U.S. patent application number 14/754787 was filed with the patent office on 2015-10-22 for rho kinase inhibitors.
The applicant listed for this patent is Aerie Pharmaceuticals, Inc.. Invention is credited to Todd Bosanac, John David Ginn, Eugene Richard Hickey, Thomas Martin Kirrane, Jr., Weimin Liu, Anthony S. Prokopowicz, Sabine K. Schlyer, Cheng-Kon Shih, Roger John Snow, Michael Robert Turner, Frank Wu, Erick Richard Young.
Application Number | 20150297581 14/754787 |
Document ID | / |
Family ID | 38740290 |
Filed Date | 2015-10-22 |
United States Patent
Application |
20150297581 |
Kind Code |
A1 |
Bosanac; Todd ; et
al. |
October 22, 2015 |
RHO KINASE INHIBITORS
Abstract
Disclosed are novel substituted 2H-isoquinolin-1-one and
3H-quinazolin-4-one derivatives useful as inhibitors of Rho kinase
and for treating a variety of diseases and disorders that are
mediated or sustained through the activity of Rho kinase, including
cardiovascular diseases, pharmaceutical compositions comprising
such compounds, methods for using such compounds and processes for
making such compounds.
Inventors: |
Bosanac; Todd; (New Milford,
CT) ; Ginn; John David; (New Milford, CT) ;
Hickey; Eugene Richard; (Ridgefield, CT) ; Kirrane,
Jr.; Thomas Martin; (Middlebury, CT) ; Liu;
Weimin; (Sandy Hook, CT) ; Prokopowicz; Anthony
S.; (Stormville, NY) ; Schlyer; Sabine K.;
(New Milford, CT) ; Shih; Cheng-Kon; (Danbury,
CT) ; Snow; Roger John; (Danbury, CT) ;
Turner; Michael Robert; (Danbury, CT) ; Wu;
Frank; (Ridgefield, CT) ; Young; Erick Richard;
(Danbury, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Aerie Pharmaceuticals, Inc. |
Research Triangle Park |
NC |
US |
|
|
Family ID: |
38740290 |
Appl. No.: |
14/754787 |
Filed: |
June 30, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14461597 |
Aug 18, 2014 |
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14754787 |
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11856740 |
Sep 18, 2007 |
8809326 |
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14461597 |
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60864484 |
Nov 6, 2006 |
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60826284 |
Sep 20, 2006 |
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Current U.S.
Class: |
514/228.2 ;
514/235.2; 514/253.05; 514/266.22; 514/266.3; 514/308; 514/309 |
Current CPC
Class: |
A61K 31/4725 20130101;
A61K 31/541 20130101; C07D 401/12 20130101; C07D 405/12 20130101;
C07D 403/12 20130101; A61K 31/5377 20130101; C07D 401/14 20130101;
A61K 31/496 20130101; A61P 27/06 20180101; C07D 239/90 20130101;
C07D 239/88 20130101; C07D 487/08 20130101; A61P 9/00 20180101;
A61K 31/472 20130101; C07D 413/12 20130101; A61K 31/517 20130101;
C07D 409/12 20130101; C07D 217/24 20130101 |
International
Class: |
A61K 31/472 20060101
A61K031/472; A61K 31/5377 20060101 A61K031/5377; A61K 31/496
20060101 A61K031/496; A61K 31/541 20060101 A61K031/541; A61K 31/517
20060101 A61K031/517; A61K 31/4725 20060101 A61K031/4725 |
Claims
1. A method for treating a cardiovascular disease or condition in a
warm-blooded animal which comprises administering to the animal a
therapeutically effective amount of a compound of formula (I)
##STR00243## wherein: R.sub.1 is chosen from C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, haloC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aryl, heteroaryl
heteroarylC.sub.1-6alkyl, heterocyclyl, --C.sub.1-3alkylOaryl,
CH.sub.2OCH.sub.2aryl, --CH.sub.2OC(O)C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3S(O).sub.0-2aryl,
--(CH.sub.2).sub.1-2S(O).sub.0-2C.sub.10-6alkyl,
--(CH.sub.2).sub.1-3CO.sub.2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkylC.sub.3-8cycloalkyl,
--(CH.sub.2).sub.1-2CN and --CH(R.sub.3)N(R.sub.4)(R.sub.5)
wherein: R.sub.3 is chosen from H, C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3aryl and --(CH.sub.2).sub.1-3heteroaryl;
R.sub.4 is chosen from H, C.sub.1-6alkyl, C.sub.3-12cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, aryl, aryl(CH.sub.2).sub.1-3,
heteroaryl(CH.sub.2).sub.1-3, C.sub.1-3alkylO(CH.sub.2).sub.1-3,
tetrahydropyran-4-ylmethyl and
(C.sub.1-3alkyl).sub.2N(CH.sub.2).sub.2-4--; and R.sub.5 is chosen
from H and C.sub.1-6alkyl; or R.sub.4 and R.sub.5 together with the
nitrogen atom they are connected to may form a heterocyclyl group;
wherein each aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkylalkyl, cycloalkyl and heterocyclyl group is optionally
substituted with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl, --CN, --NO.sub.2, --OH, oxo,
--CF.sub.3, --OCF.sub.3, --C.sub.0-3alkylCO.sub.2H,
C.sub.1-6alkylCO.sub.2--, C.sub.1-6alkylsulfonylC.sub.0-3alkyl--,
--SO.sub.2C.sub.1-6alkylNR.sub.6R.sub.7,
--C.sub.0-3alkylSO.sub.2NR.sub.6R.sub.7,
--C.sub.0-3C(O)NR.sub.6R.sub.7, heteroaryl,
heteroarylC.sub.1-3alkyl, heterocyclyl, heterocyclylSO.sub.2--,
arylC.sub.1-3alkyl, aryloxy, arylthio and C.sub.0-3NR.sub.6R.sub.7;
wherein each aryl and heteroaryl group is optionally substituted
with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.1-6alkyl, --CN, --NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3,
--C(O)NR.sub.8R.sub.9, --SO.sub.2NR.sub.8R.sub.9, --SO.sub.2Me and
amino optionally substituted by one or two C.sub.1-6alkyl groups or
a C(O)C.sub.1-6alkyl group; R.sub.2 is chosen from H, halogen,
C.sub.1-6alkoxy, --CN, --CF.sub.3 and C.sub.1-6alkyl; R.sub.6 and
R.sub.7 are independently selected from H, C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl and --C.sub.1-6alkylNH.sub.2; or R.sub.6 and
R.sub.7, together with the nitrogen they are connected to may form
a piperazine, piperidine or pyrrolidine ring; R.sub.8 and R.sub.9
are independently selected from H and methyl; R.sub.10 is selected
from H, Cl and F; X is CH; and Y is chosen from --NHC(O)--; or a
tautomer or a salt of the compound of formula (I).
2. The method of claim 1, wherein the cardiovascular disease or
condition is selected form the group consisting of hypertension,
atherosclerosis, restenosis, stroke, heart failure, coronary
vasospasm, cerebral vasospasm, ischemia/reperfusion injury,
pulmonary hypertension, angina, myocardial infarction, peripheral
artery disease, coronary artery disease and combinations
thereof.
3. The method of claim 1, wherein: R.sub.1 is chosen from
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, phenyl,
thienyl, pyridyl, isoxazolyl, pyrazolyl, thienylmethyl,
piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyranyl, --CH.sub.2Ophenyl, --CH.sub.2OCH.sub.2phenyl,
--CH.sub.2OC(O)C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3S(O).sub.0-2phenyl,
--(CH.sub.2).sub.1-2S(O).sub.0-2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3CO.sub.2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkylC.sub.3-8cycloalkyl,
--(CH.sub.2).sub.1-3CN and --CH(R.sub.3)N(R.sub.4)(R.sub.5)
wherein: R.sub.3 is chosen from H, C.sub.1-6alkyl, benzyl,
phenylethyl and pyridylmethyl; R.sub.4 is chosen from H,
C.sub.1-6alkyl, C.sub.3-12cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, phenyl, benzyl, thioenylethyl,
C.sub.1-3alkylO(CH.sub.2).sub.1-3, tetrahydropyran-4-ylmethyl and
(C.sub.1-3).sub.2N(CH.sub.2).sub.2-4--; and R.sub.5 is chosen from
H and C.sub.1-6alkyl; or R.sub.4 and R.sub.5 together with the
nitrogen atom they are connected to may form a piperidine,
piperazine or thiomorpholine group; wherein each cycloalkyl,
cycloalkylalkyl, phenyl, benzyl, phenylethyl, thienyl, pyridyl,
isoxazolyl, pyrazolyl, thienylmethyl, piperidinyl, piperazinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and
thiomorpholinyl group is optionally substituted with 1-3 groups
selected from halogen, C.sub.1-6alkoxy, C.sub.1-6alkyl, --CN,
--NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkylCO.sub.2--, C.sub.1-6alkylsulfonyl, pyrimidyl,
pyridyl, morpholinyl, benzyl, phenyloxy and phenylthio and amino
optionally substituted by one or two C.sub.1-6alkyl groups or a
C(O)C.sub.1-6alkyl group; wherein each phenyl, benzyl, pyrimidinyl
and pyridyl group is optionally substituted with 1-3 groups
selected from halogen, C.sub.1-6alkoxy, C.sub.1-6alkyl, --CN,
--NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3, --C(O)NR.sub.8R.sub.9,
--SO.sub.2NR.sub.8R.sub.9, --SO.sub.2Me and amino optionally
substituted by one or two C.sub.1-6alkyl groups or a
C(O)C.sub.1-6alkyl group; R.sub.2 is chosen from H, Br, Cl, --CN,
--CF.sub.3 and methyl; R.sub.8 and R.sub.9 are independently
selected from H and methyl; and R.sub.10 is selected from H, Cl and
F; or a tautomer or a salt of the compound of formula (I).
4. The method of claim 1, wherein: R.sub.1 is chosen from
cyclopentyl, cyclohexyl, phenyl, thienylmethyl, piperidinyl,
pyrrolodinyl, --CH.sub.2Sphenyl and
--CH(R.sub.3)N(R.sub.4)(R.sub.5) wherein: R.sub.3 is chosen from H,
C.sub.1-6alkyl, benzyl and phenylethyl; R.sub.4 is chosen from H,
C.sub.1-6alkyl, C.sub.3-12cycloalkyl, C.sub.3-7cycloalkylmethyl,
benzyl, thienylethyl, and tetrahydropyran-4-ylmethyl; and R.sub.5
is chosen from H and methyl; or R.sub.4 and R.sub.5 together with
the nitrogen atom they are connected to may form a piperidine
group; wherein each cyclopentyl, cyclohexyl, phenyl, benzyl,
phenylethyl, thienylmethyl, piperidinyl and pyrrolidinyl group is
optionally substituted with 1-3 groups selected from halogen,
C.sub.1-6alkoxy, C.sub.1-6alkyl, --CN, --NO.sub.2, --OH,
--CF.sub.3, --OCF.sub.3, and amino optionally substituted by one or
two C.sub.1-6alkyl groups or a C(O)C.sub.1-6alkyl group; R.sub.2 is
chosen from H, Br and Cl; and R.sub.10 is H; or a tautomer or a
salt of the compound of formula (I).
5. A method of treating renal disease, erectile dysfunction,
asthma, glaucoma or organ failure resulting from hypertension in a
warm-blooded animal which comprises administering to the animal a
therapeutically effective amount of a compound of formula (I):
##STR00244## wherein: R.sub.1 is chosen from C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, haloC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aryl, heteroaryl,
heteroarylC.sub.1-6alkyl, heterocyclyl, --C.sub.1-3alkylOaryl,
CH.sub.2OCH.sub.2aryl, --CH.sub.2OC(O)C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3S(O).sub.0-2aryl,
--(CH.sub.2).sub.1-2S(O).sub.0-2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3CO.sub.2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkylC.sub.3-8cycloalkyl,
--(CH.sub.2).sub.1-2CN and --CH(R.sub.3)N(R.sub.4)(R.sub.5)
wherein: R.sub.3 is chosen from H, C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3aryl and --(CH.sub.2).sub.1-3heteroaryl;
R.sub.4 is chosen from H, C.sub.1-6alkyl, C.sub.3-12cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, aryl, aryl(CH.sub.2).sub.1-3,
heteroaryl(CH.sub.2).sub.1-3, C.sub.1-3alkylO(CH.sub.2).sub.1-3,
tetrahydropyran-4-ylmethyl and
(C.sub.1-3alkyl).sub.2N(CH.sub.2).sub.2-4--; and R.sub.5 is chosen
from H and C.sub.1-6alkyl; or R.sub.4 and R.sub.5 together with the
nitrogen atom they are connected to may form a heterocyclyl group;
wherein each aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkylalkyl, cycloalkyl and heterocyclyl group is optionally
substituted with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl, --CN, --NO.sub.2, --OH, oxo,
--CF.sub.3, --OCF.sub.3, --C.sub.0-3alkylCO.sub.2H,
C.sub.1-6alkylCO.sub.2--, C.sub.1-6alkylsulfoylC.sub.0-3alkyl-,
--SO.sub.2C.sub.1-6alkylNR.sub.6R.sub.7,
--C.sub.0-3alkylSO.sub.2NR.sub.6R.sub.7,
--C.sub.0-3C(O)NR.sub.6R.sub.7, heteroaryl,
heteroarylC.sub.1-3alkyl, heterocyclyl, heterocyclylSO.sub.2,
arylC.sub.1-3alkyl, aryloxy, arylthio and C.sub.0-3NR.sub.6R.sub.7;
wherein each aryl and heteroaryl group is optionally substituted
with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.1-6alkyl, --CN, --NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3,
--C(O)NR.sub.8R.sub.9, --SO.sub.2NR.sub.8R.sub.9, --SO.sub.2Me and
amino optionally substituted by one or two C.sub.1-6alkyl groups or
a C(O)C.sub.1-6alkyl group; R.sub.2 is chosen from H, halogen,
C.sub.1-6alkoxy, --CN, --CF.sub.3 and C.sub.1-6alkyl; R.sub.6 and
R.sub.7 are independently selected from H, C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl and --C.sub.1-6alkylNH.sub.2; or R.sub.6 and
R.sub.7, together with the nitrogen they are connected to may form
a piperazine, piperidine or pyrrolidine ring; R.sub.8 and R.sub.9
are independently selected from H and methyl; R.sub.10 is selected
from H, Cl and F; X is CH; and Y is chosen from --NHC(O)--; or a
tautomer or a salt of the compound of formula (I).
6. The method of claim 5, wherein: R.sub.1 is chosen from
C.sub.3-8cycloalkyl, C.sub.3-8cycloalkylC.sub.1-6alkyl, phenyl,
thienyl, pyridyl, isoxazolyl, pyrazolyl, thienylmethyl,
piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyranyl, --CH.sub.2Ophenyl, --CH.sub.2OCH.sub.2phenyl,
--CH.sub.2OC(O)C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3S(O).sub.0-2phenyl,
--(CH.sub.2).sub.1-2S(O).sub.0-2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3CO.sub.2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkylC.sub.3-8cycloalkyl,
--(CH.sub.2).sub.1-3CN and --CH(R.sub.3)N(R.sub.4)(R.sub.5)
wherein: R.sub.3 is chosen from H, C.sub.1-6alkyl, benzyl,
phenylethyl and pyridylmethyl; R.sub.4 is chosen from H,
C.sub.1-6alkyl, C.sub.3-12cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, phenyl, benzyl, thienylethyl,
C.sub.1-3alkylO(CH.sub.2).sub.1-3, tetrahydropyran-4-ylmethyl and
(C.sub.1-3).sub.2N(CH.sub.2).sub.2-4--; and R.sub.5 is chosen from
H and C.sub.1-6alkyl; or R.sub.4 and R.sub.5 together with the
nitrogen atom they are connected to may form a piperidine,
piperazine or thiomorpholine group; wherein each cycloalkyl,
cycloalkylalkyl, phenyl, benzyl, phenylethyl, thienyl, pyridyl,
isoxazolyl, pyrazolyl, thienylmethyl, piperidinyl, piperazinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and
thiomorpholinyl group is optionally substituted with 1-3 groups
selected from halogen, C.sub.1-6alkoxy, C.sub.1-6alkyl, --CN,
--NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkylCO.sub.2--, C.sub.1-6alkylsulfonyl, pyrimidyl,
pyridyl, morpholinyl, benzyl, phenyloxy and phenylthio and amino
optionally substituted by one or two C.sub.1-6alkyl groups or a
C(O)C.sub.1-6alkyl group; wherein each phenyl, benzyl, pyrimidinyl
and pyridyl group is optionally substituted with 1-3 groups
selected from halogen, C.sub.1-6alkoxy, C.sub.1-6alkyl, --CN,
--NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3, --C(O)NR.sub.8R.sub.9,
--SO.sub.2NR.sub.8R.sub.9, --SO.sub.2Me and amino optionally
substituted by one or two C.sub.1-6alkyl groups or a
C(O)C.sub.1-6alkyl group; R.sub.2 is chosen from H, Br, Cl, --CN,
--CF.sub.3 and methyl; R.sub.8 and R.sub.9 are independently
selected from H and methyl; and R.sub.10 is selected from H, Cl and
F; or a tautomer or a salt of the compound of formula (I).
7. The method of claim 5, wherein: R.sub.1 is chosen from
cyclopentyl, cyclohexyl, phenyl, thienylmethyl, piperidinyl,
pyrrolodinyl, --CH.sub.2Sphenyl and
--CH(R.sub.3)N(R.sub.4)(R.sub.5) wherein: R.sub.3 is chosen from H,
C.sub.1-6alkyl, benzyl and phenylethyl; R.sub.4 is chosen from H,
C.sub.1-6alkyl, C.sub.3-12cycloalkyl, C.sub.3-7cycloalkylmethyl,
benzyl, thienylethyl, and tetrahydropyran-4-ylmethyl; and R.sub.5
is chosen from H and methyl; or R.sub.4 and R.sub.5 together with
the nitrogen atom they are connected to may form a piperidine
group; wherein each cyclopentyl, cyclohexyl, phenyl, benzyl,
phenylethyl, thienyl methyl, piperidinyl and pyrrolidinyl group is
optionally substituted with 1-3 groups selected from halogen,
C.sub.1-6alkoxy, C.sub.1-6alkyl, --CN, --NO.sub.2, --OH,
--CF.sub.3, --OCF.sub.3, and amino optionally substituted by one or
two C.sub.1-6alkyl groups or a C(O)C.sub.1-6alkyl group; R.sub.2 is
chosen from H, Br and Cl; and R.sub.10 is H; or a tautomer or a
salt of the compound of formula (I).
Description
[0001] This invention relates to substituted-2H-isoquinolin-1-one
and 3H-quinazolin-4-one derivatives which are useful as inhibitors
of Rho kinase and are thus useful for treating a variety of
diseases and disorders that are mediated or sustained through the
activity of Rho kinase, including cardiovascular diseases, cancer,
neurological diseases, renal diseases, bronchial asthma, erectile
dysfunction, and glaucoma. This invention also relates to
pharmaceutical compositions comprising these compounds, methods of
using these compounds in the treatment of various diseases and
disorders, processes for preparing these compounds and
intermediates useful in these processes.
BACKGROUND
[0002] Rho-Kinase (ROCK) is a member of the serine-threonine
protein kinase family. ROCK exists in two isoforms, ROCK1, and
ROCK2 (T. Ishizaki et al., EMBO J., 1996, 15, 1885-1893). ROCK has
been identified as an effector molecule of RhoA, a small
GTP-binding protein (G protein) that plays a key role in multiple
cellular signaling pathways, ROCK and RhoA are ubiquitously
expressed across tissues. The RhoA/ROCK signaling pathway is
involved in a number of cellular functions, such as acting
organization, cell adhesion, cell migration, and cytokinesis (K.
Riento and A. J. Ridley, Nat Rev Mol Cell Biol, 2003, 4, 446-56).
It is also directly involved in regulating smooth muscle
contraction (A. P. Somlyo, Nature, 1997, 389, 908-911). Upon
activation of its receptor, RhoA is activated and in turn it
activates ROCK. Activated ROCK phosphorylates the myosin-binding
subunit of myosin light chain phosphatase, which inhibits activity
of the phosphatase and leads to contraction. Contraction of the
smooth muscle in the vasculature increases blood pressure, leading
to hypertension.
[0003] There is considerable evidence in the literature that the
RhoA/ROCK signaling pathway plays an important role in signal
transduction initiated by several vasoactive factors, for example
angiotensin II, urotension II, endothelin-1, serotonin,
norepinephrine and platelet-derived growth factor (PDGF). Many of
these factors are implicated in the pathogenesis of cardiovascular
disease.
[0004] Additional studies in the literature, some using known ROCK
inhibitors fasudil (T. Asano et al., J. Pharmacol. Exp. Ther.,
1987, 24, 1033-1040) or Y-27632 (M. Uehata et al., Nature, 1997,
389, 990-994) further illustrate the link between ROCK and
cardiovascular disease. For example, ROCK expression and activity
have been shown to be elevated in spontaneously hypertensive rats,
suggesting a link to the development of hypertension in these
animals. The ROCK inhibitor Y-27632 (M. Uehata et al., Nature,
ibid) was shown to significantly decrease blood pressure in three
rat models of hypertension, including the spontaneously
hypertensive rat, renal hypertensive rat and deoxycortison acetate
salt hypertensive rat models while having only a minor effect on
blood pressure in control rats, reinforcing the link between ROCK
and hypertension.
[0005] Other studies suggest a link between ROCK and
atherosclerosis. For example, gene transfer of a dominant negative
form of ROCK suppressed neointimal formation following balloon
injury in porcine femoral arteries. In a similar model, ROCK
inhibitor Y-27632 also inhibited neointimal formation in rats. In a
porcine model of IL-1-beta-induced coronary stenosis, long term
treatment by ROCK inhibitor fasudil was shown to progressively
reduce coronary stenosis as well as promote a regression of
coronary constrictive remodeling.
[0006] Additional, investigations suggest that a ROCK, inhibitor
would be useful in treating other cardiovascular diseases. For
example, in a rat stroke model, fasudil was shown to reduce both
the infarct size and neurologic deficit. The ROCK inhibitor Y-27632
was shown to improve ventricular hypertrophy and function in a
model of congestive heart failure in Dahl salt-sensitive rats.
[0007] Other animal or clinical studies have implicated ROCK in
additional diseases including coronary vasospasm, cerebral
vasospasm, ischemia/reperfusion injury, pulmonary hypertension,
angina, renal disease and erectile dysfunction.
[0008] The above studies provide evidence for a link between ROCK
and cardiovascular diseases including hypertension,
atherosclerosis, restenosis, stroke, heart failure, coronary
vasospasm, cerebral vasospasm, ischemia/reperfusion injury,
pulmonary hypertension and angina, as well as renal disease and
erectile dysfunction. Given the demonstrated effect of ROCK on
smooth muscle, ROCK inhibitors may also be useful in other diseases
involving smooth muscle hyper reactivity, including asthma and
glaucoma. Furthermore, Rho-kinase has been indicated as a drug
target for the treatment of various other diseases, including
airway inflammation and hyperresponsiveness, cancer, as well as
neurological disorders, such as spinal-cord injury, Alzheimer
disease, multiple sclerosis, stroke and neuropathic pain.
[0009] There remains an unmet medical need for new drugs to treat
cardiovascular disease. A study published in 2003 estimated that
almost 29% of the adult U.S. population had hypertension in
1999-2000 (I. Hajjar et al., JAMA, 2003, 290, 199-206).
Furthermore, 69% of the hypertensive individuals studied during
this period did not have their hypertension controlled at the time
their blood pressure was measured. This figure was worse in
hypertensive patients with diabetes, where 75% of those patients
studied did not have their blood pressure controlled to the target
level. Another more recent study showed similar results, with less
than one-third of hypertensive patients studied having blood
pressure controlled to the target level (V. Andros, Am. J. Manag.
Care, 2005, 11, S215-S219). Therefore, despite the number of
medications available to treat hypertension, including diuretics,
beta blockers, angiotensin converting enzyme inhibitors,
angiotensin blockers and calcium channel blockers, hypertension
remains poorly controlled or resistant to current medication for
many patients. If not adequately treated, hypertension can lead to
other cardiovascular diseases and organ failure including coronary
artery disease, stroke, myocardial infarction, cardiac failure,
renal failure and peripheral artery disease.
[0010] Although there are many reports of ROCK inhibitors under
investigation (see, for example, E. Hu and D. Lee, Expert Opin.
Ther. Targets, 2005, 9, 715-736), so far fasudil is the only
marketed ROCK, inhibitor. An i.v. formulation of fasudil was
approved in Japan for treatment of cerebral vasospasm. There
remains a need for new therapeutics, including ROCK inhibitors, for
the treatment of cardiovascular diseases, cancer, neurological
diseases, renal diseases, bronchial asthma, erectile dysfunction,
and glaucoma.
BRIEF SUMMARY OF THE INVENTION
[0011] In a general aspect, the present invention is directed to
the compounds of the following formula (I):
##STR00001##
wherein R.sub.1, R.sub.2X and Y are as defined herein, as well as
the tautomers thereof, and salts thereof. It has been found that
the compounds of formula (I) have valuable pharmacological
properties, particularly an inhibiting activity on Rho kinase.
[0012] In another aspect, the present invention is directed to a
method of inhibiting Rho kinase activity in an individual
comprising administering to the individual a compound described
above.
[0013] In another aspect, the present invention is directed to a
method of treating a disease or disorder associated with the
activation of Rho kinase comprising administering to an individual
a compound described above.
[0014] In another aspect, the present invention is directed to a
method of treating a cardiovascular or disease or condition
comprising administering to an individual a compound described
above. Examples of such diseases that may be treated include, for
example, hypertension, atherosclerosis, stroke, heart failure,
restenosis, myocaridial infarction, organ failure, renal failure,
coronary artery disease, peripheral artery disease, coronary
vasospasm, cerebral vasospasm, ischemia/reperfusion injury,
pulmonary hypertension, angina, erectile dysfunction and renal
disease.
[0015] In another aspect, the present invention is directed to a
method of treating diseases involving smooth muscle hyper
reactivity including asthma and glaucoma, comprising administering
to an individual a compound described above.
[0016] In another aspect, the present invention is directed to a
method of treating diseases involving Rho-kinase under
pathophysiological conditions, including airway inflammation and
hyper-responsiveness, cancer, and various neurological diseases,
comprising administering to an individual in need of such treatment
a compound of the present invention as described above.
[0017] In yet additional aspects, the present invention is directed
to pharmaceutical compositions comprising the above-mentioned
compounds, processes for preparing the above-mentioned compounds
and intermediates used in these processes.
DETAILED DESCRIPTION OF THE INVENTION
[0018] In an embodiment, there is provided compounds of the formula
(I)
##STR00002##
wherein: R.sub.1 is chosen from C.sub.1-6alkyl,
C.sub.3-8cycloalkyl, C.sub.3-8cyclocalkylC.sub.1-6alkyl,
haloC.sub.1-6alkyl, aminoC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl,
aryl, arylC.sub.1-6alkyl, heteroaryl, heteroarylC.sub.1-6alkyl,
heterocyclyl, --C.sub.1-3alkylOaryl,
--C(H).sub.0-1(C.sub.1-6alkyl).sub.1-2aryl, --CH(OH)aryl,
--C(OH)(CH.sub.3)aryl, --CH[OC(O)C.sub.1-6alkyl]aryl,
--CH.sub.2OCH.sub.2aryl, --CH.sub.2OC(O)C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3S(O).sub.0-2aryl,
--(CH.sub.2).sub.1-2S(O).sub.0-2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3CO.sub.2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkylC.sub.3-8cycloalkyl,
--(CH.sub.2).sub.1-2CN and --CH(R.sub.3)N(R.sub.4)(R.sub.5)
wherein: R.sub.3 is chosen from H, aryl, C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3aryl and --(CH.sub.2).sub.1-3heteroaryl;
R.sub.4 is chosen from H, C.sub.1-6alkyl, C.sub.3-12cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, aryl, aryl(CH.sub.2).sub.1-3,
heteroaryl(CH.sub.2).sub.1-3, C.sub.1-3alkylO(CH.sub.2).sub.1-3,
tetrahydropyran-4-ylmethyl and
(C.sub.1-3alkyl).sub.2N(CH.sub.2).sub.2-4--; and R.sub.5 is chosen
from H and C.sub.1-6alkyl; or R.sub.4 and R.sub.5 together with the
nitrogen atom they are connected to may form a heterocyclyl group;
wherein each aryl, arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkylalkyl, cycloalkyl and heterocyclyl group is optionally
substituted with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl, --CH, --NO.sub.2, --OH, oxo,
--CF.sub.3, --OCF.sub.3, --C.sub.0-3alkylCO.sub.2H,
C.sub.1-6alkylCO.sub.2--, C.sub.1-6alkylsulfonylC.sub.0-3alkyl-,
--SO.sub.2C.sub.-1-6alkylNR.sub.6R.sub.7,
--C.sub.0-3alkylSO.sub.2NR.sub.yR.sub.7,
--C.sub.0-3C(O)NR.sub.6R.sub.7, aryl, heteroaryl,
heteroarylC.sub.1-3alkyl, heterocyclyl, heterocyclylSO.sub.2--,
arylC.sub.1-3alkyl, aryloxy, arylthio and C.sub.0-3NR.sub.6R.sub.7;
wherein each aryl and heteroaryl group is optionally substituted
with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.1-6alkyl, --CH, --NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3,
--C(O)NR.sub.8R.sub.9, --SO.sub.2NR.sub.8R.sub.9, --SO.sub.2Me and
amino optionally substituted by one or two C.sub.1-6alkyl groups or
a C(O)C.sub.1-6alkyl group; R.sub.2 is chosen from H, halogen,
C.sub.1-6alkoxy, --CN, --CF.sub.3 and C.sub.1-6alkyl; R.sub.6 and
R.sub.7 are independently selected from H, C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl and --C.sub.1-6alkylNH.sub.2; or R.sub.6 and
R.sub.7 together with the nitrogen they are connected to may form a
piperazine, piperidine or pyrrolidine ring; R.sub.8 and R.sub.9 are
independently selected, from H and methyl; R.sub.10 is selected
from C, Cl and F; X is chosen from C and N; and Y is chosen from
--NHC(O)--, --NHC(O)NH-- and --NHC(O)O--; or a tautomer thereof or
a salt thereof, preferably a pharmaceutically acceptable salt
thereof. Preferably if R.sub.1 is a C.sub.1-6alkyl, and Y is
--NHC(O)--, then R.sub.1 is not a methyl group.
[0019] In an embodiment, there is provided compounds of the formula
(I)
##STR00003##
wherein: R.sub.1 is chosen from C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, haloC.sub.1-6alkyl,
aminoC.sub.1-6alkyl, hydroxyC.sub.1-6alkyl, aryl,
arylC.sub.1-6alkyl, heteroaryl, heteroarylC.sub.1-6alkyl,
heterocyclyl, --C.sub.1-3alkylOaryl,
--C(H).sub.0-1(C.sub.1-6alkyl).sub.1-2aryl, --CH(OH)aryl,
--C(OH)(CH.sub.3)aryl, --CH[OC(O)C.sub.1-6alkyl]aryl,
--CH.sub.2OCH.sub.2aryl, --CH.sub.2OC(O)C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3S(O).sub.0-2aryl,
--(CH.sub.2).sub.1-2S(O).sub.0-2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3CO.sub.2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkylC.sub.3-8cycloalkyl,
--(CH.sub.2).sub.1-2CN and --CH(R.sub.3)N(R.sub.4)(R.sub.5)
wherein: R.sub.3 is chosen from H, aryl, C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3aryl and --(CH.sub.2).sub.1-3heteroaryl;
R.sub.4 is chosen from H, C.sub.1-6alkyl, C.sub.3-12cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, aryl, aryl(CH.sub.2).sub.1-3,
heteroaryl(CH.sub.2).sub.1-3, C.sub.1-3alkylO(CH.sub.2).sub.1-3,
tetrahydropyran-4-ylmethyl and
(C.sub.1-3alkyl).sub.2N(CH.sub.2).sub.2-4--; and R.sub.5 is chosen
from H and C.sub.1-6alkyl; or R.sub.4 and R.sub.5 together with the
nitrogen atom they are connected to may form a heterocyclyl group;
wherein each aryl arylalkyl, heteroaryl, heteroarylalkyl,
cycloalkylalkyl, cycloalkyl and heterocyclyl group is optionally
substituted with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.3-8cycloalkyl, C.sub.1-6alkyl, --CN, --NO.sub.2, --OH, oxo,
--CF.sub.3, --OCF.sub.3, --C.sub.0-3alkylCO.sub.2H,
C.sub.1-6alkylCO.sub.2--, C.sub.1-6alkylsulfonylC.sub.0-3alkyl--,
--SO.sub.2C.sub.-1-6alkylNR.sub.6R.sub.7,
--C.sub.0-3alkylSO.sub.2NR.sub.6R.sub.7,
--C.sub.0-3C(O)NR.sub.6R.sub.7, aryl, heteroaryl,
heteroarylC.sub.1-3alkyl, heterocyclyl, heterocyclylSO.sub.2--,
arylC.sub.1-3alkyl, aryloxy, arylthio and C.sub.0-3NR.sub.6R.sub.7;
wherein each aryl and heteroaryl group is optionally substituted
with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.1-6alkyl, --CN, --NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3,
--C(O)NR.sub.8R.sub.9, --SO.sub.2NR.sub.8R.sub.9, --SO.sub.2Me and
amino optionally substituted by one or two C.sub.1-6alkyl groups or
a C(O)C.sub.1-6alkyl group; R.sub.2 is chosen from H, halogen,
C.sub.1-6alkoxy, --CN, --CF.sub.3 and C.sub.1-6alkyl; R.sub.6 and
R.sub.7 are independently selected from H, C.sub.1-6alkyl,
--C(O)C.sub.1-6alkyl and --C.sub.1-6alkylNH.sub.2; or R.sub.6 and
R.sub.7, together with the nitrogen they are connected to may form
a piperazine, piperidine or pyrrolidine ring; R.sub.8 and R.sub.9
are independently selected from H and methyl; R.sub.10 is selected
from H, Cl and F; X is chosen from C and N; and Y is chosen from
--NHC(O)--, --NHC(O)NH-- and --NHC(O)O--; or a tautomer thereof or
a salt thereof, preferably a pharmaceutically acceptable salt.
[0020] In another embodiment, there are provided compounds of the
formula (I) as described above and wherein:
R.sub.1 is chosen from C.sub.3-8cycloalkyl,
C.sub.3-8cycloalkylC.sub.1-6alkyl, phenyl, benzyl, phenylethyl,
thienyl, pyridyl, isoxazolyl, pyrazolyl, thienylmethyl,
piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl,
tetrahydropyranyl, --CH.sub.2Ophenyl, --CH(C.sub.1-3alkyl)phenyl,
--CH(OH)phenyl, --C(OH)(CH.sub.3)phenyl, --CH[OC(O)CH.sub.3]phenyl,
--CH.sub.2OCH.sub.2phenyl, --CH.sub.2OC(O)C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3S(O).sub.0-2phenyl,
--(CH.sub.2).sub.1-2S(O).sub.0-2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3CO.sub.2C.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkyl,
--(CH.sub.2).sub.1-3NHC.sub.1-6alkylC.sub.3-8cycloalkyl,
--(CH.sub.2).sub.1-3CN and --CH(R.sub.3)N(R.sub.4)(R.sub.5)
wherein: R.sub.3 is chosen from H, phenyl, C.sub.1-6alkyl, benzyl,
phenylethyl and pyridylmethyl; R.sub.4 is chosen from H,
C.sub.1-6alkyl, C.sub.3-12cycloalkyl,
C.sub.3-7cycloalkylC.sub.1-6alkyl, phenyl, benzyl, thienylethyl,
C.sub.1-3alkylO(CH.sub.2).sub.1-3, tetrahydropyran-4-ylmethyl and
(C.sub.1-3).sub.2(N(CH.sub.2).sub.2-4--; and R.sub.5 is chosen from
H and C.sub.1-6alkyl; or R.sub.4 and R.sub.5 together with the
nitrogen atom they are connected to may form a piperidine,
piperazine or thiomorpholine group; wherein each cycloalkyl,
cycloalkylalkyl, phenyl, benzyl, phenylethey, thienyl, pyridyl,
isoxazolyl, pyrazolyl, thienylmethyl, piperidine, piperazinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, and
thiomorpholinyl group is optionally substituted with 1-3 groups
selected from halogen, C.sub.1-6alkoxy, C.sub.1-6alkyl, --CN,
--NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3,
C.sub.1-6alkylCO.sub.2--, C.sub.1-6alkylsulfonyl, phenyl,
pyrimidyl, pyridyl, morpholinyl, benzyl, phenyloxy and phenylthio
and amino optionally substituted by one or two C.sub.1-6alkyl
groups or a C(O)C.sub.1-6alkyl group; wherein each phenyl, benzyl,
pyrimidinyl and pyridyl group is optionally substituted with 1-3
groups selected from halogen, C.sub.1-6alkoxy, C.sub.1-6alkyl,
--CH, --NO.sub.2, --OH, --CF.sub.3, --OCF.sub.3,
--C(O)NR.sub.8R.sub.9, --SO.sub.2NR.sub.8R.sub.9, --SO.sub.2Me and
amino optionally substituted by one or two C.sub.1-6alkyl groups or
a C(O)C.sub.1-6alkyl group; R.sub.2 is chosen from H, Br, Cl, --CN,
--CF.sub.3 and methyl; R.sub.8 and R.sub.9 are independently
selected from H and methyl; R.sub.10 is selected from H, Cl and F;
X is chosen from C and N; and Y is chosen from --NHC(O)--,
--NHC(O)NH-- and --NHC(O)O--; or a tautomer thereof or a salt
thereof preferably a pharmaceutically acceptable salt thereof.
[0021] In a further embodiment, there are provided compounds of the
formula (I) as described above and wherein:
R.sub.1 is chosen from cyclopentyl, cyclohexyl, phenyl, benzyl,
phenylethyl, thienylmethyl, piperidinyl, pyrrolodinyl,
--CH.sub.2Sphenyl and --CH(R.sub.3)N(R.sub.4)(R.sub.5) wherein:
R.sub.3 is chosen from H, phenyl, C.sub.1-6alkyl, benzyl and
phenylethyl; R.sub.4 is chosen from H, C.sub.1-6alkyl,
C.sub.3-12cycloalkyl, C.sub.3-7cycloalkylmethyl, benzyl,
thienylethyl, and tetrahydropyran-4-ylmethyl; and R.sub.5 is chosen
from H and methyl; or R.sub.4 and R.sub.5 together with the
nitrogen atom they are connected to may form a piperidine group;
wherein each cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl,
thienylmethyl, piperidinyl and pyrrolidinyl group is optionally
substituted with 1-3 groups selected from halogen, C.sub.1-6alkoxy,
C.sub.1-6alkyl, --CN, --NO.sub.2, --OH --CF.sub.3, --OCF.sub.3,
phenyl and amino optionally substituted by one or two
C.sub.1-6alkyl groups or a C(O)C.sub.1-6alkyl group; wherein each
phenyl group is optionally substituted with 1-3 groups selected
from halogen, C.sub.1-6alkoxy, C.sub.1-6alkyl, --CN, --NO.sub.2,
--OH, --CF.sub.3, --OCF.sub.3, and amino optionally substituted by
one or two C.sub.1-6alkyl groups or a C(O)C.sub.1-6alkyl group;
R.sub.2 is chosen from H, Br and Cl;
R.sub.10 is H;
[0022] X is chosen from C and N; and
Y is --NHC(O)--
[0023] or a tautomer thereof or a salt thereof, preferably a
pharmaceutically acceptable salt thereof.
[0024] In still a further embodiment of the invention, there are
provided compounds of the formula (I) selected from the group below
or a tautomer thereof or a salt thereof, preferably a
pharmaceutically acceptable salt thereof:
TABLE-US-00001 Structure Name ##STR00004## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-dimethylamino-2- phenyl-acetamide
##STR00005## N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-(4-methyl- piperazin-1-yl)- acetamide ##STR00006##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-(cyclohexylmethyl- amino)-acetamide ##STR00007##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-(4-hydroxy-
piperidin-1-yl)-2-phenyl- acetamide ##STR00008##
2-Benzylamino-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-phenyl-acetamide ##STR00009## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-thiomorpholin-4- yl-propionamide
##STR00010## N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-(1,2,3,4-tetrahydro- naphthalen-1-ylamino)- acetamide
##STR00011## N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-(2-thiophen-2-yl- ethylamino)- propionamide ##STR00012##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-methylamino-2-
phenyl-acetamide ##STR00013## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-cyclopropylamino- 2-phenyl-acetamide
##STR00014## N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-(ethyl-methyl- amino)-2-phenyl- acetamide ##STR00015##
(S)-2-Amino-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-3-phenyl- propionamide ##STR00016## (R)-2-Amino-N-(7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-3-phenyl- propionamide
##STR00017## (R)-2-Amino-N-(7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-phenyl-acetamide ##STR00018##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-cyclobutylamino- 2-phenyl-acetamide ##STR00019##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-cyclopropylmethyl- amino)-2-phenyl- acetamide ##STR00020##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-(3-ethoxy-
propylamino)-2-phenyl- acetamide ##STR00021##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-[(2-dimethylamino- ethyl)-ethyl-amino]-2- phenyl-acetamide
##STR00022## N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-[(tetrahydro-pyran- 4-ylmethyl)-amino]- acetamide
##STR00023## 2-(Adamantan-1- ylamino)-N-(7-chloro-1-
oxo-1,2-dihydro- isoquinolin-6-yl)- acetamide ##STR00024##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-[(pyridin-2-
ylmethyl)-amino]- acetamide ##STR00025## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-[(pyridin-3- ylmethyl)-amino]-
acetamide ##STR00026## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-[(pyridin-4- ylmethyl)-amino]-
acetamide ##STR00027## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-(cyclohexylmethyl- amino)-propionamide
##STR00028## (7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-carbamic acid isopropyl ester ##STR00029##
2-Dimethylamino-N-(1- oxo-1,2-dihydro- isoquinolin-6-yl)- acetamide
##STR00030## 2-(Cyclohexylmethyl- amino)-N-(1-oxo-1,2-
dihydro-isoquinolin-6- yl)-acetamide ##STR00031##
2-Dimethylamino-N-(1- oxo-1,2-dihydro- isoquinolin-6-yl)-2-
phenyl-acetamide ##STR00032## Acetic acid (7-chloro-1-
oxo-1,2-dihydro- isoquinolin-6- ylcarbamoyl)-phenyl- methyl ester
##STR00033## 1-Benzyl-3-(1-oxo-1,2- dihydro-isoquinolin-6- yl)-urea
##STR00034## N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-hydroxy-2-phenyl- acetamide ##STR00035##
(R)-2-Amino-N-(1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-2-phenyl-
acetamide ##STR00036## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-(4-chloro-phenyl)- 3-methyl-butyramide
##STR00037## 2,5-Dichloro-thiophene- 3-carboxylic acid (1-
oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00038##
N-(1-Oxo-1,2-dihydro- isoquinolin-6-yl)-2- phenylsulfanyl-
nicotinamide ##STR00039## 2-(3-Methoxy-phenyl)-
N-(1-oxo-1,2-dihydro- isoquinolin-6-yl)- acetamide ##STR00040##
2-(4-Chloro-phenoxy)- N-(1-oxo-1,2-dihydro- isoquinolin-6-yl)-
nicotinamide ##STR00041## 2-(4-Chloro-phenoxy)-2-
methyl-N-(1-oxo-1,2- dihydro-isoquinolin-6- yl)-propionamide
##STR00042## N-(1-Oxo-1,2-dihydro- isoquinolin-6-yl)- succinamic
acid ethyl ester ##STR00043## Thiophene-2-carboxylic acid
(1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00044##
1-(4-Chloro-phenyl)- cyclopentanecarboxylic acid
(1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00045##
2-(4-Chloro-phenoxy)- N-(1-oxo-1,2-dihydro- isoquinolin-6-yl)-
acetamide ##STR00046## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-methyl-benzamide ##STR00047##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-phenyl-acetamide ##STR00048## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2,3,6-trifluoro- benzamide ##STR00049##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-5-fluoro-2-methyl- benzamide ##STR00050##
2-Chloro-N-(7-chloro-1- oxo-1,2-dihydro- isoquinolin-6-yl)-4-
nitro-benzamide ##STR00051## 2-Bromo-N-(7-chloro-1-
oxo-1,2-dihydro- isoquinolin-6-yl)- benzamide ##STR00052##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-(4-fluoro-phenyl)- acetamide ##STR00053##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2,2-dimethyl-
propionamide ##STR00054## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-3,3-dimethyl- butyramide ##STR00055##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-phenylsulfanyl-
nicotinamide ##STR00056## 2,4-Dichloro-N-(7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-benzamide ##STR00057##
5-Methyl-3-phenyl- isoxazole-4-carboxylic acid (7-chloro-1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-amide ##STR00058##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2,4,6-trifluoro-
benzamide ##STR00059## 2,3-Dichloro-N-(7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-benzamide ##STR00060##
1-(4-Chloro-phenyl)- cyclopentanecarboxylic acid
(4-oxo-3,4-dihydro- quinazolin-7-yl)-amide ##STR00061##
Piperidine-4-carboxylic acid (4-oxo-3,4-dihydro-
quinazolin-7-yl)-amide ##STR00062## 2-Benzylamino-N-(4-
oxo-3,4-dihydro- quinazolin-7-yl)- acetamide ##STR00063##
1-Benzyl-piperidine-4- carboxylic acid (4-oxo-
3,4-dihydro-quinazolin- 7-yl)-amide ##STR00064##
Piperidine-3-carboxylic acid (4-oxo-3,4-dihydro-
quinazolin-7-yl)-amide ##STR00065## Pyrrolidine-2-carboxylic acid
(4-oxo-3,4-dihydro- quinazolin-7-yl)-amide ##STR00066##
2-Amino-4-methyl- pentanoic acid (4-oxo- 3,4-dihydro-quinazolin-
7-yl)-amide ##STR00067## (R)-2-Amino-N-(4-oxo-
3,4-dihydro-quinazolin- 7-yl)-3-phenyl- propionamide ##STR00068##
(S)-2-Amino-N-(4-oxo- 3,4-dihydro-quinazolin- 7-yl)-3-phenyl-
propionamide ##STR00069## 2-(Cyclohexylmethyl- amino)-N-(4-oxo-3,4-
dihydro-quinazolin-7- yl)-acetamide ##STR00070##
2-Methylamino-N-(4- oxo-3,4-dihydro- quinazolin-7-yl)-2-
phenyl-acetamide ##STR00071## 2-Amino-N-(4-oxo-3,4-
dihydro-quinazolin-7- yl)-2-phenyl-acetamide ##STR00072##
2-Cyclopropylamino-N- (4-oxo-3,4-dihydro- quinazolin-7-yl)-2-
phenyl-acetamide ##STR00073## (R)-2-Amino-N-(4-oxo-
3,4-dihydro-quinazolin- 7-yl)-2-phenyl- acetamide ##STR00074##
(R)-Pyrrolidine-2- carboxylic acid (4-oxo- 3,4-dihydro-quinazolin-
7-yl)-amide ##STR00075## (R)-2-Amino-3-methyl-
N-(4-oxo-3,4-dihydro- quinazolin-7-yl)- butyramide ##STR00076##
2-(Cyclopropylmethyl- amino)-N-(4-oxo-3,4- dihydro-quinazolin-7-
yl)-acetamide ##STR00077## N-(4-Oxo-3,4-dihydro-
quinazolin-7-yl)-2-(2- thiophen-2-yl- ethylamino)-acetamide
##STR00078## 2-(Cyclohexyl-methyl- amino)-N-(4-oxo-3,4-
dihydro-quinazolin-7- yl)-acetamide ##STR00079##
N-(6-Chloro-4-oxo-3,4- dihydro-quinazolin-7- yl)-2-dimethylamino-2-
phenyl-acetamide ##STR00080## N-(6-Chloro-4-oxo-3,4-
dihydro-quinazolin-7- yl)-2-cyclopropylamino- 2-phenyl-acetamide
##STR00081## 2,5-Dimethyl-2H- pyrazole-3-carboxylic acid
(4-oxo-3,4-dihydro- quinazolin-7-yl)-amide ##STR00082##
2-Amino-N-(7-chloro-1- oxo-1,2-dihydro- isoquinolin-6-yl)-3-(4-
fluoro-phenyl)- propionamide ##STR00083## 2-Amino-N-(7-chloro-1-
oxo-1,2-dihydro- isoquinolin-6-yl)-2-(3- chloro-phenyl)-acetamide
##STR00084## (R)-2-Amino-2- cyclohexyl-N-(1-oxo- 1,2-dihydro-
isoquinolin-6-yl)- acetamide ##STR00085## (R)-2-Amino-2-(4-
chloro-phenyl)-N- (1-oxo-1,2-dihydro- isoquinolin-6-yl)- acetamide
##STR00086## (R)-Pyrrolidine-2- carboxylic acid (7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide
##STR00087## (S)-Pyrrolidine-2- carboxylic acid (7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00088##
2-Amino-N-(7-chloro-1- oxo-1,2-dihydro- isoquinolin-6-yl)-
acetamide ##STR00089## Piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide, ##STR00090##
(R)-2-Amino-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-3-(4-chloro-phenyl)- propionamide ##STR00091##
(R)-2-Amino-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-p-tolyl-acetamide ##STR00092## (S)-2-Amino-N-(7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-3-cyclohexyl-
propionamide ##STR00093## (R)-2-Amino-N-(7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-3-cyclohexyl- propionamide ##STR00094##
(R)-2-Amino-4,4- dimethyl-pentanoic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00095## (S)-2-Amino-4,4-
dimethyl-pentanoic acid (7-chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-amide ##STR00096## 2-Chloro-N-(7-chloro-1- oxo-1,2-dihydro-
isoquinolin-6-yl)-4- methanesulfonyl- benzamide ##STR00097##
2-Chloro-N-(7-chloro-1- oxo-1,2-dihydro- isoquinolin-6-yl)-4-
morpholin-4-yl- benzamide ##STR00098## (R)-2-Amino-N-(7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-3-naphthalen-2-yl-
propionamide ##STR00099## (R)-2-Amino-N-(7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-3-naphthalen-1-yl- propionamide
##STR00100## (R)-2-Amino-N-(7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-3-pyridin-4-yl- propionamide
##STR00101## 2-Methyl-2- methylamino-N-(1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-propionamide ##STR00102##
2-Amino-2-methyl-N-(1- oxo-1,2-dihydro- isoquinolin-6-yl)-
propionamide ##STR00103## (R)-N-(7-Chloro-1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-2-methoxy-2- phenyl-acetamide
##STR00104## (S)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin-
6-yl)-2-methoxy-2- phenyl-acetamide ##STR00105##
3-Amino-N-(7-chloro-1- oxo-1,2-dihydro- isoquinolin-6-yl)-
propionamide ##STR00106## (R)-2-Amino-N-(7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-3-methyl-butyramide ##STR00107##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-3,3,3-trifluoro-2- methoxy-2-phenyl- propionamide ##STR00108##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-oxo-2-phenyl-
acetamide ##STR00109## (R)-Piperidine-2- carboxylic acid (7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00110##
2-tert-Butylamino-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-acetamide ##STR00111## (R)-2-Methoxy-N-(7- methoxy-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-phenyl-acetamide ##STR00112##
(S)-2-Methoxy-N-(7- methoxy-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-phenyl-acetamide ##STR00113## (R)-2-Amino-2- cyclohexyl-N-(7-
methoxy-1-oxo-1,2- dihydro-isoquinolin-6- yl)-acetamide
##STR00114## (S)-2-Amino-2- cyclohexyl-N-(7- methoxy-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-acetamide ##STR00115##
4-Bromo-2-chloro-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-benzamide ##STR00116## 2-Chloro-N-(7-chloro-1- oxo-1,2-dihydro-
isoquinolin-6-yl)-5- methanesulfonyl- benzamide ##STR00117##
(R)-Tetrahydro-furan-2- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00118##
(S)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-2-hydroxy-2-
phenyl-acetamide ##STR00119## (R)-N-(7-Chloro-1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-2-hydroxy-2- phenyl-acetamide
##STR00120## N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-cyano-benzamide ##STR00121## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-methyl-4-nitro- benzamide ##STR00122##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-4-nitro-2-trifluoro- methyl-benzamide ##STR00123##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-morpholin-4-
ylmethyl-benzamide ##STR00124## 1-Amino- cyclohexanecarboxylic acid
(1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00125##
(R)-2-Amino-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-cyclohexyl- acetamide ##STR00126## (R)-2-Amino-4-methyl-
pentanoic acid (7-chloro- 1-oxo-1,2-dihydro-
isoquinolin-6-yl)-amide ##STR00127## (S)-2-Amino-N-(7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-cyclohexyl-
acetamide ##STR00128## (S)-2-Amino-4-methyl- pentanoic acid
(7-chloro- 1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00129##
(S)-2-Amino-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-3-methyl-butyramide ##STR00130## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-(4-methyl- piperazin-1-ylmethyl)-
benzamide ##STR00131## 1,2,3,4-Tetrahydro-
isoquinoline-5-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00132## 1,2,3,4-Tetrahydro-
isoquinoline-8-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00133##
1-Methyl-piperidine-4- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00134##
(R)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-3-methyl-
succinamic acid methyl ester ##STR00135## 2-Chloro-N-(7-chloro-1-
oxo-1,2-dihydro- isoquinolin-6-yl)-3-nitro- benzamide ##STR00136##
2-Chloro-N-(7-chloro-1- oxo-1,2-dihydro- isoquinolin-6-yl)-5-nitro-
benzamide ##STR00137## (S)-Tetrahydro-furan-2- carboxylic acid (7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00138##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-3-methylsulfanyl-
propionamide ##STR00139## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-cyano-acetamide ##STR00140##
2-Bromo-N-(7-chloro-1- oxo-1,2-dihydro- isoquinolin-6-yl)-4-
methyl-benzamide ##STR00141## Tetrahydro-pyran-4- carboxylic acid
(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00142##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-3-phenyl-succinamic acid ##STR00143## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-malonamic acid ethyl ester ##STR00144##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-methylsulfanyl-
acetamide ##STR00145## (S)-Pyrrolidine-3- carboxylic acid (7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00146##
(S)-Piperidine-3- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00147## (R)-Piperidine-3-
carboxylic acid (7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-amide ##STR00148## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-2-methanesulfonyl- acetamide
##STR00149## N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-2-phenyl-malonamic acid ##STR00150## (S)-Piperidine-2-
carboxylic acid (7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-amide ##STR00151## 1-Methanesulfonyl-4- methyl-piperidine-4-
carboxylic acid (7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-amide ##STR00152## 2-Chloro-N-(7-chloro-1- oxo-1,2-dihydro-
isoquinolin-6-yl)-4-nitro- benzamide ##STR00153##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-4-methanesulfonyl- benzamide ##STR00154## (R)-Pyrrolidine-3-
carboxylic acid (7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-amide ##STR00155## 4-Amino- cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00156##
4-Amino- cyclohexanecarboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00157##
4-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- ylcarbamoyl)-
cyclohexanecarboxylic acid ##STR00158## 4-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- ylcarbamoyl)- cyclohexanecarboxylic acid
##STR00159## (R)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin-
6-yl)-2-isopropoxy-2- phenyl-acetamide ##STR00160##
(R)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-2-phenoxy-
propionamide ##STR00161## (S)-N-(7-Chloro-1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-2-phenoxy- propionamide ##STR00162##
4-Phenyl-piperidine-4- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00163## 4-(4-Chloro-phenyl)-
piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00164##
4-Benzyl-piperidine-4- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00165## (R)-Piperidine-3-
carboxylic acid (1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-amide
##STR00166## (S)-Piperidine-3- carboxylic acid (1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-amide ##STR00167##
1-Methyl-piperidine-4- carboxylic acid (1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-amide ##STR00168##
(R)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-2-hydroxy-3-
methyl-butyramide ##STR00169## Piperazine-2-carboxylic acid
(7-chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00170##
4-Methyl-piperidine-4- carboxylic acid (7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00171##
(3S,4S)-3-Methyl- piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00172## (trans)-4-Phenyl-
piperidine-3-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00173## Acetic acid
4-(7-chloro- 1-oxo-1,2-dihydro- isoquinolin-6-
ylcarbamoyl)-cyclohexyl ester ##STR00174## (1R,3S)-3-Amino-
cyclopentanecarboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00175## 4-Hydroxy-
cyclohexanecarboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00176##
(S)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin-
6-yl)-2-cyclohexyl-2- hydroxy-acetamide ##STR00177##
(R)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin-
6-yl)-2-cyclohexyl-2- hydroxy-acetamide ##STR00178##
(S)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-2-hydroxy-2-
phenyl-propionamide ##STR00179## (R)-N-(7-Chloro-1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-2-hydroxy-2- phenyl-propionamide
##STR00180## (1R,3S)-3-Amino- cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00181##
(1R,3S)-3-Amino- cyclohexanecarboxylic acid (7-methoxy-1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-amide ##STR00182## (3R,4S)-3-Methyl-
piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00183## 4-Dimethylamino-
cyclohexanecarboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00184## 3-Amino-
cyclobutanecarboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00185## 3-Amino-
cyclobutanecarboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00186## 4-Amino-1-(4-chloro-
phenyl)-cyclohexane- carboxylic acid (7- chloro-1-oxo-1,2-dihydro-
isoquinolin-6-yl)-amide ##STR00187## 4-Amino-1-(4-chloro-
phenyl)-cyclohexane- carboxylic acid (7- chloro-1-oxo-1,2-dihydro-
isoquinolin-6-yl)-amide ##STR00188## N-(7-Chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-4-methanesulfonyl-2- methyl-benzamide
##STR00189## (1S,3S)-3-Amino- cyclohexanecarboxylic acid
(7-chloro-1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-amide ##STR00190##
(S)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin-
6-yl)-2-cyclohexyl-2- isopropylamino- acetamide ##STR00191##
4-(4-Fluoro-phenyl)- pyrrolidine-3-carboxylic acid
(1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00192##
(1S,2S)-2-Methyl-4-oxo- cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00193##
3-Phenyl-pyrrolidine-3- carboxylic acid (7- chloro-1-oxo-1,2-
dihyro-isoquinolin-6- yl)-amide ##STR00194##
1-Isopropyl-piperidine-4- carboxylic acid (7- chloro-1-oxo-1,2-
dihyro-isoquinolin-6- yl)-amide ##STR00195##
4-Phenyl-pyrrolidine-3- carboxylic acid (1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-amide ##STR00196##
1-Cyclohexyl-piperidine- 4-carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00197## 1-Pyridin-4-ylmethyl-
piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00198##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-methyl-4-
(piperazine-1-sulfonyl)- benzamide ##STR00199##
(R)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-2-(2-chloro-
phenyl)-2-hydroxy- acetamide ##STR00200## (R)-N-(7-Chloro-1-oxo-
1,2-dihydro-isoquinolin- 6-yl)-2-(3-chloro- phenyl)-2-hydroxy-
acetamide ##STR00201## (2S,3R)-2-Amino-3- methyl-pentanoic acid (7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00202##
N-(7-Chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-2-phenyl-
isobutyramide ##STR00203## 1-Benzyl-piperidine-4- carboxylic acid
(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00204##
(trans)-4-Phenyl- pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00205##
(trans)-4-(4-Fluoro- phenyl)-pyrrolidine-3- carboxylic acid (7-
chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00206##
(3R,4S)-1,3-Dimethyl- piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2- dihydro-isoquinolin-6- yl)-amide ##STR00207##
5-Phenyl-piperidine-3- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00208## 1,2,3,4-Tetrahydro-
isoquinoline-7-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00209## 1,2,3,4-Tetrahydro-
isoquinoline-6-carboxylic acid (7-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00210## 4-(3-Amino-propane-1-
sulfonyl)-2-chloro-N-(7- chloro-1-oxo-1,2- dihydro-isoquinolin-6-
yl)-benzamide ##STR00211## (trans)-4-(3-Bromo-
phenyl)-pyrrolidine-3- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00212## (trans)-4-(4-Chloro-
phenyl)-pyrrolidine-3- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide, ##STR00213## (1R,5S,6R)-3-Aza-
bicyclo[3.1.0]hexane-6- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00214## (1R,5S,6S)-3-Aza-
bicyclo[3.1.0]hexane-6- carboxylic acid (7- chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00215## (trans)-4-(3-Bromo-
phenyl)-pyrrolidine-3- carboxylic acid (6-chloro-
4-oxo-3,4-dihydro- quinazolin-7-yl)-amide ##STR00216##
(R)-N-(7-Chloro-1-oxo- 1,2-dihydro-isoquinolin- 6-yl)-2-(4-chloro-
phenyl)-2-hydroxy- propionamide ##STR00217## (R)-N-(6-Chloro-4-oxo-
3,4-dihydro-quinazolin- 7-yl)-2-(4-chloro- phenyl)-2-hydroxy-
propionamide ##STR00218## (R)-2-(4-Chloro-phenyl)-
2-hydroxy-N-(4-oxo-3,4- dihydro-quinazolin-7-yl)- propionamide
##STR00219## 1-Methyl-piperidine-4- carboxylic acid (7-bromo-
1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00220##
1-Methyl-piperidine-4- carboxylic acid (7-fluoro-
1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00221##
1-Methyl-piperidine-4- carboxylic acid (7-chloro-
1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide ##STR00222##
1-Methyl-piperidine-4- carboxylic acid (7-cyano- 1-oxo-1,2-dihydro-
isoquinolin-6-yl)-amide ##STR00223## (trans)-4-Phenyl-
pyrrolidine-3-carboxylic acid (7-bromo-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00224## (trans)-4-(4-Chloro-
phenyl)-pyrrolidine-3- carboxylic acid (7- bromo-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide, ##STR00225## (trans)-4-Phenyl-
pyrrolidine-3-carboxylic acid (5-chloro-1-oxo-1,2-
dihydro-isoquinolin-6- yl)-amide ##STR00226## (trans)-4-Phenyl-
pyrrolidine-3-carboxylic acid (7-chloro-5-fluoro-
1-oxo-1,2-dihydro- isoquinolin-6-yl)-amide
[0025] In an additional embodiment of the invention, there are
provided compounds of the formula (I) selected from the group below
or a tautomer thereof or a salt thereof, preferably a
pharmaceutically acceptable salt thereof:
[0026]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-dimethylamino-2-p-
henyl-acetamide;
[0027]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-methyl-piperaz-
in-1-yl)-acetamide;
[0028]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(cyclohexylmethyl-
-amino)-acetamide;
[0029]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-hydroxy-piperi-
din-1-yl)-2-phenyl-acetamide;
[0030]
2-Benzylamino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phe-
nyl-acetamide;
[0031]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-thiomorpholin-4-y-
l-propionamide;
[0032]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(1,2,3,4-tetrahyd-
ro-naphthalen-1-ylamino)-acetamide;
[0033]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(2-thiophen-2-yl--
ethylamino)-propionamide;
[0034]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methylamino-2-phe-
nyl-acetamide;
[0035]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclopropylamino--
2-phenyl-acetamide;
[0036]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(ethyl-methyl-ami-
no)-2-phenyl-acetamide;
[0037]
(S)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-pheny-
l-propionamide;
[0038]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-pheny-
l-propionamide;
[0039]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-pheny-
l-acetamide;
[0040]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclobutylamino-2-
-phenyl-acetamide;
[0041]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(cyclopropylmethy-
l-amino)-2-phenyl-acetamide;
[0042]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(3-ethoxy-propyla-
mino)-2-phenyl-acetamide;
[0043]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(2-dimethylamino-
-ethyl)-ethyl-amino]-2-phenyl-acetamide;
[0044]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(tetrahydro-pyra-
n-4-ylmethyl)-amino]-acetamide;
[0045]
2-(Adamantan-1-ylamino)-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-
-yl)-acetamide;
[0046]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(pyridin-2-ylmet-
hyl)-amino]-acetamide;
[0047]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(pyridin-3-ylmet-
hyl)-amino]-acetamide;
[0048]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(pyridin-4-ylmet-
hyl)-amino]-acetamide;
[0049]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(cyclohexylmethyl-
-amino)-propionamide;
[0050] (7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-carbamic acid
isopropyl ester;
[0051]
2-Dimethylamino-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)acetamide;
[0052]
2-(Cyclohexylmethyl-amino)-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-a-
cetamide
[0053]
2-Dimethylamino-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenyl-ace-
tamide;
[0054] Acetic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-ylcarbamoyl)-phenyl-methyl
ester;
[0055] 1-Benzyl-3-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-urea;
[0056]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-hydroxy-2-phenyl--
acetamide;
[0057]
(R)-2-Amino-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenyl-acetami-
de;
[0058]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-chloro-phenyl)-
-3-methyl-butyramide;
[0059] 2,5-Dichloro-thiophene-3-carboxylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0060]
N-(1-Oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenylsulfanyl-nicotinamid-
e;
[0061]
2-(3-Methoxy-phenyl)-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-acetami-
de;
[0062]
2-(4-Chloro-phenoxy)-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-nicotin-
amide;
[0063]
2-(4-Chloro-phenoxy)-2-methyl-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl-
)-propionamide;
[0064] N-(1-Oxo-1,2-dihydro-isoquinolin-6-yl)-succinamic acid ethyl
ester;
[0065] Thiophene-2-carboxylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0066] 1-(4-Chloro-phenyl)-cycloopentanecarboxcylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0067]
2-(4-Chloro-phenoxy)-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-acetami-
de;
[0068]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-benzamide;
[0069]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenyl-acetamide;
[0070]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2,3,6-trifluoro-ben-
zamide;
[0071]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-5-fluoro-2-methyl-b-
enzamide
[0072]
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-nitro-be-
nzamide;
[0073]
2-Bromo-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-benzamide;
[0074]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-fluoro-phenyl)-
-acetamide;
[0075]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2,2-dimethyl-propio-
namide;
[0076]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3,3-dimethyl-butyra-
mide;
[0077]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenylsulfanyl-ni-
cotinamide;
[0078]
2,4-Dichloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-benzam-
ide;
[0079] 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0080]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2,4,6-trifluoro-ben-
zamide;
[0081]
2,3-Dichloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-benzam-
ide;
[0082]
2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-(4-fluoro-
-phenyl)-propionamide;
[0083]
2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(3-chloro-
-phenyl)-acetamide;
[0084]
(R)-2-Amino-2-cyclohexyl-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-ace-
tamide;
[0085]
(R)-2-Amino-2-(4-chloro-phenyl)-N-(1-oxo-1,2-dihydro-isoquinolin-6--
yl)-acetamide;
[0086] (R)-Pyrrolidine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0087] (S)-Pyrrolidine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0088]
2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-acetamide;
[0089] Piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0090]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-(4-ch-
loro-phenyl)-propionamide;
[0091]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-p-tol-
yl-acetamide;
[0092]
(S)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-cyclo-
hexyl-propionamide;
[0093]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-cyclo-
hexyl-propionamide;
[0094] (R)-2-Amino-4,4-dimethyl-pentanoic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0095] (S)-2-Amino-4,4-dimethyl-pentanoic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0096]
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-methanes-
ulfonyl-benzamide;
[0097]
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-morpholi-
n-4-yl-benzamide;
[0098]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-napht-
halen-2-yl-propionamide;
[0099]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-napht-
halen-1-yl-propionamide;
[0100]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-pyrid-
in-4-yl-propionamide;
[0101]
2-Methyl-2-methylamino-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-propi-
onamide;
[0102]
2-Amino-2-methyl-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-propionamid-
e;
[0103]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methoxy-2-phe-
nyl-acetamide;
[0104]
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methoxy-2-phe-
nyl-actetamide;
[0105]
3-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-propionamid-
e;
[0106]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-methy-
l-butyramide;
[0107]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3,3,3-trifluoro-2-m-
ethoxy-2-phenyl-propionamide;
[0108]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-oxo-2-phenyl-acet-
amide;
[0109] (R)-Piperidine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0110]
2-tert-Butylamino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-a-
cetamide;
[0111]
(R)-2-Methoxy-N-(7-methoxy-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-ph-
enyl-acetamide;
[0112]
(S)-2-Methoxy-N-(7-methoxy-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-ph-
enyl-acetamide;
[0113]
(R)-2-Amino-2-cyclohexyl-N-(7-methoxy-1-oxo-1,2-dihydro-isoquinolin-
-6-yl)-acetamide;
[0114]
(S)-2-Amino-2-cyclohexyl-N-(7-methoxy-1-oxo-1,2-dihydro-isoquinolin-
-6-yl)-acetamide;
[0115]
4-Bromo-2-chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-be-
nzamide
[0116]
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-5-methanes-
ulfonyl-benzamide;
[0117] (R)-Tetrahydro-furan-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0118]
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-hydroxy-2-phe-
nyl-acetamide;
[0119]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-hydroxy-2-phe-
nyl-acetamide;
[0120]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyano-benzamide;
[0121]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-4-nitro-be-
nzamide;
[0122]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-2-trifluoromethyl-
-nitro-benzamide;
[0123]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-morpholin-4-ylmet-
hyl-benzamide;
[0124] 1-Amino-cyclohexanecarboxylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0125]
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclo-
hexyl-acetamide;
[0126] (R)-2-Amino-4-methyl-pentanoic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0127]
(S)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclo-
hexyl-acetamide;
[0128] (S)-2-Amino-4-methyl-pentanoic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0129]
(S)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-methy-
l-butyramide;
[0130]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-methyl-piperaz-
in-1-ylmethyl)-benzamide;
[0131] 1,2,3,4-Tetrahydro-isoquinoline-5-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0132] 1,2,3,4-Tetrahydro-isoquinoline-8-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0133] 1-Methyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0134]
(R)-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-methyl-succin-
amic acid methyl ester;
[0135]
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-nitro-be-
nzamide;
[0136]
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-5-nitro-be-
nzamide;
[0137] (S)-Tetrahydro-furan-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0138]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-methylsulfanyl-pr-
opionamide;
[0139]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyano-acetamide
[0140]
2-Bromo-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-methyl-be-
nzamide;
[0141] Tetrahydro-pyran-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0142]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-phenyl-succinamic
acid;
[0143] N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-malonamic
acid ethyl ester;
[0144]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methylsulfanyl-ac-
etamide;
[0145] (S)-Pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0146] (S)-Piperidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0147] (R)-Piperidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0148]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methanesulfonyl-a-
cetamide;
[0149]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methanesulfonyl-a-
cetamide;
[0150] (S)-Piperidine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0151] 1-Methanesulfonyl-4-methyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0152]
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-nitro-be-
nzamide;
[0153]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-methanesulfonyl-b-
enzamide;
[0154] (R)-Pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0155] 4-Amino-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0156] 4-Amino-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0157]
4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-cyclohexanecarboxyl-
ic acid;
[0158]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-isopropoxy-2--
phenyl-acetamide;
[0159]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenoxy-propi-
onamide;
[0160]
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenoxy-propi-
onamide;
[0161] 4-Phenyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0162] 4-(4-Chloro-phenyl)-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0163] 4-Benzyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0164] (R)-Piperidine-3-carboxylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0165] (S)-Piperidine-3-carboxylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0166] 1-Methyl-piperidine-4-carboxylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0167]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-hydroxy-3-met-
hyl-butyramide;
[0168] Piperazine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0169] 4-Methyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0170] (3S,4S)-3-Methyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0171] (3R,4S)-4-Phenyl-piperidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0172] Acetic acid 4-Acetic acid
4-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-ylcarbamoyl)-cyclohexyl
ester
[0173] (1R,3S)-3-Amino-cyclopentanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
[0174] 4-Hydroxy-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
[0175]
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclohexyl-2--
hydroxy-acetamide;
[0176]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclohexyl-2--
hydroxy-acetamide;
[0177]
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-hydroxy-2-phe-
nyl-propionamide;
[0178]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-hydroxy-2-phe-
nyl-propionamide;
[0179] (1R,3S)-3-Amino-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0180] (1R,3S)-3-Amino-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0181] (3R,4S)-3-Methyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0182] 4-Dimethylamino-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0183] 3-Amino-cyclobutanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0184] 4-Amino-1-(4-chloro-phenyl)-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0185]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-methanesulfonyl-2-
-methyl-benzamide;
[0186] (1S,3S)-3-Amino-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0187]
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclohexyl-2--
isopropylamino-acetamide;
[0188] 4-(4-Fluoro-phenyl)-pyrrolidine-3-carboxylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0189] (1S,2S)-2-Methyl-4-oxo-cyclohexanecarboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0190] 3-Phenyl-pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0191] 1-Isopropyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0192] 4-Phenyl-pyrrolidine-3-carboxylic acid
(1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0193] 1-Cyclohexyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0194] 1-Pyridin-4-ylmethyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0195]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-4-(piperaz-
ine-1-sulfonyl)-benzamide;
[0196]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(2-chloro-phe-
nyl)-2-hydroxy-acetamide;
[0197]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(3-chloro-phe-
nyl)-2-hydroxy-acetamide;
[0198] (2S,3R)-2-Amino-3-methyl-pentanoic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0199]
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-yl-isobutyramide;
[0200] 1-Benzyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0201] (3R,4S)-4-Phenyl-pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0202] (3R,4S)-4-(4-Fluoro-phenyl)-pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0203] (3R,4S)-1,3-Dimethyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0204] 5-Phenyl-piperidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0205] 1,2,3,4-Tetrahydro-isoquinoline-7-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0206] 1,2,3,4-Tetrahydro-isoquinoline-6-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0207]
4-(3-Amino-propane-1-sulfonyl)-2-chloro-N-(7-chloro-1-oxo-1,2-dihyd-
ro-isoquinolin-6-yl)-benzamide;
[0208] 4-(3-Bromo-phenyl)-pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0209] 4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0210] (1R,5S,6R)-3-Aza-bicyclo[3.1.0]hexane-6-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0211] (1R,5S,6S)-3-Aza-bicyclo[3.1.0]hexane-6-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0212]
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-chloro-phe-
nyl)-2-hydroxy-propionamide;
[0213] 1-Methyl-piperidine-4-carboxylic acid
(7-bromo-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0214] 1-Methyl-piperidine-4-carboxylic acid
(7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0215] 1-Methyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0216] 1-Methyl-piperidine-4-carboxylic acid
(7-cyano-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide;
[0217] 4-Phenyl-pyrrolidine-3-carboxylic acid
(7-bromo-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide; and
[0218] 4-(4-Chloro-phenyl)-pyrrolidine-3-carboxylic acid
(7-bromo-1-oxo-1,2-dihydro-isoquinolin-6-yl)amide.
[0219] In another embodiment of the invention, there are provided
compounds of the formula (I) selected from the group below or a
tautomer thereof or a salt thereof, preferably a pharmaceutically
acceptable salt thereof:
[0220] 1-(4-Chloro-phenyl)-cycloopentanecarboxylic acid
(4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0221] Piperidine-4-carboxylic acid
(4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0222]
2-Benzylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acetamide;
[0223] 1-Benzyl-piperidine-4-carboxylic acid
(4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0224] Piperidine-3-carboxylic acid
(4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0225] Pyrrolidine-2-carboxylic acid
(4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0226] 2-Amino-4-methyl-pentanoic acid
(4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0227]
(R)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-3-phenyl-propiona-
mide;
[0228]
(S)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-3-phenyl-propiona-
mide;
[0229]
2-(Cyclohexylmethyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-ac-
etamide;
[0230]
2-Methylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetam-
ide;
[0231]
2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamide;
[0232]
2-Cyclopropylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-a-
cetamide;
[0233]
(R)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl-acetamid-
e;
[0234] (R)-Pyrrolidine-2-carboxylic acid
(4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0235]
(R)-2-Amino-3-methyl-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-butyrami-
de;
[0236]
2-(Cyclopropylmethyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-a-
cetamide;
[0237]
N-(4-Oxo-3,4-dihydro-quinazolin-7-yl)-2-(2-thiophen-2-yl-ethylamino-
)-acetamide;
2-(Cyclohexyl-methyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-acertam-
ide;
[0238]
N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2-dimethylamino-2-ph-
enyl-acetamide;
[0239]
N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2-cyclopropylamino-2-
-phenyl-acetamide;
[0240] 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid
(4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0241] 4-(3-Bromo-phenyl)-pyrrolidine-3-carboxylic acid
(6-chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-amide;
[0242]
(R)-N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2-(4-chloropheny-
l)-2-hydroxy-propionamide; and
[0243]
(R)-2-(4-Chloro-phenyl)-2-hydroxy-N-(4-oxo-3,4-dihydro-quinazolin-7-
-yl)-propionamide;
[0244] For the compounds disclosed hereinabove in this application,
in the event the nomenclature is in conflict with the structure, it
shall be understood that the compound is defined by the
structure.
[0245] In another embodiment of the invention the above described
compounds of formula (I) are used in methods of treating a
disease-state or condition mediated by Rho kinase in an individual,
the method, comprising administering to the individual an effective
amount of a compound of formula (I) or tautomer thereof, or salt
thereof, preferably a pharmaceutically acceptable salt thereof.
[0246] In another embodiment of the invention the above described
compounds of formula (I) are used in methods of treating a
cardiovascular disease or condition in an individual, the method
comprising administering to the individual an effective amount of a
compound of formula (I) or tautomer thereof, or salt thereof,
preferably a pharmaceutically acceptable salt thereof. Preferred
cardiovascular disease or conditions are hypertension,
atherosclerosis, restenosis, stroke, heart failure, coronary
vasospasm, cerebral vasospasm, ischemia/reperfusion injury,
pulmonary hypertension, angina, myocardial infarction, peripheral
artery disease, coronary artery disease and conciliations
thereof.
[0247] In yet another embodiment of the invention the above
described compounds of formula (I) are used in methods of treating
renal disease, erectile dysfunction, asthma, glaucoma, or organ,
failure resulting from hypertension in an individual, the method
comprising administering to the individual an effective amount of a
compound of formula (I) or tautomer thereof, or salt thereof,
preferably a pharmaceutically acceptable salt thereof.
[0248] Any compounds of this invention containing one or more
asymmetric carbon atoms may occur as racemates and racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. All such isomeric forms of these
compounds are expressly included in the present invention. Each
stereogenic carbon may be in the R or S configuration, or a
combination of configurations.
[0249] Some of the compounds of formula (I) can exist in more than
one tautomeric form. The invention includes methods using all such
tautomers.
[0250] The compounds of the invention are meant to embrace
compounds of Formula (I) as herein described, including the
prodrugs, and the solvates and hydrates thereof.
[0251] All terms as used herein in this specification, unless
otherwise stated, shall be understood in their ordinary meaning as;
known in the art. For example, "C.sub.1-4alkyl" is a saturated
aliphatic hydrocarbon monovalent radical containing 1-4 carbons
such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl
or t-butyl; "C.sub.1-4 alkoxy" is a C.sub.1-4 alkyl with a terminal
oxygen, such as methoxy, ethoxy, propoxy, butoxy. All alkyl,
alkenyl and alkynyl groups shall be understood as being branched or
unbranched, cyclized or uncyclized where structurally possible and
unless otherwise specified. Other more specific definitions are as
follows:
[0252] Carbocycles including Cycloalkyl and Cycloalkenyl groups,
are hydrocarbon rings containing from three to twelve carbon atoms.
These carbocycles may be either aromatic or non-aromatic ring
systems, monocyclic or polycyclic. The non-aromatic ring systems
may be mono- or polyunsaturated. Preferred carbocycles include but
are not limited to cyclopropyl, cyclobutyl, cyclopentyl,
cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl,
cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl,
dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl,
benzocycloheptanyl and benzocycloheptenyl. Certain terms for
cycloalkyl such as cyclobutanyl and cyclobutyl shall be used
interchangeably.
[0253] The term "heterocycle" refers to a stable nonaromatic 4-8
membered (but preferably, 5 or 6 membered) monocyclic or
nonaromatic 8-11 membered bicyclic heterocycle radical which may be
either saturated or unsaturated. Each heterocycle consists of
carbon atoms and one or more, preferably from 1 to 4 heteroatoms
chosen from nitrogen, oxygen and sulfur. The heterocycle may be
attached by any atom of the cycle, which results in the creation of
a stable structure. Unless otherwise stated, heterocycles include
but are not limited to, for example pyrrolidinyl, pyrrolinyl,
morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide,
thiomorpholinyl sulfone, dioxalanyl, piperidinyl, piperazinyl,
tetrahydrofuranyl, tetrahydropyranyl, tetrahydrofuranyl,
1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, piperidinonyl,
tetrahydropyrimidonyl, pentamethylene sulfide, pentamethylene
sulfoxide, pentamethylene sulfone, tetramethylene sulfide,
tetramethylene sulfoxide and tetramethylene sulfone.
[0254] The term "heteroaryl" shall be understood to mean an
aromatic S-8 membered monocyclic or 8-11 membered bicyclic ring
containing 1-4 heteroatoms such as N, O and S. Unless otherwise
stated, such heteroaryls include thienyl, furanyl isoxazolyl,
oxazolyl, thiaxolyl, thiadiazolyl, tetrazolyl, pyrazolyl, pyrrolyl,
imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,
pyranyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl,
benzothiazolyl, benzothienyl, quinolinyl, quinazolinyl,
naphthyridinyl, indazolyl, triazolyl, pyrazolo[3,4-b]pyrimidinyl,
purinyl, pyrrolo[2,3-b]pyridinyl, pyrazolo[3,4-b]pyridinyl,
tubercidinyl, oxazo[4,5-b]pyridinyl and
imidazo[4,5-b]pyridinyl.
[0255] The term "heteroatom" as used herein shall be understood to
mean atoms other than carbon such as O, N, S and P.
[0256] In all alkyl groups or carbon chains one or more carbon
atoms can be optionally replaced by heteroatoms: O, S or N, it
shall be understood that if N is not substituted then it is NH, it
shall also be understood that the heteroatoms may replace either
terminal carbon atoms or internal carbon atoms within a branched or
unbranched carbon chain. Such groups can be substituted as herein
above described by groups such as oxo to result in definitions such
as but not-limited, to: alkoxycarbonyl, acyl, amido and thioxo.
[0257] The term "aryl" as used herein shall be understood to mean
aromatic carbocycle, such as phenyl or naphthyl or heteroaryl as
defined above. Each aryl or heteroaryl unless otherwise specified
includes it's partially or fully hydrogenated derivative. For
example, quinolinyl may include decahydroquinolinyl and
tetrahydroquinolinyl, naphthyl may include it's hydrogenated
derivatives such as tetrahydranaphthyl. Other partially or fully
hydrogenated derivatives of the aryl and heteroaryl compounds
described herein will be apparent to one of ordinary skill in the
art.
[0258] As used herein, "nitrogen" and "sulfur" include any oxidized
form of nitrogen and sulfur and the quaternized form of any basic
nitrogen. For example, for an --S--C.sub.1-6 alkyl radical, unless
otherwise specified, this shall be understood to include
--S(O)--C.sub.1-6 alkyl and -S(O).sub.2--C.sub.1-6 alkyl, likewise,
--S--R.sub.a may be represented as phenyl-S(O).sub.m-- when R.sub.a
is phenyl and where m is 0, 1 or 2.
[0259] The term, "halogen" as used in the present specification
shall be understood to mean bromine, chlorine, fluorine or iodine,
preferably fluorine or chlorine. The definitions "partially or
fully halogenated"; partially or fully fluorinated; "substituted by
one or more halogen atoms", includes for example, mono, di or tri
halo derivatives on one or more carbon atoms. For alkyl, a
nonlimiting example would be --CH.sub.2CHF.sub.2, --CF.sub.3
etc.
[0260] The compounds of the invention are only those which are
contemplated to be `chemically stable` as will be appreciated by
those skilled in the art. For example, a compound which would have
a `dangling valency`, or a `carbanion` are not compounds
contemplated by the inventive methods disclosed herein.
[0261] In another aspect of the invention, the compounds of the
invention are formulated into pharmaceutical compositions
comprising an effective amount, preferably a pharmaceutically
effective amount, of a compound of the invention, or a tautomer, or
salt thereof and a pharmaceutically acceptable excipient or
carrier. Pharmaceutically acceptable salts are preferred.
[0262] The invention also provides a kit for the in vitro
diagnostic determination of Rho kinase function in a sample,
comprising: (a) a diagnostically effective amount of a compound
according to the invention or a tautomer thereof or salt thereof;
and (b) instructions for use of the diagnostic kit.
[0263] The invention includes pharmaceutically acceptable
derivatives of compounds of formula (I). A "pharmaceutically
acceptable derivative" refers to any pharmaceutically acceptable
salt or ester, or any other compound which, upon administration to
an individual, is capable of providing (directly or indirectly) a
compound useful for the invention, or a pharmacologically active
metabolite or pharmacologically active residue thereof. A
pharmacologically active metabolite shall be understood to mean any
compound of the invention capable of being metabolized,
enzymatically or chemically. This includes, for example,
hydroxylated or oxidized, derivative compounds of the formula
(I).
[0264] Pharmaceutically acceptable salts include those derived from
pharmaceutically acceptable inorganic and organic acids and bases.
Examples of suitable acids include hydrochloric, hydrobromic,
sulfuric, nitric, perchloric, fumaric, maleic, phosphoric,
glycolic, lactic, salicylic, succinic, toluene-p-sulfonic,
tartaric, acetic, citric, methanesulfonic, formic, benzoic,
malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other
acids, such as oxalic acid, while not themselves pharmaceutically
acceptable, may be employed in the preparation of salts useful as
intermediates in obtaining the compounds and their pharmaceutically
acceptable acid addition salts. Salts derived from appropriate
cases include alkali metal (e.g., sodium), alkaline earth metal
(e.g., magnesium), ammonium and N--(C.sub.1-C.sub.4
alkyl).sub.4.sup.+ salts.
[0265] In addition, within the scope of the invention is use of
prodrugs of compounds of the formula (I). Prodrugs include those
compounds that, upon simple chemical transformation, are modified
to produce compounds of the invention. Simple chemical
transformations include hydrolysis, oxidation and reduction.
Specifically, when a prodrug is administered to an individual, the
prodrug may be transformed into a compound disclosed hereinabove,
thereby imparting the desired pharmacological effect.
General Synthetic Methods
[0266] The invention additionally provides for methods for making
the compounds of the formula (I). The compounds of the invention
may be prepared by the general methods and examples presented
below, and methods known to those of ordinary skill in the art.
Optimum reaction conditions and reaction times may vary depending
on the particular reactants used. Unless otherwise specified,
solvents, temperatures, pressures, and other reaction conditions
may be readily selected by one of ordinary skill in the art.
Specific procedures are provided in the Synthetic Examples section.
Reaction progress may be monitored by conventional methods such as
thin layer chromatography (TLC). Intermediates and products may be
purified by methods known in the art, including column
chromatography, HPLC or recrystallization.
[0267] The isoquinolinone core structures used to prepare compounds
of formula (I) having X.dbd.C may be prepared by methods known in
the art (for example, F. Eloy and A. Deryckere, J. Heterocyclic
Chem, 1971, 8, 57; N. Briet et al., Tetrahedron, 2002, 58, 5761)
and outlined in Scheme 1.
##STR00227##
[0268] A nitro substituted cinnamic acid (II) is reduced to the
corresponding amine using for example tin II chloride in
hydrochloric acid. The amine is protected with a protecting group
compatible with the cyclization conditions, such as an acetyl
group. The resulting amide substituted cinnamic acid (III) is
converted to the corresponding acyl azide by methods known in the
art, for example, activation of the carboxylic acid by treatment
with a chloroformate such as ethyl chloroformate, in the presence
of an amine such as triethylamine, followed by treatment of the
resulting mixed anhydride with an aqueous solution of an azide such
as sodium aside. The resulting acyl azide (IV) is converted to the
isoquinolone by heating in a solvent such as an ether of diethylene
glycol, such as diethylene glycol dibutyl ether (dibutyl carbitol)
or diphenyl ether, preferably in the presence of a base such as
tributyl amine, at a temperature of 200-300.degree. C., preferably
230-260.degree. C. In some cases, depending on the nature of
R.sub.1, a mixture of regioisomeric products is formed, (Va and Vb)
which can be separated by chromatography.
[0269] The protecting group may be removed from the separated
6-amino isomer by hydrolysis, preferably under acidic conditions
using an acid such as concentrated hydrochloric acid. The resulting
amino isoquinolinone formed (VI) can be used to prepare amide
derivatives of formula (I) (X.dbd.C, Y.dbd.-NHC(O)--) by coupling
with a carboxylic acid or carboxylic acid derivative using methods
well known in the art and described in the Synthetic Examples
section below. Ureas (X.dbd.C, Y.dbd.-NHC(O)NH--) and carbamates
(X.dbd.C, Y.dbd.--NHC(O)O--) may be prepared by reaction of the
isoquinolinome VI with an isocyanate or chloroformate
respectively.
[0270] Quinazolinone intermediates (IX) used to prepare compounds
of formula (I) having X.dbd.N may be prepared by methods known in
the art as described in Scheme 2.
##STR00228##
[0271] Heating the nitro anthranilic acid (VII) with a salt of
formamidine, preferably the hydrochloride or acetate salt, at a
temperature of about 200.degree. C., provides VIII (Q. Chao et al.,
J. Med. Chem. 1999, 42, 3860). Alternatively, the anthranilic acid
may be heated with formamide at a temperature of 130 to 150.degree.
C. in a microwave reactor (F.-R, Alexandre et al., Tet. Lett, 2002,
43, 3911, and F.-R. Alexandre et al., Tet. Lett. 2003, 44, 4455) to
provide VIII. Reduction of the nitro group to the amine (IX) may be
carried out by standard methods, such as catalytic hydrogenation
over palladium, or transfer hydrogenation using a palladium
catalyst and ammonium formate as the hydrogen source. The resulting
amino quinazolinone formed (IX) can be used to prepare amide
derivatives of formula (I) (X.dbd.N, Y.dbd.--NHC(O)--) by coupling
with a carboxylic acid or carboxylic acid derivative) using methods
well known in the art and described in the Synthetic Examples
section below. Ureas (X.dbd.N, Y.dbd.--NHC(O)NH--) and carbamates
(X.dbd.C, Y.dbd.--NHC(O)O--) may be prepared by reaction of the
isquinolinone VI with an isocyanate or chloroformate
respectively.
SYNTHETIC EXAMPLES
[0272] Examples 1-7 illustrate the synthesis of
6-aminoisoquinolin-1-one and 7-aminoquinazolin-4-one intermediates
that may be used to prepare desired compounds of formula (I).
Example 1
Synthesis of 6-aminoisoquinolin-1-one
##STR00229##
[0274] Tin II chloride dihydrate (170 g, 0.75 mol) was dissolved in
concentrated HCl (200 mL). Warming was necessary to obtain a clear
solution. 3-Nitrocinnamic acid (35 g, 0.181 mol) was added
portionwise with stirring. After about 20% of the 3-nitrocinnamic
acid had been added, the mixture was warmed with a heat gun to
45.degree. C. to initiate reaction. The rate of addition was
controlled to maintain a temperature of 65-75.degree. C. The
reaction was exothermic, but not vigorous on this scale. After the
addition was complete, and the reaction started to subside, the
flask was transferred to an oil bath at 65.degree. C. for 1 h. The
mixture was then cooled to room temperature. The solid was
filtered, washed with 2 N HCl, (100 ml) and sucked dry. The filter
cake was dried in a vacuum oven for 1 h, then in air overnight, to
give about 65 g of the crude amine. This material was suspended in
acetic acid (300 mL) and acetic anhydride (150 mL, 1.6 mol) was
added gradually with stirring. After the initial exotherm subsided,
the mixture was stirred in an oil bath at 110.degree. C. for 2 h,
resulting in a clear solution. LCMS showed complete conversion to
the desired acetanilide. The solution was cooled and water (50 mL)
was added. After standing overnight the solution was concentrated
to about 300 mL. More water (100 mL) and 2 N HCl (50 mL) were
added. The precipitate was filtered, washed with water and dried to
give 3-acetamido cinnamic acid (33.2 g, 89%).
[0275] A solution of 3-acetamido cinnamic acid (3.0 g, 15 mmol) and
triethylamine (4.2 mL, 30 mmol) in acetone (27 mL) was cooled in an
ice bath. Ethyl chloroformate (1.86 mL, 19.5 mmol) was added, and
the solution was stirred in ice for 40 min. Triethylamine
hydrochloride precipitated. A solution of sodium azide (1.46 g,
22.5 mmol) in water (3 mL) was added. The mixture was stirred in
ice for 40 min, then for 1 h at room temperature. Water (15 mL) was
added, and the solution was extracted three times with
dichloromethane. The combined organic layers were dried over
magnesium sulfate and evaporated to dryness, to give the
crystalline azide.
[0276] While this reaction was in progress, a 100 mL 3-neck round
bottom flask, equipped with magnetic stirrer, pressure-equalizing
addition funnel, thermocouple connected to a J-KEM controller and
an air condenser topped by short-path distillation head and
receiver, was charged with a mixture of diethyleneglyeol dibutyl
ether (dibutyl carbitol) (10 mL) and tributyl amine (3.57 mL, 15
mmol). The stirred solution was heated to 240.degree. C. using a
heating mantle connected to the J-KEM controller. Nitrogen was
passed through the apparatus via an inlet connected to the top of
the addition funnel. The aside was redissolved in dichloromethane
(80 mL, with warming), and this solution was placed in the addition
funnel. The nitrogen stream way stopped. The azide solution was
added slowly dropwise, to maintain the temperature between
230.degree. C. and 240.degree. C. Very vigorous gas evolution
occurred as the aside was added. The dichloromethane boiled off as
the solution was added. The addition took 2 h 10 min, during which
time a distillate collected in the receiver, which was a mixture of
dichloromethane and dibutyl carbitol. Periodically during the
addition, the receiver was changed. The dichloromethane was
evaporated, and the liquid remaining in the flask was returned to
the reaction vessel. After the addition was complete, the
temperature was maintained at 240.degree. C. for 40 min. The
heating mantle was removed. A dark solid had deposited on the walls
of the flask. On cooling, a crystalline precipitate formed. The
precipitate was collected by filtration, and washed with ether. The
dark solid remained in the flask. More solid crystallized from the
ether filtrate on standing. The supernatant was decanted, and the
solid combined with the filtered precipitate. The supernatant was
distilled under high vacuum, to remove the carbitol and
tributylamine. The combined solids and pot residue from the
distillation contained both the 8-acetamido isoquinolin-1-one and
6-acetamido isoquinolin-1-one. This material was purified by
chromatography on silica, using a dichloromethane/methanol gradient
from 2% to 15%. The first eluted component was the 8-acetamido
isomer (700 mg isolated pure). The second eluted component was the
desired 6-acetamido isomer (600 mg). This component contained
impurities, which were removed by triturating the material with a
little methanol (ea. 3 mL). The crystals were filtered, washed with
a few drops of methanol and dried to give pure 6-acetamido
isoquinolin-1-one (3545 mg, 12%).
[0277] A stirred suspension of 6-acetamidoisoquinolin-1-one (1.62
g, 8.0 mmol) in 6 M HCl (60 mL) was heated in an oil bath at
65.degree. C. with stirring. After 2 h a clear solution was
obtained, and the reaction was complete by LCMS. The solution was
cooled and evaporated almost to dryness. Methanol was evaporated
from residue to leave the hydrochloride salt as a crystalline
solid. The salt was suspended in water (40 mL) and heated to at
60.degree. C. to dissolve. To the resulting solution at 60.degree.
C., ammonium hydroxide was added dropwise, immediately forming a
precipitate. The mixture was cooled in ice, the crystals filtered,
and washed with water, and finally with a few drops of methanol,
which removed some brown color. The crystals were dried to give the
title compound (1.00 g, 78%).
Example 2
Synthesis of 6-amino-5-chloroisoquinolin-1-one
##STR00230##
[0279] Tin II chloride dihydrate (103 g, 0.46 mol) was dissolved in
concentrated HCl (120 mL). Warming was necessary to obtain a clear
solution, 4-Chloro-3-nitrocinnamic acid (25 g, 0.11 mol) was added
portionwise with stirring. After about 20% of the starting material
had been added, the mixture was warmed with a heat gun to
45.degree. C. to initiate reaction. The rate of addition was
controlled to maintain a temperature of 65-75.degree. C. Cooling
with a water bath was used to prevent the temperature exceeding
80.degree. C. After the addition was complete and reaction started
to subside, the mixture was transferred to an oil bath, at
65.degree. C. for 1 h. The mixture was cooled to room temperature.
The solid was filtered, washed with 2 M HCL (60 mL) and sucked dry.
The filter cake was dried in a vacuum oven for 1 h, then in air
overnight, to give about 34 g crude product. This material was
suspended in acetic acid (1.00 mL) with stirring and acetic
anhydride (100 mL, 1.1 mol) was added in one portion. The
temperature rose to 35.degree. C. After the initial exotherm
subsided, the mixture was stirred in an oil bath at 110.degree. C.
for 2 h, but did not dissolve. LCMS showed complete conversion to
the desired acetanilide. The solution was cooled and water (50 mL)
was added cautiously. The mixture was concentrated to about 200 mL.
More water (100 mL) and 2 M HCl (50 mL) were added. The precipitate
was filtered, washed with water and dried to give
3-acetamido-4-chlorocinnamic acid (25.0 g, 95%).
[0280] A suspension of 3-acetamido-4-chlorocinnamic acid (7.19 g,
30 mmol) and triethylamine (8.4 mL, 60 mmol) in acetone (100 mL)
was cooled in an ice bath. Ethyl chloroformate (3.73 mL, 39 mmol)
was added, and the solution was stirred in ice for 40 min. The acid
dissolved and a precipitate formed. A solution of sodium azide
(2.93 g, 45 mmol) in water (10 mL) was added. The mixture was
stirred in ice for 40 min, then for 1 h at room temperature. Water
(75 mL) was added, and the solution was extracted three times with
dichloromethane. The combined organic layers were dried over
magnesium sulfate and evaporated to dryness, to give the
crystalline azide.
[0281] While this reaction was in progress, the apparatus described
above in Example 1 was assembled, using a 250 mL 3-neck round
bottom flask, which was charged with diethyleneglycol dibutyl ether
(dibutyl carbitol) (75 mL) and tributyl amine (7.2 mL, 30 mmol).
the stirred solution was heated to 240.degree. C. using a heating
mantle connected to the J-KEM controller. Nitrogen w2as passed
through the apparatus via an inlet connected to the top of the
addition funnel. The azide was redissolved in dichloromethane (160
mL), with warming, and this solution was placed in the addition
funnel. The nitrogen stream was stopped. The azide solution was
added dropwise, to maintain temp between 230.degree. C. and
250.degree. C., so that the dichloromethane boiled off as the
solution was added. The addition took 1 h 40 min. A distillate
collected in the receiver, which was a mixture of dichloromethane
and dibutyl carbitol. Periodically during the addition, the
receiver was changed. The dichloromethane was evaporated, and the
liquid remaining the flask was returned to the reaction vessel.
After the addition was complete, the temperature was maintained at
240.degree. C. for 30 min. the heating mantle was removed. On
cooling, a crystalline precipitate formed. The cooled solution was
diluted with ether (150 mL) and stirred overnight. The precipitate
was collected by filtration, washed well with ether, then with a
few drops of MeOH, which removed some dark color. The resulting
off-white solid was dried at 60.degree. C. under vacuum to give
6-acetamido-5-chloroisoquinoline-1-one (3.1 g). This material
contained a minor component which was not removed at this
stage.
[0282] A stirred suspension of
6-acetamido-5-chloroisoquinolin-1-one (1.4 g, 5.9 mmol) in
concentrated HCl (50 mL) was heated in an oil bath, at 65.degree.
C. with stirring. After 1 h, a clear solution was obtained, and the
reaction was complete by LCMS. The solution was cooled and
evaporated almost to dryness. Methanol was evaporated from the
residue to leave the hydrochloride salt as a crystalline solid. The
salt was dissolved in methanol and treated with excess ammonium
hydroxide to form the free base. The solution was evaporated to
dryness and was purified by chromatography on a Combiflash system,
using a dichloromethane/methanol gradient from 2% to 10%. The
major, second during, spot was collected to yield the title
compound (883 mg, 72%).
[0283] Analogous procedures were used to make the 7-H, 7-bromo,
7-fluoro, and 7-trifluoromethyl derivatives using commercially
available starting materials. The 7-cyano and 7-methoxy analogs
were made by the following methods below.
Example 3
Synthesis of 6-amino-7-cyano isoquinolin-1-one
##STR00231##
[0285] A reaction vial was charged with 7-bromo-6-aminoisoquinolone
hydrochloride (203 mg, 0.74 mmol) Zn(CN).sub.2 (1.55 mmol) and
Pd(Ph.sub.3P).sub.4 (0.37 mmol) in 1.5 mL of dry dimethylacetamide.
The vial was sealed and warmed to 100.degree. C. for 20 minutes in
a microwave. The reaction was recharged with additional
Pd(Ph.sub.3P).sub.4 (0.37 mmol) and warmed for another 20 minutes.
The reaction was then diluted with 1 N aqueous NaOH and the
resulting solids were isolated by filtration (615 mg). The desired
product was present in both the solids as well as the filtrate. The
solids were purified by suspension in dimethylacetamide, filtration
to remove insoluble material and reverse phase HPLC chromatography
of the filtrate to afford the desired product as a white solid (62
mg, 46%). The aqueous filtrate from above was neutralized with 1 N
aqueous HCl and the resulting crude product was isolated by
filtration (233 mg). This additional material was used without
further purification.
Example 4
Synthesis of 6-Amino-7-methoxy isoquinolin-1-one
##STR00232##
[0287] To a solution of 3-methoxy-4-nitrobenzoic acid (10.00 g,
50.72 mmol) in CH.sub.2Cl.sub.2 (250 mL) was added pyridine (4.89
mL, 60.87 mmol) followed by SOCl.sub.2 (4.06 mL, 55.80 mmol). The
reaction was stirred for 5 min then volatiles were removed in
vacuo. The crude was dissolved in CH.sub.2Cl.sub.2 (200 mL) and a
solution of triethylamine (8.72 mL, 60.87 mmol) and
aminoacetaldehyde dimethyl acetal (6.40 g, 60.87 mmol) in
CH.sub.2Cl.sub.2 (50 mL) was added via syringe. The mixture was
stirred for 5 min then diluted with CH.sub.2Cl.sub.2 (250 mL),
washed with saturated aqueous NaHCO.sub.3 (2.times.200 mL), dried
with MgSO.sub.4, filtered, and concentrated to afford the crude
product (14.0 g) which was used as is in the next
transformation.
[0288] A solution of the above nitro compound (14.0 g)and 20%
Pd(OH).sub.2 on carbon (1.8 g) was dissolved in MeOH (150 mL). A
balloon filled with hydrogen was attached and the system was purged
and evacuated (3.times.). The suspension was allowed to stir for 20
h then was filtered through a pad of diatomaceous earth. The
filtrate was concentrated in vacuo to afford the desired aniline
intermediate as a gold foam (12.25 g, 98%). MS (ES+) m/e 255
[M+H].sup.+
[0289] A solution of the aniline (11.00 g, 43.26 mmol) in
concentrated H.sub.2SO.sub.4 (100 mL) was stirred at 100.degree. C.
for 1 h. The mixture was cooled to 0.degree. C. and carefully
treated with 6 M NaOH to pH=10. The aqueous mixture was extracted
with EtOAc (5.times.300 mL), dried with MgSO.sub.4, filtered, and
concentrated to give a crude beige solid that was purified by
suspending in CH.sub.2Cl.sub.2 (50 mL) and filtering the solid. The
solid was dried to give the desired
6-amino-7-methoxy-isoquinolin-1-one (1.55 g, 19%), MS (ES+) m/e 191
[M+H].sup.+
Example 5
Synthesis of 6-amino-5-chloro isoquinolin-1-one
##STR00233##
[0291] To a solution of 0.500 g (3.12 mmol) of
6-amino-2H-isoquinolin-1-one in DMF (30 mL) was added 0.45 g (3.4
mol) of N-chlorosuccinimide. The mixture was stirred at room
temperature for 15 h then poured over ice and stirred until all the
ice was melted during which time a solid precipitated from
solution. The tan solid was collected by filtration, washed with
water and dried on the filter pad to provide 0.50 g (82% yield) of
the title compound. MS calc. for C.sub.9H.sub.8ClN.sub.2O
[M+H].sup.+: 195.63. Found 195.23.
Example 7
Synthesis of 6-amino-7-chloro-5-fluoro-isoquinolin-1-one
##STR00234##
[0293] To 20.0 mL (215 mmol) of phosphorous oxychloride, cooled to
0.degree. C., was added 5.00 g (25.7 mmol) of
6-amino-7-chloro-2H-isoquinolin-1-one in portions. The mixture was
heated to 100.degree. C. for 3 h then cooled to room temperature
and poured over ice. After all of the ice had melted the pH of the
mixture was adjusted to slightly alkaline by the slow addition of a
10% aqueous NaOH solution. A yellow solid precipitated from
solution and was collected by filtration, washed with water and
dried over anhydrous Na.sub.2SO.sub.4 to provide 3.0 g (55%) of
1,7-dichloro-isoquinolin-6-ylamine. MS calc. for
C.sub.9H.sub.7Cl.sub.2N.sub.2 [M+H].sup.+: 214.08. Found 213.23 and
215.23.
[0294] To a solution of 2.62 g (12.3 mmol) of
1,7-dichloro-isoquinolin-6-ylamine m DMF (130 mL) was added 5.5 g
(15.5 mmol) of Selectfluor.RTM. as a solid in one portion. The
mixture was stirred at room temperature for 15 h. The mixture was
poured over ice and stirred until all of the ice had melted during
which time a solid precipitated from solution. The brown solid was
collected by filtration, washed with water and dried on the filter
pad to provide 10 g (60% by .sup.1H-NMR, 21%) of
1,7-dichloro-5-fluoro-isoquinolin-6-ylamine. MS calc. for
C.sub.9H.sub.5Cl.sub.2FN.sub.2 [M].sup.+: 231.05. Found:
231.68.
[0295] A mixture of 1.0 g (4.3 mmol) of the above crude
intermediate in 50 mL (100 mmol) of a 2 N solution of hydrochloric
acid was heated at 100.degree. C. for 15 h then cooled to room
temperature. The pH of the solution was adjusted to slightly
alkaline by the addition of a 10% NaOH solution. A solid
precipitated from solution and was collected by filtration and
dried on the filter pad. The residue was purified by flash silica
gel chromatography using a 0-50% gradient of MeCN to hexanes to
provide 0.15 g (16%) of the tide compound. MS calc. for
C.sub.9H.sub.7ClFN.sub.2O [M+H].sup.+: 213.62. Found: 214.42.
Example 8
Synthesis of 7-aminoquinazolin-4-one
##STR00235##
[0297] 4-Nitroanthranilic acid (10.0 g, 54.9 mmol) and formamidine
hydrochloride (6.63 g, 82.4 mmol) were ground together in a mortar
and pestle to produce a fine, intimate mixture. The mixture was
placed in a 250 mL round-bottom flask, and spread evenly over the
surface. The flask was placed in an oilbath at 200.degree. C. The
solid underwent a color change, and a distillate was seen on the
side of flask, but did not really melt. After 30 min the flask was
removed from the heating bath. 0.3M sodium hydroxide solution (150
mL) was added to the cooled flask, the black solid mass was broken
up with a spatula, and stirred for 1 h. The solid was filtered off
and washed with water. The filtrate was discarded. The black solid
was suspended in dichloromethane/methanol (10:1) and filtered
through a plug of silica, eluting with the same solvent until no
more product came off. The material was one spot by TLC, plus black
baseline material, but was poorly soluble, so a large volume of
solvent was needed. The filtrate was evaporated to dryness and the
solid residue triturated with a little methanol and filtered to
give 7-nitroquinazolin-4-one (4.65 g, 44%).
[0298] A suspension of 7-nitroquinazolinone (5.2 g, 22.7 mmol) in
DMF (150 mL) and methanol (100 mL) was hydrogenated over 10%
palladium on carbon (600 mg) in a Parr shaker at 50 psi. The
starting material was consumed in 3 h, but hydrogenation was
continued for 18 h to ensure complete reaction. The mixture was
filtered through diatomaceous earth, washing with methanol/DMF 2:1
until all of the product was eluted. The filtrate was evaporated to
dryness. The solid residue was stirred with methanol (20 mL) for 1
h, filtered, washed with methanol and dried to give the crude amine
(3.88 g), which contained a minor component (ca. 10%). The crude
product was dissolved in 2 N HCl (100 mL), with warming, and the
resulting solution was evaporated to dryness to give the
hydrochloride salt. The salt was dissolved in boiling water (30 mL)
and ethanol (30 mL) was added. The solvent was boiled down to 50
mL. The hydrochloride crystallized on cooling. The crystals were
filtered, washed with a little ethanol and dried to give the pure
salt (3.02 g). The salt was dissolved in water (30 mL) with warming
to 65.degree. C. in an oil bath. Ammonium hydroxide was added
dropwise, causing immediate precipitation of the free base. The
flask was cooled in ice, the crystals filtered, washed with water
and dried to give the title compound (2.35 g, 54%).
Example 9
Synthesis of 6-chloro-7-aminoquinazolin-4-one
##STR00236##
[0300] Methanol (500 mL) and concentrated H.sub.2SO.sub.4 (25 mL)
were added to 4-nitroanthranilic acid (30.0 g, 165.0 mmol) and the
reaction mixture was heated at reflux for 48 h. The resulting
solution was concentrated and saturated NaHCO.sub.3 (200 mL) was
added. The aqueous layer was extracted with EtOAc (2.times.150 mL).
The combined organic extracts were washed with water (100 mL), and
brine (100 mL), dried over Na.sub.2SO.sub.4, filtered, and
concentrated to give the methyl ester (29.0 g, 90%) as an intense
orange solid.
[0301] To a suspension of 4-nitroanthranilic acid methyl ester
(16.5 g, 84 mmol) in glacial acetic acid (500 mL), a solution of
sulfuryl chloride (13.6 g, 0.1 mol) in glacial acetic acid (20 mL)
was added dropwise. The homogeneous mixture was stirred at room
temperature for 18 h and the solvent was evaporated in vacuo. The
residue was dissolved in CH.sub.2Cl.sub.2 (200 mL) and washed with
saturated NaHCO.sub.3 (100 mL) and water (100 mL). The organic
layer was dried over Na.sub.2SO.sub.4, filtered, and concentrated.
The .sup.1H NMR spectrum of the crude compound revealed the
formation of a mixture of products, namely the desired 5-chloro
regioisomer, and the byproducts 3-chloro regioisomer and the
3,5-dichlorinated compound. The crude mixture was purifed by flash
chromatography (silica gel, gradient 30-100%
hexanes/CH.sub.2Cl.sub.2) to afford the desired
5-chloro-4-nitroanthranilic acid methyl ester (7.1 g, 36%) as a
pale yellow solid.
[0302] To a solution of 5-chloro-4-nitroanthranilic acid methyl
ester (10.0 g, 43 mmol) in THF (120 mL) was added LiOH (2.7 g, 65
mmol) dissolved in water (40 mL). The reaction mixture was stirred
at room temperature for 18 h and acidified to pH .about.4 with 1 N
HCl. The aqueous layer was extracted with EtOAc (2.times.150 mL);
the combined organic layers were dried over Na.sub.2SO.sub.4,
filtered, and concentrated to give 5-chloro-4-nitroanthranilic acid
(8.7 g, 88%) as an orange solid.
[0303] A mixture of 5-chloro-4-nitroanthranilic acid (8.7 g, 0.040
mol) and formamidine hydrochloride (4.9 g, 60 mmol) were ground to
a fine, intimate powder using a mortar and pestle. The mixture was
transferred info a 250 mL round bottomed flask and immersed in an
oil bath maintained at 205.degree. C. After 40 min, LCMS analysis
of the reaction mixture showed mass corresponding to the product.
The reaction mixture was cooled and the crude product was crushed
into pieces and washed several times with saturated NaHCO.sub.3
(300 mL) and water (200 mL). The solid was air dried and triturated
with a minimum amount of MeOH (20 mL) to obtain
6-chloro-7-nitroquinazolin-4-one (7.6 g, 83%) as a tan powder.
[0304] To a suspension of 6-chloro-7-nitroquinazolin-4-one (7.5 g,
33 mmol) in MeOH (250 mL) was added NH.sub.4Cl (17.7 g, 0.33 mol)
dissolved in water (75 mL). Iron powder (18.5 g, 330 mmol) was
added and the suspension was heated at 65.degree. C. for 2 h. The
warm reaction mixture was filtered over diatomaceous earth and
washed several times with THF (1 L) and methanol (500 mL). The
filtrate was concentrated, washed with water and dried under vacuum
at 50.degree. C. to afford the title compound (6.5 g, 90%) as a
brown solid. ESI-MS m/z 196 [C.sub.8H.sub.6ClN.sub.3O/H].sup.+.
Example 10
Parallel Synthesis of Amides of Formula (I)
Method 1
##STR00237##
[0306] Intermediates from Examples 1-4 were acylated with a variety
of acid chlorides as follows: Acid chlorides were dissolved in
dimethylacetamide (DMA) to give a 0.67 mM solution. The amine
intermediates were dissolved in DMA to give a 0.171 mM solution.
150 microL (100 micromol) of acid chloride solution was transferred
to each well of a deep-well microtitre plate. 350 microL (60
micromol) of the appropriate amine solution was added to each well.
The plate was sealed and placed on a shaker for 24 h. Silica-bound
amine scavenger (about 50 mg) was added to each well, and the plate
was shaken for 30 min. Silica-bound carbonate scavenger (about 125
mg) was added to each well and the plates were shaken for a further
20 h. The contents of the plate were transferred to a filter plate
and filtered into a fresh deep-well plate. The scavenger was washed
with two 400 microL portions of DMA. Aliquots were removed from
each well for LCMS analysis. The solutions were evaporated in a
Genevac. The purity was assessed by UV at 240 nm. Samples below 80%
parity were purified by preparative HPLC.
Example 11
Synthesis of
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclopropylamino-2-phen-
yl-acetamide
Method 2
##STR00238##
[0308] 7-Chloro, 6-aminoisoquinolone (25 mg, 0.13 mmol) was
dissolved in DMF. 2-Chlorophenylacetyl chloride (1.2 eq, 22 microL,
0.15 mmol) was added followed by diisopropylethylamide (2 eq., 45
microL, 0.26 mmol). The reaction mixture was shaken for 3 hr on a
reaction block at 75.degree. C. This crude mixture was carried on
to the next step without purification.
[0309] The crude reaction mixture from the previous step was taken
as is and excess cyclopropylamine (100 microL, 11 eq.) was added.
The reaction mixture was shaken on a reaction block for 16 hr at
75.degree. C. This crude reaction mixture was purified directly as
is on preparative LC-MS.
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyclopropylamino-2-phen-
yl-acetamide (21 mg, 0.05 mmol) was isolated as an amorphous solid
in 40% yield. ES+=368.
Example 12
Synthesis of
2-amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-phenyl-propiona-
mide
Method 3
##STR00239##
[0311] 6-Amino-7-chloro-2H-isoquinolin-1-one (0.2 mmol, 39 mg) and
L-Fmoc-2-amino-3-phenyl-propionyl chloride (0.2 mmol, 81 mg) were
dissolved in 3 ml DMF. The mixture was allowed to stir at room
overnight. HPLC-MS confirmed the product had formed. The crude
product was carried on to the next step without further
purification. MS (M+1) 565.
[0312] The above crude product in DMF was treated with piperidine
(5-10% total concentration), and the reaction mixture was allowed
to stir at room overnight. The title compound was obtained after
prep-HPLC purification. MS (M+1) 342.
Example 13
Synthesis of
1-benzyl-3-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-urea
Method 4.
##STR00240##
[0314] 6-Amino-2H-isoquinolin-1-one (0.2 mmol, 30 mg) and benzyl
isocyanate (0. mmol, 27 mg) were dissolved in 1 mL DMA. The mixture
was allowed to stir at 60.degree. C. overnight. The product was
obtained by HPLC purification. MS (M+1) 294.
Example 14
Synthesis of 4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)amide
##STR00241## ##STR00242##
[0316] To a solution of
benzyl-methoxymethyl-trimethylsilanylmethyl-amine (2.05 mL, 8.0
mmol) and (E)-3-(4-chloro-phenyl)-acrylic acid methyl ester (1.57
g, 8.0 mmol) in dichloromethane (16 mL) was added TFA (275 mg, 2.4
mmol). The mixture was stirred at 23.degree. C. for 30 min then
treated with saturated aqueous NaHCO.sub.3 (20 mL), extracted with
dichloromethane (2.times.50 ml), dried with MgSO.sub.4, filtered,
and concentrated. Purification of the crude by flash chromatography
(SiO.sub.2, hexane to 1:1 hexane:EtOAc) gave
(trans)-1-benzyl-4-(4-chloro-phenyl)pyrrolidine-3-carboxylic acid
ethyl ester (2.11 g, 80%).
[0317] A solution of the ester from above (1.01 g, 2.94 mmol) in
MeOH (15 mL) and THF (5 mL) was treated with a 6 M aqueous NaOH
solution (4.9 mL, 29.4 mmol) and heated at reflux for 2 h. The
mixture was then acidified to pH=1 with 6 M aqueous HCl, extracted
with dichloromethane, dried with MgSO.sub.4, filtered, and
concentrated to afford
1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid as the
HCL salt (1.00 g, 97%).
[0318] To a solution of the acid from above (1.06 g, 3.0 mmol) and
6-amino-5-chloroisoquinolin-1-one (450 mg, 2.3 mmol) in pyridine (5
mL) was added POCL (320 .mu.L, 3.5 mmol). The mixture was stirred
for 1 h then treated with water, extracted with EtOAc, dried with
MgSO.sub.4, filtered, and concentrated to afford
1-benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide (454 mg,
40%).
[0319] The above N-benzyl pyrrolidine (216 mg, 0.44 mmol) was
dissolved in dichloroethane (5 mL) and treated with alpha
chloroethyl chloroformate (95 microL, 0.88 mmol) followed by proton
sponge (69 mg, 0.44 mmol). The mixture wax stirred at 23.degree. C.
for 1 h then heated at reflux for 3 h. The mixture was then
concentrated in vacuo, diluted with MeOH (10 mL), and heated at
reflux tor 2 h. The solution was concentrated in vacuo then
purified by RP HPLC to afford the desired product as the TFA salt
(88 mg, 40%) MS MH+=402.3.
[0320] The following compounds were also prepared using the methods
described in the General Synthetic Methods section and the
synthetic examples above:
TABLE-US-00002 Name MH+
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 357
dimethylamino-2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-methyl- 336
piperazin-1-yl)-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 349
(cyclohexylmethyl-amino)-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4- 413
hydroxy-piperidin-1-yl)-2-phenyl-acetamide
2-Benzylamino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6- 419
yl)-2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 353
thiomorpholin-4-yl-propionamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(1,2,3,4- 383
tetrahydro-naphthalen-1-ylamino)-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(2- 377
thiophen-2-yl-ethylamino)-propionamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 343
methylamino-2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(ethyl- 371
methyl-amino)-2-phenyl-acetamide
(S)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 343
3-phenyl-propionamide
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 343
3-phenyl-propionamide
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 329
2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquiolin-6-yl)-2- 383
cyclobutylamino-2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 383
(cyclopropylmethyl-amino)-2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(3-ethoxy- 415
propylamino)-2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(2- 428
dimethlamino-ethyl)-ethyl-amino]-2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 351
[(tetrahydro-pyran-4-ylmethyl)-amino]-acetamide
2-(Adamantan-1-ylamino)-N-(7-chloro-1-oxo-1,2-dihydro- 387
isoquiolin-6-yl)-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(pyridin-2- 344
ylmethyl)-amino]-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(pyridin-3- 344
ylmethyl)-amino]-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-[(pyridin-4- 344
ylmethyl)-amino]-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 349
(cyclohexyl-methyl-amino)-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 281
methylamino-propionamide
2-Dimethylamino-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)- 246
acetamide 2-(Cyclohexylmethyl-amino)-N-(1-oxo-1,2-dihydro- 314
isoquinolin-6-yl)-acetamide
2-Dimethylamino-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 322
phenyl-acetamide Acetic acid
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6- 372
ylcarbamoyl)-phenyl-methyl ester
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-hydroxy-2- 330
phenyl-acetamide
(R)-2-Amino-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenyl- 294
acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-chloro- 390
phenyl)-3-methyl-butamide 2,5-Dichloro-thiophene-3-carboxylic acid
(1-oxo-1,2-dihydro- 340 isoquinolin-6-yl)-amide
N-(1-Oxo-1,2-dihydro-isoquiolin-6-yl)-2-phenylsulfanyl- 374
nictinamide
2-(3-Methoxy-phenyl)-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)- 309
acetamide
2-(4-Chloro-phenoxy)-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)- 393
nicotinamide 2-(4-Chloro-phenoxy)-2-methyl-N-(1-oxo-1,2-dihydro-
358 isoquinolin-6-yl)-propionamide
N-(1-Oxo-1,2-dihydro-isoquinolin-6-yl)-succinamic acid ethyl 289
ester Thiophene-2-carboxylic acid (1-oxo-1,2-dihydro-isoquinolin-6-
271 yl)-amide 1-(4-Chloro-phenyl)-cyclopentanecarboxylic acid
(1-oxo-1,2- 368 dihydro-isoquinolin-6-yl)-amide
2-(4-Chloro-phenoxy)-N-(1-oxo-1,2-dihydro-isoquinolin-6-yl)- 330
acetamide N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-
314 benzamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenyl- 314
acetamide N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2,3,6-
354 trifluoro-benzamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-5-fluoro-2- 332
methyl-benzamide
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4- 379
nitro-benzamide
2-Bromo-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 379
benzamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-fluoro- 332
phenyl)-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2,2-dimethyl- 280
propionamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3,3-dimethyl- 294
butyamide N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 409
phenylsulfanyl-nicotinamide
2,4-Dichloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 369
benzamide 5-Methyl-3-phenyl-isoxazole-4-carboxylic acid
(7-chloro-1- 381 oxo-1,2-dihydro-isoquinolin-6-yl)-amide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2,4,6- 354
trifluoro-benzamide 1-(4-Chloro-phenyl)-cyclopentanecarboxylic acid
(4-oxo-3,4- 368 dihydro-quinazolin-7-yl)-amide
Piperidine-4-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7- 273
yl)-amide 2-Benzylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)- 309
acetamide 1-Benzyl-piperdine-4-carboxylic acid (4-oxo-3,4-dihydro-
363 quinaolin-7-yl)-amide Piperidine-3-carboxylic acid
(4-oxo-3,4-dihydro-quinazolin-7- 273 yl)-amide
Pyrrolidine-2-carboxylic acid (4-oxo-3,4-dihydro-quinazolin-7- 259
yl)-amide 2-Amino-4-methyl-pentanoic acid (4-oxo-3,4-dihydro 275
quinazolin-7-yl)-amide
(R)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-3-phenyl- 309
propionamide
(S)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-3-phenyl- 309
propionamide
2-(Cyclobexylmethyl-amino)-N-(4-oxo-3,4-dihydro-quinazolin- 315
7-yl)-acetamide
2-Methylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2- 309
phenyl-acetamide
2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl- 295
acetamide
2-Cyclopropylamino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2- 335
phenyl-acetamide
(R)-2-Amino-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)-2-phenyl- 295
acetamide (R)-Pyrrolidine-2-carboxylic acid (4-oxo-3,4-dihydro- 259
quinazolin-7-yl)-amide
(R)-2-Amino-3-methyl-N-(4-oxo-3,4-dihydro-quinazolin-7-yl)- 261
butramide 2-(Cyclopropylmethyl-amino)-N-(4-oxo-3,4-dihydro- 273
quinazolin-7-yl)-acetamide
N-(4-Oxo-3,4-dihydro-quinazolin-7-yl)-2-(2-thiophen-2-yl- 329
ethylamino)-acetamide
2-(Cyclohexyl-methyl-amino)-N-(4-oxo-3,4-dihydro- 315
quinazolin-7-yl)-acetamide
N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2- 357
dimethylamino-2-phenyl-acetamide
N-(6-Chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-2- 369
cyclopropylamino-2-phenyl-acetamide
2,5-Dimethyl-2H-pyrazole-3-carboxylic acid (4-oxo-3,4- 284
dihydro-quinazolin-7-yl)-amide
2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-(4- 360
fluoro-phenyl)-propionamide
(R)-2-Amino-2-cyclohexyl-N-(1-oxo-1,2-dihydro-isoquinolin- 300
6-yl)-acetamide
(R)-2-Amino-2-(4-chloro-phenyl)-N-(1-oxo-1,2-dihydro- 362
isoquinolin-6-yl)-acetamide (R)-Pyrrolidine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro- 292 isoquinolin-6-yl)-amide
(S)-Pyrrolidine-2-carboxylic acid (7-chloro-1-oxo-1,2-dihydro- 292
isoquinolin-6-yl)-amide
2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 252
acetamide Piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2-dihydro-
306 isoquinolin-6-yl)-amide,
(R)-2-Amino-N-)7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 376
3-(4-chloro-phenyl)-propionamide
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 342
2-p-tolyl-acetamide
(S)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 348
3-cyclohexyl-propionamide (R)-2-Amino-4,4-dimethyl-pentanoic acid
(7-chloro-1-oxo1,2 322 dihydro-isoquinolin-6-yl)-amide
(S)-2-Amino-4,4-dimethyl-pentanoic acid (7-chloro-1-oxo-1,2- 322
dihydro-isoquinolin-6-yl)-amide
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4- 411
methanesulfonyl-benzamide
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4- 418
morpholin-4-yl-benzamide
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 392
3-naphthalen-2-yl-propionamide
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 392
3-naphthalen-1-yl-propionamide
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 343
3-pyridin-4-yl-propionamide
2-Metyl-2-methylamino-N-(1-oxo-1,2-dihydro-isoquinolin-6- 260
yl)-propionamide
2-Amino-2-methyl-N-(1-oxo-1,2-dihydro-isoquinolin-6- 260
propionamide (R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-
343 methoxy-2-phenyl-acetamide
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 343
methoxy-2-phenyl-acetamide
3-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 266
propionamide
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 294
3-methyl-butyramide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3,3,3- 411
trifluoro-2-methoxy-2-phenyl-propionamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-oxo-2- 327
phenyl-acetamide (R)-Piperidine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro- 306 isoquinolin-6-yl)-amide
2-tert-Bertylamino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin- 308
6-yl)-acetamide
(R)-2-Methoxy-N-(7-methoxy-1-oxo-1,2-dihydro-isoquinolin- 339
6-yl)-2-phenyl-acetamide
(S)-2-Methoxy-N-(7-methoxy-1-oxo-1,2-dihydro-isoquinolin-6- 339
yl)-2-phenyl-acetamide
(R)-2-Amino-2-cyclohexyl-N-(7-methoxy-1-oxo-1,2-dihydro- 330
isoquinolin-6-yl)-acetamide
(S)-2-Amino-2-cyclohexyl-N-(7-methoxy-1,2-dihydro- 330
isoquinolin-6-yl)-acetamide
4-Bromo-2-chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin- 413
6-yl)-benzamide
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-5- 412
methanesulfonayl-benzamide (R)-Tetrahydro-furan-2-carboxylic acid
(7-chloro-1-oxo-1,2- 293 dihydro-isoquinolin-6-yl)-amide
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 329
hydroxy-2-phenyl-acetamide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 329
hydroxy-2-phenyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-cyano- 324
benzamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-4- 358
nitro-benzamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4-nitro-2- 412
trifluoromethyl-benzamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-morpholin- 398
4-ylmethyl-benzamide 1-Amino-cyclohexanecarboxylic acid
(1-oxo-1,2-dihydro- 286 isoquinolin-6-yl)-amide
(R)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 334
2-cyclohexyl-acetamide (R)-2-Amino-4-methyl-pentanoic acid
(7-chloro-1-oxo-1,2- 308 dihydro-isoquinolin-6-yl)-amide
(S)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 334
2-cyclohexyl-acetamide (S)-2-Amino-4-methyl-pentanoic acid
(7-chloro-1-oxo-1,2- 308 dihydro-isoquinolin-6-yl)-amide
(S)-2-Amino-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)- 294
3-methyl-butyramide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4-methyl- 411
piperazin-1-ylmethyl)-benzamide
1,2,3,4-Tetrahydro-isoquinoline-5-carboxylic acid (7-chloro-1- 354
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
1,2,3,4-Tetrahydro-isoquinoline-8-carboxylic acid (7-chloro-1-
354
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
1-Methyl-piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2- 320
dihydro-isoquinoplin-6-yl)-amide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-methyl- 323
succinamic acid methyl ester
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3- 378
nitro-benzamide
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-5- 378
nitro-benzamide (S)-Tetrahydro-furan-2-carboylic acid
(7-chloro-1-oxo-1,2- 293 dihydro-isoquinolin-6-yl)-amide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4- 392
methyl-benzamide Tetrahydro-pyran-4-carboylic acid
(7-chloro-1-oxo-1,2- 307 dihydro-isoquinolin-6-yl)-amide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-phenyl- 371
succinamic acid
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-malonamic 309 acid
ethyl ester N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 283
methylsulfanyl-acetamide (S)-Pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro- 292 isoquinolin-6-yl)-amide
(S)-Pyrrolidine-3-carboxylic acid (7-chloro-1-oxo-1,2-dihydro- 306
isoquinolin-6-yl)-amide (R)-Pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro- 306 isoquinolin-6-yl)-amide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 315
methanesulfanyl-acetamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-3-phenyl- 357
malonamic acid (S)-Piperidine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro- 306 isoquinolin-6-yl)-amide
1-Methanesulfonyl-4-methyl-piperidine-4-carboxylic acid (7- 398
chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
2-Chloro-N-(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4- 378
nitro-benzamide N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-4
377 methanesulfonyl-benzamide (R)-Pyrrolidine-3-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro- 292 isoquinolin-6-yl)-amide
4-Amino-cyclohexanecarboxylic acid (7-chloro-1-oxo-1,2- 320
dihydro-isoquinolin-6-yl)-amide
4-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-ylcarbamoyl)- 349
cyclohexanecarboxylic acid
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 371
isopropoxy-2-phenyl-acetamide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 343
phenoxy-propionamide
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 343
phenoxy-propionamide 4-Phenyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2- 382 dihydro-isoquinolin-6-yl)-amide
4-(4-Chloro-phenyl)-piperidine-4-carboxylic acid (7-chloro-1- 416
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
4-Benzyl-piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2- 396
dihydro-isoquinolin-6-yl)-amide (R)-Piperidine-3-carboxylic acid
(1-oxo-1,2-dihydro- 272 isoquinolin-6-yl)-amide
(S)-Piperidine-3-carboxylic acid (1-oxo-1,2-dihydro- 272
isoquinolin-6-yl)-amide 1-Methyl-piperidine-4-carboxylic acid
(1-oxo-1,2-dihydro- 286 isoquinolin-6-yl)-amide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 295
hydroxy-3-methyl-butyramide Piperizine-2-carboxylic acid
(7-chloro-1-oxo-1,2-dihydro- 307 isoquinolin-6-yl)-amide
4-Methyl-piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2- 320
dihydro-isoquinolin-6-yl)-amide
(3S,4S)-3-Methyl-piperidine-4-carboxylic acid (7-chloro-1-oxo- 306
1,2-dihydro-isoquinolin-6-yl)-amide
(trans)-4-Phenyl-piperidine-3-carboxylic acid (7-chloro-1-oxo- 382
1,2-dihydro-isoquinolin-6-yl)-amide
(1R,3S)-3-Amino-cyclopentanecarboxylic acid (7-chloro-1-oxo- 306
1,2-dihydro-isoquinolin-6-yl)-amide 4-Hydroxy-cyclohexanecarboxylic
acid (7-chloro-1-oxo-1,2- 321 dihydro-isoquinolin-6-yl)-amide
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 335
cyclohexyl-2-hydroxy-acetamide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 335
cyclohexyl-2-hydroxy-acetamide
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 343
hydroxy-2-phenyl-propionamide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 343
hydroxy-2-phenyl-propionamide (1R,3S)-3-Amino-cyclohexanecarboxylic
acid (7-chloro-1-oxo- 320 1,2-dihydro-isoquinolin-6-yl)-amide
(1R,3S)-3-Amino-cyclohexanecarboxylic acid (7-methoxy-1- 316
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
(3R,4S)-3-Methyl-piperidine-4-carboxylic acid (7-chloro-1- 320
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
4-Dimethyamino-cyclohexanecarboxylic acid (7-chloro-1-oxo- 348
1,2-dihydro-isoquinolin-6-yl)-amide
Trans-3-amino-cyclobutanecarboxylic acid (7-chloro-1-oxo-1,2- 292
dihydro-isoquinolin-6-yl)-amide Cis-3-amino-cyclobutanecarboxlic
acid (7-chloro-1-oxo-1,2- 292 dihydro-isoquinolin-6-yl)-amide
4-Amino-1-(cis-4-chloro-phenyl)-cyclohexanecarboxylic acid 430
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
4-Amino-1-(trans-4-chloro-phenyl)-cyclohexanecarboxylic acid 430
(7-chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 391
cyclohexyl-2-isopropylamino-acetamide
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 320
cyclohexyl-2-isopropylamino-acetamide
(S)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2- 376
cyclohexyl-2-isopropylamino-acetamide
4-(4-Fluoro-phenyl)-pyrrolidine-3-carboxylic acid (1-oxo-1,2- 352
dihydro-isoquinolin-6-yl)-amide
(1S,2S)-2-Methyl-4-oxo-cyclohexanecarboxylic acid (7-chloro- 333
1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
3-Phenyl-pyrrolidine-3-carboxylic acid (7-chloro-1-oxo-1,2- 368
dihydro-isoquinolin-6-yl)-amide 1-Isopropyl-piperidine-4-carboxylic
acid (7-chloro-1-oxo-1,2- 348 dihydro-isoquinolin-6-yl)-amide
1-Cyclohexyl-piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2- 334
dihydro-isoquinolin-6-yl)-amide
1-Cyclohexyl-piperidine-4-carboxylic acid (7-chloro-1-oxo-1,2- 338
dihydro-isoquinolin-6-yl)-amide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-4- 397
(piperzine-1-sulfonyl)-benzamide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-4- 461
(piperazine-1-sulfonyl)-benzamide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(2- 363
chloro-phenyl)-2-hydroxy-acetamide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(3- 363
chloro-phenyl)-2-hydroxy-acetamide
(2S,3S)-2-Amino-3-methyl-pentanoic acid (7-chloro-1-oxo-1,2- 308
dihydro-isoquinolin-6-yl)-amide
N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-phenyl 341
isobutyramide 1-Benzyl-piperidine-4-carboxylic acid
(7-chloro-1-oxo-1,2- 396 dihydro-isoquinolin-6-yl)-amide
(trans)-4-Phenyl-pyrrolidine-3-carboxylic acid (7-chloro-1-oxo- 368
1,2-dihydro-isoquinolin-6-yl)-amide
(trand)-4-(4-Fluro-phenyl)-pyrrolidine-3-carboxylic acid (7- 386
chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
(3R,4S)-1,3-Dimethyl-piperidine-4-carboxylic acid (7-chloro-1- 334
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
5-Phenyl-piperidine-3-carboxylic acid (7-chloro-1-oxo-1,2- 382
dihydro-isoquinolin-6-yl)-amide
1,2,3,4-Tetrahydro-isoquinolin-7-carboxylic acid (7-chloro-1- 354
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
1,2,3,4-Tetrahydro-isoquinolin-6-carboxylic acid (7-chloro-1- 354
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
4-(3-Amino-propane-1-sulfonyl)-2-chloro-N-(7-chloro-1-oxo- 454
1,2-dihydro-isoquinolin-6-yl)-benzamide
(trans)-4-(3-Bromo-phenyl)-pyrrolidine-3-carboxylic acid (7- 447
chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
(trans)-4-(4-Chloro-phenyl)-pyrrolidine-3-carboxylic acid (7- 402
chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide,
(1R,5S,6R)-3-Aza-bicyclo[3.1.0]hexane-6-carboxylic acid (7- 304
chloro-1-oxo1,2-dihydro-isoquinolin-6-yl)-amide
(1R,5S,6S)-3-Aza-bicyclo[3.1.0]hexane-6-carboxylic acid (7- 304
chloro-1-oxo1,2-dihydro-isoquinolin-6-yl)-amide
(trans)-4-(3-Bromo-phenyl)-pyrrolidine-3-carboxylic acid (6- 448
chloro-4-oxo-3,4-dihydro-quinazolin-7-yl)-amide
(R)-N-(7-Chloro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-(4- 377
chloro-phenyl)-2-hydroxy-propionamide
(R)-N-(7-Chloro-4-oxo-3,4-dihydro-isoquinolin-7-yl)-2-(4- 378
chloro-phenyl)-2-hydroxy-propionamide
(R)-2-(4-Chloro-phenyl)-2-hydroxy-N-(4-oxo-3,4-dihydro- 344
quinazolin-7-yl)-propionamide 1-Methyl-piperidine-4-carboxylic acid
(7-bromo-1-oxo-1,2- 365 dihydro-isoquinolin-6-yl)-amide
1-Methyl-piperidine-4-carboxylic acid (7-bromo-1-oxo-1,2- 304
dihydro-isoquinolin-6-yl)-amide 1-Methyl-piperidine-4-carboxylic
acid (7-bromo-1-oxo-1,2- 311 dihydro-isoquinolin-6-yl)-amide
(trans)-4-Phenyl-pyrrolidine-3-carboxylic acid (7-bromo-1-oxo- 413
1,2-dihydro-isoquinolin-6-yl)-amide 4-(4-Chloro
phenyl)-pyrrolidine-3-carboxylic acid (7-bromo-1- 447
oxo-1,2-dihydro-isoquinolin-6-yl)-amide
(trans)-4-Phenyl-pyrrolidine-3-carboxylic acid (5-chloro-1-oxo- 369
1,2-dihydro-isoquinolin-6-yl)-amide
(trans)-4-Phenyl-pyrrolidine-3-carboxylic acid (7-chloro-5- 386
fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-amide
Selected compounds were evaluated in a Rat Aortic Rings issue
assay:
Rat Aortic Rings Tissue Assay
[0321] Segments of rat thoracic aorta were dissected from Sprague
Dawley rats cleaned of excess connective tissue, and cut into 3-4
mm rings in a petri dish filled with 4.degree. C. PBS, containing
118 mM NaCl; 4.7 mM KCl; 1.6 mM CaCl.sub.2; 1.2 mM KH2PO4; 1.2 mM
MgCl.sub.2; 10.0 mM Dextrose; 25 mM NaHCO3; 0.02 mM NaEDTA; pH
7.25, and kept on ice before dissection. The rings were then
suspended on a force transducer device and placed into 37.degree.
C. temperature-controlled tissue baths containing PBS that was
constantly oxygenated with 95% O.sub.2 and 5% CO.sub.2. Isometric
force was continually measured and the data collected by a digital
acquisition system. The rings were placed under a preload of 2.5 g
of force for a 1 hr equilibration period to serve as baseline
force. Rings were contracted with 50 mM KCl to obtain the maximum
contraction level for normalization. Following a washout period of
30 min, the rings were pre-constricted with 10.sup.-6 M
phenylephrine and relaxed with a bolus dose of 10.sup.-7M
acetylcholine to check the integrity of the endothelium. Following
a second washout period of 30 min, rings were pre-constricted a
second time with 10.sup.-6 M phenylephrine and the contraction
allowed to stabilize. A cumulative dose response of a Rho-kinase
inhibitor was tested in a DMSO vehicle at a 1:1000 dilution using
half log intervals. After each dose of inhibitor the response was
allowed to stabilize before the addition of the next dose.
Following the cumulative dose response with inhibitor, the tissues
were washed 3.times. in PBS and allowed to equilibrate at resting
tension. A second KCl contraction was performed as stated above to
check the viability of the tissue. Following this, a second
phenylephrine contraction and acetylcholine bolus dose were given
as above to check for the integrity of the endothelium following
inhibitor testing. The effect of the Rho-kinase inhibitors were
expressed as a percentage relaxation from the phenylephrine-induced
contraction at each dose. The IC.sub.50 for each inhibitor was
determined from the concentration that produced 50% relaxation from
the phenylephrine-induced contraction. The data for each inhibitor
represents the mean from four different segments from four
different rats.
[0322] Preferred compounds have an IC.sub.50<10 .mu.M in this
assay.
Methods of Therapeutic Use
[0323] In accordance with the invention, there are provided novel
methods of using the compounds of the formula (I). The compounds
disclosed therein effectively inhibit Rho kinase. The inhibition of
Rho kinase is an attractive means for preventing and treating a
variety of cardiovascular diseases or conditions associated with
Rho kinase activation. Thus, the compounds are useful for the
treatment of diseases and conditions as described in the Background
section, including the following conditions and diseases:
hypertension, atherosclerosis, restenosis, stroke, myocardial
infarction, heart failure, coronary artery disease, peripheral
artery disease, coronary vasospasm, cerebral vasospasm,
ischemia/reperfusion injury, pulmonary hypertension, angina,
erectile dysfunction, renal disease and organ failure. As disclosed
in the Background section, the compounds of the invention will also
be useful for treating diseases or conditions associated with
smooth muscle hyper reactivity or with activated Rho-kinase under
other pathophysiological conditions. These diseases include but are
not limited to asthma, glaucoma, cancer, Alzheimer's disease,
multiple sclerosis, spinal cord injury and neuropathic pain.
[0324] These disorders have been well characterized in man, but
also exist with a similar etiology in other mammals, and can be
treated by pharmaceutical compositions of the present
invention.
[0325] For therapeutic use, the compounds of the invention may be
administered via a pharmaceutical composition in any conventional
pharmaceutical dosage form in any conventional manner. Conventional
dosage forms typically include a pharmaceutically acceptable
carrier suitable to the particular dosage form selected. Routes of
administration include, but are not limited to, intravenously,
intramuscularly, subcutaneously, intrasynovially, by infusion,
sublingually, transdermally, orally, topically or by inhalation.
The preferred modes of administration are oral and intravenous.
[0326] The compounds of this invention may be administered alone or
in combination with adjuvants that enhance stability of the
inhibitors, facilitate administration of pharmaceutical
compositions containing them in certain embodiments, provide
increased dissolution or dispersion, increase inhibitory activity,
provide adjunct therapy, and the like, including other active
ingredients. In one embodiment, for example, multiple compounds of
the present invention can be administered. Advantageously, such
combination therapies utilize lower dosages of the conventional
therapeutics, thus avoiding possible toxicity and adverse side
effects incurred when those agents are used as monotherapies.
Compounds of the invention may be physically combined with the
conventional therapeutics or other adjuvants into a single
pharmaceutical composition. Advantageously, the compounds may then
be administered together in a single dosage form. In some
embodiments, the pharmaceutical compositions comprising such
combinations of compounds contain at least about 5%, but more
preferably at least about 20%, of a compound of formula (I) (w/w)
or a combination thereof. The optimum percentage (w/w) of a
compound of the invention may vary and is within the purview of
those skilled in the art. Alternatively, the compounds of the
present invention and the conventional therapeutics or other
adjuvants may be administered separately (either serially or in
parallel). Separate dosing allows for greater flexibility in the
dosing regime.
[0327] As mentioned above, dosage forms of the compounds of this
invention may include pharmaceutically acceptable carriers and
adjuvants known to those of ordinary skill in the art and suitable
to the dosage form. These carriers and adjuvants include, for
example, ion exchangers, alumina, aluminum stearate, lecithin,
serum proteins, buffer substances, water, salts or electrolytes and
cellulose-based substances. Preferred dosage forms include tablet,
capsule, caplet, liquid, solution, suspension, emulsion, lozenges,
syrup, reconstitutable powder, granule, suppository and transdermal
patch. Dosage levels and requirements for the compounds of the
present invention may be selected by those of ordinary skill in the
art from available methods and techniques suitable for a particular
patient. In some embodiments, dosage levels range front about
1-1000 mg/dose for a 70 kg patient. Although one dose per day may
be sufficient, up to 5 doses per day may be given. For oral doses,
up to 2000 mg/day may be required. As the skilled artisan will
appreciate, lower or higher doses may be required depending on
particular factors. For instance, specific dosage and treatment
regimens will depend, on factors such as the patient's general
health profile, the severity and coarse of the patient's disorder
or disposition thereto, and the judgment of the treating
physician.
* * * * *