux
chamber (Physiologic Instruments, Inc., San Diego, Calif.).
[0368] The apical (i.e., mucosal) and basolateral (i.e., serosal)
surface of each tissue was bathed with 6 ml of an oxygenated KRB
solution maintained at 36.degree. C. Once mounted, tissues were
allowed to equilibrate for 0.5-1 h before electrical field
stimulation and addition of secretagogues or drugs. The KRB
solution contained (in mM) 120 NaCl, 6 KCl, 1.2 MgCl.sub.2, 1.2
NaH.sub.2PO.sub.4, 14.4 NaHCO.sub.3, 2.5 CaCl.sub.2, and 11.5
glucose or 11.5 mannitol. The KRB solution was continuously aerated
with 95% O.sub.2: 5% CO.sub.2 and maintained at pH 7.3. Each
chamber was equipped with a pair of saturated KCl-agar bridges for
measurement of transmural electrical potential difference (PD)
across the tissue, and a pair of Ag--AgCl agar electrodes connected
to an automated voltage-clamp device (model VCC MC6, or model VCC
MC8, Physiologic Instruments, Inc., San Diego, Calif.) that
compensated for solution resistance between the PD-sensing bridges
and for deviations detected from a transmural potential difference
(PD) across the tissues that were clamped at 0 mV. Tissue
conductance (G) was calculated (in mS) by determining the current
necessary to change PD by 1 mV using bipolar pulses from a pulse
generator. Short-circuit current (lsc in A), an index of net active
ion transport, was measured continuously. Tissue conductance (Gt in
mS), an index of the barrier function to passive flow of ions, was
calculated from changes in lsc and the transepithelial potential
difference for each tissue.
[0369] Baseline recordings of short-circuit current (lsc) and G for
each tissue were acquired and recorded for an additional 15 min
period prior to the start of an experimental protocol. Stimulated
changes in lsc were measured and recorded continuously with a
computerized data acquisition system (PowerLab 8SP, ADInstruments,
Inc., Colorado Springs, Colo.). Neurally-evoked changes in lsc were
obtained by application of electrical field stimulation (80V, 0.5
ms, 10 Hz, 5 s) from the outputs of an electronic stimulator (S-48,
Grass-Telefactor, Astro-Med, Inc., West Warwick, R.I.) attached via
aluminum foil electrodes placed in direct contact with the mucosal
surface at opposite poles of each tissue. Pharmacological agents
and secretagogues were routinely added to the basolateral-side
reservoir. Agonist or secretagogue effects on lsc were continuously
recorded following basolateral addition. Concentration-response
curves were constructed from the cumulative, step-wise addition of
pre-determined increasing amounts of agonist or secretagogue that
were added at or near the peak lsc response to the preceding lower
concentration. Effects of antagonists or inhibitors of secretion
were evaluated after a 10-20 minute exposure period that was
followed by challenge with a specific agonist or secretagogue.
[0370] Statistical Analysis. All values are reported as
means.+-.SE. Electrophysiological data obtained with Ussing
flux-type chambers were normalized to tissue surface area and
expressed per cm.sup.2. Stimulated changes in ion transport were
determined as the absolute difference between a baseline value
prior to stimulation and the maximal response (lsc) evoked by a
given stimulus or secretagogue. An estimated EC.sub.50 for the
stimulatory action of PK1 on epithelial secretion was determined
from a 7-point cumulative concentration-response test using a
computer calculated curve-fitting function in PRISM (GraphPad
Software, Inc.). An unpaired, two-tailed Student's t-test was used
to determine statistical significance between any two groups, e.g.,
control and experimental tissues. An ANOVA in conjunction with a
post hoc Neuman-Keuls multiple comparisons test was used to
determine significant differences among multiple groups. P<0.05
was considered statistically significant.
[0371] Summary of Results.
[0372] The basal lsc was 35.2.+-.2.4 A/cm.sup.2 and tissue
conductance (G) was 33.7.+-.0.9 mS/cm.sup.2 (n=79 tissues from 34
rats). Following a single-dose addition of PK1 to the Krebs
solution bathing the basolateral tissue surface, lsc gradually
increased to a peak value within 2-4 min and then declined back
toward baseline within 10-15 min. The PK1-evoked increases in lsc
were concentration dependent with an EC.sub.50 of approximately 8.2
nM determined from cumulative concentration-response studies (see
FIG. 2). The maximal response for the PK1-evoked response occurred
at 100 nM; 100 nM PK1 evoked an increase in lsc of 28.7.+-.2.9
A/cm.sup.2 from baseline (n=42 tissues from 29 rats) and 10 nM PK1
evoked an increase of 13.5.+-.2. A/cm.sup.2 (n=33 tissues from 22
rats). The concentrations of 10 nM and 100 nM were used in all
subsequent studies. PK1 had no significant effect on G in any of
our studies. The pro-secretory effect of PK1 was not blocked in the
presence of the nerve conduction toxin, Tetrodotoxin (TTX), or
blockade of muscarinic receptors present on mucosal enterocytes by
the anti-cholinergic drug, Atropine, indicating that the its action
is not dependent on intrinsic neural activity in the tissues. The
PK1 evoked increase in lsc requires the presence of endogenous PK1
receptors since exogenous PK1 peptide added to ileum mucosal
tissues from PK1 receptor knock-out mice failed to elicit a
significant change in lsc compared to wild-type littermates.
Biological Example 4
Small Molecule P1<1 Receptor Antagonists Are Effective at
Suppressing Both PK1 and Cholera Toxin Stimulated Gut Secretion in
Rat Ileum
[0373] Methodology.
[0374] The basic methodology for Ussing-type ion flux chambers used
in these studies was the same as that described in detail above
with the following modifications to the experimental protocol.
Following a 30-45 minute equilibration period, baseline-stable
tissues were subjected to a train of electrical field stimulation
(EFS; 80 V, 0.5 ms, 10 Hz, 5 s) applied from contacts connecting
the foil electrodes on opposite poles of the tissue to the
polarized, isolated outputs from an electronic square-pulse
stimulator. The responses to two sequential EFS were used to gauge
tissue viability and comparability of the responses of individual
tissues from each rat and between rats. Tissue conductance was
measured at periodic intervals as changes in the amplitudes of
brief short-circuit current responses evoked by application of 1 mV
amplitude bi-polar pulses from a pulse generator using Ohm's Law.
Three to four tissues from each rat were studied. The tissues from
a given animal were grouped and assigned accordingly: one control
tissue which received only vehicle followed by two consecutive
doses of PK-1 ligand added in a cumulative fashion to the
basolateral surface of the tissue; the remaining two to three
tissues from the same animal were assigned to be exposed to a given
PK-1 receptor antagonist (e.g., 3-4 tissues from 1 rat: Control,
Antagonist.sub.1, Antagonist.sub.2, and/or Antagonist.sub.3). Test
compound was added to the basolateral tissue side reservoir at a
final concentration of 1 M and allowed a 15 minute incubation
period prior to challenge with the PK1 peptide. At the end of this
15 min exposure period, PK1 ligand at 10 and 100 nM was added in a
cumulative fashion to each tissue to characterize the inhibitory
effect of the test compound. At the conclusion of the experiment,
EFS was re-applied to gauge tissue viability and stability of
responsiveness.
[0375] For the Cholera toxin studies, paired mucosal tissues were
obtained from each rat and mounted in Ussing-type chambers.
Following tissue equilibration, baseline-stable and
conductance-stable tissues were exposed to 1 g/ml Cholera toxin
(i.e., one tissue from each pair) added to the mucosa together with
simultaneous addition of DMSO vehicle or Compound 3 of the present
invention (i.e., one tissue from each pair) to the serosa at a
final concentration of 10 M to start the experiment. From this
point on, baseline lsc and periodic assessment of tissue
conductance were monitored and recorded for up to 4 hours.
[0376] Summary of Results.
[0377] Pre-treatment of tissues with PK1 antagonists alone had no
measurable effect on baseline lsc and tissue conductance (G). The
results indicate that suppression of the PK1 evoked increase in lsc
in isolated rat ileum mucosa was successfully achieved in the
presence of Compound 3 of the present invention, which
wasidentified using a functional cell based screening assay (i.e.,
mobilization of intracellular Ca.sub.2+) as a putative antagonist
at the PK1 receptor. In trials with this compound, the observed
suppression of the lsc response evoked by two ascending cumulative
concentrations of PK1 showed characteristics of a significant
surmountable antagonism(see FIG. 3). The PK1 evoked increase in lsc
was suppressed by Cpd 3, a small molecule antagonist at the PK1
receptor. These data strongly suggest that good efficacy can be
achieved in the selective functional blockade of the PK1 receptor
by this small molecule inhibitor to modulate the pro-secretory
effect of PK1 on the intestinal epithelium. The selectivity of the
functional blockade of the PK1 receptor by Compound 3 was confirmed
by testing this compound against an unrelated cholinergic
secretagogue, carbachol. Compound 3 failed to suppress the
pro-secretory effect of carbachol tested at two different
concentrations added in an ascending cumulative fashion to the
serosal side of each tissue in the Ussing-type flux chambers (see
FIG. 4). Increased lsc evoked in response to the cholinergic
agonist Carbachol was not suppressed by Compound 3, a small
molecule antagonist at the PK1 receptor. To investigate the
potential anti-secretory efficacy of selective small molecule PK1
receptor antagonists, we established a model of secretory diarrhea
ex vivo in the Ussing-type flux chambers with mucosal exposure to
Cholera toxin. Mucosal application of Cholera toxin mimics the
route of exposure for this disease-causing agent in animals and
man. Pre-treatment of isolated rat ileum mucosa with Compound 3
(10_M added to the serosa), did significantly suppress the
sustained increase in baseline lsc over time evoked by 1_g/ml
Cholera toxin added to the mucosa by approximately 50-60% (see FIG.
5).
[0378] Compound 3 (1 .mu.M), had no significant effect versus the
increased baseline short-circuit current (lsc) evoked by Vibrio
cholera toxin (20 .mu.g/ml) added to the mucosal surface of
muscle-stripped rat ileum. These data suggest the potential for the
efficacious use of PK1 receptor antagonists from this chemical
class in gut disease states that have a significant secretory
diarrhea component.
[0379] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
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