U.S. patent application number 15/409369 was filed with the patent office on 2017-10-05 for pyrimidinedione compounds.
The applicant listed for this patent is MYOKARDIA, INC.. Invention is credited to Robert ANDERSON, Danielle AUBELE, Marc EVANCHIK, Jonathan Charles FOX, Brian KANE, Puping LU, Robert McDOWELL, Johan OSLOB, Hector RODRIGUEZ, Yonghong SONG, Arvinder SRAN.
Application Number | 20170281626 15/409369 |
Document ID | / |
Family ID | 51177189 |
Filed Date | 2017-10-05 |
United States Patent
Application |
20170281626 |
Kind Code |
A1 |
OSLOB; Johan ; et
al. |
October 5, 2017 |
PYRIMIDINEDIONE COMPOUNDS
Abstract
Provided are novel pyrimidine dione compounds and
pharmaceutically acceptable salts thereof, that are useful for the
treatment of hypertrophic cardiomyopathy (HCM) and conditions
associated with left ventricular hypertrophy or diastolic
dysfunction. The synthesis and characterization of the compounds
and pharmaceutically acceptable salts thereof, are described, as
well as methods for treating HCM and other forms of heart
disease.
Inventors: |
OSLOB; Johan; (Sunnyvale,
CA) ; ANDERSON; Robert; (Brisbane, CA) ;
AUBELE; Danielle; (San Mateo, CA) ; EVANCHIK;
Marc; (San Jose, CA) ; FOX; Jonathan Charles;
(San Francisco, CA) ; KANE; Brian; (Oakland,
CA) ; LU; Puping; (Foster City, CA) ;
McDOWELL; Robert; (San Francisco, CA) ; RODRIGUEZ;
Hector; (Brisbane, CA) ; SONG; Yonghong;
(Foster City, CA) ; SRAN; Arvinder; (Fremont,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MYOKARDIA, INC. |
South San Francisco |
CA |
US |
|
|
Family ID: |
51177189 |
Appl. No.: |
15/409369 |
Filed: |
January 18, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14883152 |
Oct 14, 2015 |
9585883 |
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15409369 |
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|
14309381 |
Jun 19, 2014 |
9181200 |
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14883152 |
|
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61838088 |
Jun 21, 2013 |
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61939655 |
Feb 13, 2014 |
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61981366 |
Apr 18, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 403/12 20130101;
A61K 45/06 20130101; C07D 413/04 20130101; A61P 9/04 20180101; C07D
405/04 20130101; C07D 401/12 20130101; C07D 405/12 20130101; C07D
239/545 20130101; C07D 403/04 20130101; A61K 31/513 20130101; C07D
239/553 20130101; A61P 9/12 20180101; A61P 9/00 20180101; A61P 9/10
20180101; C07D 401/04 20130101; C07D 413/12 20130101 |
International
Class: |
A61K 31/513 20060101
A61K031/513; C07D 405/12 20060101 C07D405/12; C07D 405/04 20060101
C07D405/04; C07D 403/12 20060101 C07D403/12; C07D 413/04 20060101
C07D413/04; C07D 401/04 20060101 C07D401/04; C07D 239/553 20060101
C07D239/553; C07D 239/545 20060101 C07D239/545; A61K 45/06 20060101
A61K045/06; C07D 403/04 20060101 C07D403/04; C07D 413/12 20060101
C07D413/12; C07D 401/12 20060101 C07D401/12 |
Claims
1. A compound having the formula: ##STR00218## or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 is a
member selected from the group consisting of C.sub.1-C.sub.8 alkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl-C.sub.1-C.sub.4 alkyl, 4- to 7-membered
heterocycloalkyl, phenyl, phenyl-C.sub.1-C.sub.4 alkyl, 5- to
6-membered heteroaryl and 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, wherein each R.sup.1 is
optionally substituted with from 1-3 R.sup.a; R.sup.2 is a member
selected from the group consisting of phenyl,
phenyl-C.sub.1-C.sub.4 alkyl, 5- to 6-membered heteroaryl and 5- to
6-membered heteroaryl-C.sub.1-C.sub.4 alkyl, wherein each R.sup.2
is optionally substituted with from 1-5 R.sup.b; R.sup.3 is a
member selected from the group consisting of C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.4 cycloalkyl, and 4- to 7-membered heterocycloalkyl
wherein each R.sup.3 is optionally substituted with from 1-3
R.sup.c; R.sup.4 is H; X is a member selected from the group
consisting of H and F; each R.sup.a is independently selected from
the group consisting of halo, CN, hydroxyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, phenyl,
phenyl-C.sub.1-C.sub.4 alkyl, phenyl-C.sub.1-C.sub.4 alkoxy,
phenoxy, --COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1,
--SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a1, wherein
each R.sup.a1 and R.sup.A2 is independently selected from the group
consisting of H, C.sub.1-C.sub.4 alkyl and phenyl, or optionally
R.sup.a1 and R.sup.a2 when attached to a nitrogen atom are combined
to form a 4- to 6-membered ring; each R.sup.b is independently
selected from the group consisting of halo, CN, hydroxyl,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, phenoxy, phenyl-C.sub.1-C.sub.4 alkoxy, methylenedioxy,
difluoromethylenedioxy, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, --SO.sub.2NR.sup.b1R.sup.b2,
CONR.sup.b1R.sup.ba2, NR.sup.b1R.sup.b2, 5- to 6-membered
heteroaryl, and 5- to 6-membered heterocyclyl optionally
substituted with oxo, wherein each R.sup.b1 and R.sup.b2 is
independently selected from the group consisting of H and
C.sub.1-C.sub.4 alkyl or optionally R.sup.b1 and R.sup.b2 when
attached to a nitrogen atom are combined to form a 4- to 6-membered
ring; and each R is independently selected from the group
consisting of halo, hydroxyl and C.sub.1-C.sub.2 alkoxy.
2. A compound of claim 1, or a pharmaceutically acceptable salt
thereof, wherein, R.sup.1 is a member selected from the group
consisting of C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, 4-
to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered
heteroaryl, wherein each R.sup.1 is optionally substituted with
from 1-3 R.sup.a; R.sup.2 is phenyl, which is optionally
substituted with from 1-5 R.sup.b; R.sup.3 is a member selected
from the group consisting of C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4
cycloalkyl, and 4- to 7-membered heterocycloalkyl wherein each
R.sup.3 is optionally substituted with from 1-2 R.sup.c; R.sup.4 is
H, X is a member selected from the group consisting of H and F;
each R.sup.a is independently selected from the group consisting of
halo, CN, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
--COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1,
--SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein
each R.sup.a1 and R.sup.a2 is independently selected from the group
consisting of H and C.sub.1-C.sub.4 alkyl or optionally R.sup.a1
and R.sup.a2 when attached to a nitrogen atom are combined to form
a 4- to 6-membered ring; each R.sup.b is independently selected
from the group consisting of halo, CN, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, --SO.sub.2NR.sup.b1R.sup.b2,
CONR.sup.b1R.sup.b2, NR.sup.b1R.sup.ba2, 5- to 6-membered
heteroaryl, and 5- to 6-membered heterocyclyl optionally
substituted with oxo, wherein each R.sup.b1 and R.sup.b2 is
independently selected from the group consisting of H and
C.sub.1-C.sub.4 alkyl or optionally R.sup.b1 and R.sup.b2 when
attached to a nitrogen atom are combined to form a 4- to 6-membered
ring; and each R is independently selected from the group
consisting of halo and C.sub.1-C.sub.2 alkoxy.
3. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein X is H.
4. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is selected from the group consisting
of C.sub.3-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl, and 4- to
6-membered heterocycloalkyl, wherein each R.sup.1 is optionally
substituted with from 1-2 R.sup.a.
5. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is selected from the group consisting
of phenyl and 5- to 6-membered heteroaryl, wherein each R.sup.1 is
optionally substituted with from 1-3 R.sup.a.
6. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is selected from the group consisting
of C.sub.3-C.sub.4 alkyl, C.sub.3-C.sub.8 cycloalkyl, and 4- to
6-membered heterocycloalkyl.
7. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is 4- to 6-membered heterocycloalkyl,
optionally substituted with from 1-2 R.sup.a selected from the
group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
--COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1,
--SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein
each R.sup.a1 and R.sup.a2 is independently selected from the group
consisting of H and C.sub.1-C.sub.4 alkyl.
8. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is selected from the group consisting
of cyclobutyl, isopropyl, isobutyl, 1-methoxypropan-2-yl,
cyclopentyl, cyclohexyl, 4-tetrahydropyranyl,
1-(methylsulfonyl)piperidin-4-yl,
1-(methoxycarbonyl)piperidin-4-yl, 4,4-difluorocyclohexyl, phenyl,
2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, and
1-methyl-3-pyrazolyl.
9. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.2 is optionally substituted with from
1-2 R.sup.b.
10. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.2 is selected from the group consisting
of phenyl, 3-methylphenyl, 2-3 fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 3-4
chlorophenyl, 3-methoxyphenyl, 3-(3-oxazolidin-2-onyl)phenyl,
3-(2-methyl-1-imidazyl)phenyl, 3-(1-pyrazolyl)phenyl, and
3-(1,2,4-triazol-1-yl)phenyl.
11. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.3 is selected from the group consisting
of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxyalkyl, and
C.sub.3-C.sub.4 cycloalkyl.
12. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.3 is selected from the group consisting
of methyl, ethyl, propyl, cyclopropyl, cyclobutyl and
2-methoxymethyl.
13. A compound of any of claims 1 to 10, or a pharmaceutically
acceptable salt thereof, wherein R.sup.3 is methyl.
14. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is isopropyl; R.sup.2 is optionally
substituted with 1-2 R.sup.b; and R.sup.3 is methyl.
15. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is 4- to 6-membered heterocycloalkyl,
optionally substituted with from 1-2 R.sup.a selected from the
group consisting of C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
--COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1,
--SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein
each R.sup.a1 and R.sup.a2 is independently selected from the group
consisting of H and C.sub.1-C.sub.4 alkyl; R.sup.2 is optionally
substituted with 1-2 R.sup.b; and R.sup.3 is methyl.
16. A compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof, wherein R.sup.1 is selected from the group consisting
of phenyl and 5- to 6-membered heteroaryl, wherein each R.sup.1 is
optionally substituted with from 1-3 R.sup.a; R.sup.2 is optionally
substituted with from 1-2 R.sup.b; and R.sup.3 is methyl.
17. A pharmaceutical composition comprising a compound of any of
claims 1-16, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable excipient.
18. A compound of claim 1, selected from the group consisting of:
##STR00219## ##STR00220## or a pharmaceutically acceptable salt
thereof.
19. A method of treating hypertrophic cardiomyopathy (HCM), or a
cardiac disorder having a pathophysiological feature associated
with HCM, comprising administering to a subject in need thereof an
effective amount of a compound of any of claims 1-16, or 18 or a
pharmaceutically acceptable salt thereof.
20. A method of treating a disease or disorder selected from the
group consisting of diastolic heart failure with preserved ejection
fraction, ischemic heart disease, angina pectoris, and restrictive
cardiomyopathy, comprising administering to a subject in need
thereof an effective amount of a compound of any of claims 1-16, or
18 or a pharmaceutically acceptable salt thereof.
21. A method of treating a disease or disorder characterized by
left ventricular hypertrophy due to volume or pressure overload,
said disease or disorder selected from the group consisting of
chronic mitral regurgitation, chronic aortic stenosis, and chronic
systemic hypertension; in conjunction with therapies aimed at
correcting or alleviating the primary cause of volume or pressure
overload, including valve repair/replacement or effective
antihypertensive therapy, comprising administering to a subject in
need thereof an effective amount of a compound of any of claims
1-16, or 18 or a pharmaceutically acceptable salt thereof.
22. A method of treating hypertrophic cardiomyopathy (HCM), or a
cardiac disorder having a pathophysiological feature associated
with HCM, comprising administering to a subject in need thereof an
effective amount of a compound of any of claims 1-16, or 18 or a
pharmaceutically acceptable salt thereof combined with therapies
that retard the progression of heart failure by down-regulating
neurohormonal stimulation of the heart and attempt to prevent
cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor
blockers (ARBs), .beta.-blockers, aldosterone receptor antagonists,
or neural endopeptidase inhibitors); therapies that improve cardiac
function by stimulating cardiac contractility (e.g., positive
inotropic agents, such as the .beta.-adrenergic agonist dobutamine
or the phosphodiesterase inhibitor milrinone); and therapies that
reduce cardiac preload (e.g., diuretics, such as furosemide) or
afterload (vasodilators of any class, including but not limited to
calcium channel blockers, phosphodiesterase inhibitors, endothelin
receptor antagonists, renin inhibitors, or smooth muscle myosin
modulators).
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/833,152 filed Oct. 14, 2015, which is a divisional of U.S.
application Ser. No. 14/309,381 filed Jun. 19, 2014 (now U.S. Pat.
No. 9,181,200), which claims benefit under 35 U.S.C. .sctn.119(e)
of U.S. Provisional Application No. 61/838,088 filed Jun. 21, 2013,
and U.S. Provisional Application No. 61/939,655 filed Feb. 13,
2014, and U.S. Provisional Application No. 61/981,366 filed Apr.
18, 2014, each of which is incorporated herein by reference in its
entirety.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0002] NOT APPLICABLE
BACKGROUND OF THE INVENTION
[0003] Genetic (heritable) hypertrophic cardiomyopathy (HCM)
comprises a group of highly penetrant, monogenic, autosomal
dominant myocardial diseases. HCM is caused by one or more of over
1,000 known point mutations in any one of the structural protein
genes contributing to the functional unit of myocardium, the
sarcomere. About 1 in 500 individuals in the general population are
found to have left ventricular hypertrophy unexplained by other
known causes (e.g., hypertension or valvular disease), and many of
these can be shown to have HCM, once other heritable (e.g.,
lysosomal storage diseases), metabolic, or infiltrative causes have
been excluded.
[0004] Sarcomere gene mutations that cause HCM are highly
penetrant, but there is wide variability in clinical severity and
clinical course. Some genotypes are associated with a more
malignant course, but there is considerable variability between and
even within families carrying the same mutation. Sex differences
have also been noted, with male patients generally more severely
affected than female patients. While many patients with HCM report
minimal or no symptoms for extended periods of time, HCM is a
progressive disease with a significant cumulative burden of
morbidity. Symptoms of effort intolerance predominate, and can be
exacerbated by exercise and other maneuvers that increase heart
rate and/or decrease preload. As with many other disorders,
symptoms tend to worsen with age. By far the most prevalent
clinical burden for patients with HCM is exertional dyspnea, which
limits their activities of daily living and can be
debilitating.
[0005] Patients with HCM are often symptomatic in the absence of
documented hemodynamic abnormalities like left ventricular outflow
tract obstruction (with or without mitral regurgitation). Patients'
symptoms of exertional dyspnea can rapidly worsen with the onset of
atrial fibrillation, a common complication of HCM that can
precipitate acute pulmonary edema that increases the risk of
systemic arterial thromboembolic disease, including stroke. Other
adverse events associated with HCM include intolerance of
hypovolemia or hypervolemia, and syncope. Concomitant coronary
artery disease may confer a higher risk of acute coronary syndromes
than in patients without HCM. Sudden cardiac death (SCD) in
patients with HCM is both uncommon and difficult to predict but is
a leading cause of non-traumatic death in young adults. For
survivors of SCD, ICD placement is standard practice, and in other
HCM patients risk profiling, while imprecise, is used to identify
those for whom ICD placement for primary prevention is deemed
prudent.
[0006] Medical therapy for HCM is limited to the treatment of
symptoms and does not address the fundamental, underlying cause of
disease--disruptions in normal sarcomere function. Currently
available therapies are variably effective in alleviating symptoms
but typically show decreased efficacy with increasing disease
duration. Patients are thus empirically managed with beta-blockers,
non-dihydropyridine calcium channel blockers, and/or disopyramide.
None of these agents carry labeled indications for treating HCM,
and essentially no rigorous clinical trial evidence is available to
guide their use. Compounding this unfortunate situation is the fact
that no new medical therapies for HCM have been identified for many
years. For patients with hemodynamically significant outflow tract
obstruction (resting gradient >30 mmHg), in appropriately
selected patients surgical myectomy or alcohol septal ablation is
usually required to alleviate the hemodynamic obstruction. Provided
are new therapeutic agents and methods that remedy the long-felt
need for improved treatment of HCM and related cardiac
disorders.
BRIEF SUMMARY OF THE INVENTION
[0007] In one aspect, provided is a compound having the
formula:
##STR00001##
or a pharmaceutically acceptable salt thereof. In some embodiments,
the above formula, R.sup.1 is a member selected from
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl-C.sub.1-C.sub.4 alkyl, 4- to 7-membered
heterocycloalkyl, phenyl, phenyl-C.sub.1-C.sub.4 alkyl, 5- to
6-membered heteroaryl and 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, wherein each R.sup.1 is
optionally substituted with from 1-3 R.sup.a; R.sup.2 is a member
selected from phenyl, phenyl-C.sub.1-C.sub.4 alkyl, 5- to
6-membered heteroaryl and 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, wherein each R.sup.2 is
optionally substituted with from 1-5 R.sup.b; R.sup.3 is a member
selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl,
and 4- to 7-membered heterocycloalkyl wherein each R.sup.3 is
optionally substituted with from 1-3 R.sup.c, R.sup.4 is H; X is a
member selected from H and halo, and in some embodiments X is
selected from H and F. Each R.sup.a, when present, is independently
selected from halo, CN, hydroxyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, phenyl,
phenyl-C.sub.1-C.sub.4 alkyl, phenyl-C.sub.1-C.sub.4 alkoxy,
phenoxy, --COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1,
--SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein
each R.sup.a1 and R.sup.a2 is independently selected from H,
C.sub.1-C.sub.4 alkyl and phenyl, or optionally R.sup.a1 and
R.sup.a2 when attached to a nitrogen atom are combined to form a 4-
to 6-membered ring. Similarly, each R.sup.b, when present, is
independently selected from halo, CN, hydroxyl, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, phenoxy,
phenyl-C.sub.1-C.sub.4 alkoxy, methylenedioxy,
difluoromethylenedioxy, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, --SO.sub.2NR.sup.b1R.sup.b2,
CONR.sup.b1R.sup.b2, NR.sup.b1R.sup.b2, 5- to 6-membered
heteroaryl, and 5- to 6-membered heterocyclyl optionally
substituted with oxo, wherein each R.sup.b1 and R.sup.b2 is
independently selected from H and C.sub.1-C.sub.4 alkyl or
optionally R.sup.b1 and R.sup.b2 when attached to a nitrogen atom
are combined to form a 4- to 6-membered ring; and each R.sup.c,
when present, is independently selected from halo, hydroxyl and
C.sub.1-C.sub.2 alkoxy.
[0008] In another aspect, provided is a pharmaceutical composition
containing a compound or or pharmaceutically acceptable salt
described herein and a pharmaceutically acceptable excipient.
[0009] In another aspect, provided is a method of treating
hypertrophic cardiomyopathy (HCM) or a cardiac disorder having one
or more pathophysiological features associated with HCM. The method
includes administering to a subject in need thereof an effective
amount of a compound or pharmaceutically acceptable salt described
herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows a schematic route for the synthesis of the
compounds or pharmaceutically acceptable salts described herein
(FIG. 1A) and a route for the preparation of chiral amines (FIG.
1B).
DETAILED DESCRIPTION OF THE INVENTION
I. General
[0011] A series of pyrimidine dione compounds and pharmaceutically
acceptable salts thereof has been found to reduce excess
contractility in hypercontractile states and/or promote cardiac
relaxation in hearts with diastolic dysfunction by stabilizing the
conformation of beta cardiac myosin post-ATP hydrolysis but prior
to strongly binding the actin filament and releasing phosphate,
thus reducing the proportion of myosin molecules that are available
to participate in the "powerstroke" portion of the muscle
contraction cycle. As such, the compounds can improve cardiac
elasticity, reduce dynamic and/or static left ventricular outflow
obstruction, improve diastolic left ventricular relaxation, reduce
left ventricular diastolic (filling) pressures, reduce functional
mitral regurgitation, and/or reduce left atrial and pulmonary
capillary wedge pressures in patients with HCM helping overcome the
debilitating exertional dyspnea and/or symptoms referable to left
ventricular outflow obstruction (presyncope or syncope) that often
accompanies the disease. The compounds can also be used to treat
other cardiac disorders.
II. Definitions
[0012] As used herein, the term "alkyl" refers to a straight or
branched, saturated, aliphatic radical having the number of carbon
atoms indicated. Alkyl can include any number of carbons, such as
C.sub.1-2, C.sub.1-3, C.sub.1-4, C.sub.1-5, C.sub.1-6, C.sub.1-7,
C.sub.1-8, C.sub.2-3, C.sub.2-4, C.sub.2-5, C.sub.2-6, C.sub.3-4,
C.sub.3-5, C.sub.3-6, C.sub.4-5, C.sub.4-6 and C.sub.5-6. For
example, C.sub.1-6 alkyl includes, but is not limited to, methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, hexyl, etc. Alkyl can refer to alkyl groups
having up to 20 carbons atoms, such as, but not limited to heptyl,
octyl, nonyl, decyl, etc. Unless stated otherwise, alkyl groups are
unsubstituted. A "substituted alkyl" group can be substituted with
one or more moieties selected from halo, hydroxy, amino,
alkylamino, nitro, cyano, and alkoxy.
[0013] As used herein, the term "cycloalkyl" refers to a saturated
or partially unsaturated, monocyclic, fused bicyclic or bridged
polycyclic ring assembly containing from 3 to 12 ring atoms, or the
number of atoms indicated. Cycloalkyl can include any number of
carbons, such as C.sub.3-6, C.sub.4-6, C.sub.5-6, C.sub.3-8,
C.sub.4-8, C.sub.5-8, and C.sub.6-8. Saturated monocyclic
cycloalkyl rings include, for example, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and
polycyclic cycloalkyl rings include, for example, norbornane,
[2,2,2] bicyclooctane, decahydronaphthalene and adamantane.
Cycloalkyl groups can also be partially unsaturated, having one or
more double bonds in the ring. Representative cycloalkyl groups
that are partially unsaturated include, but are not limited to,
cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and
1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene,
cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and
norbornadiene. Unless otherwise stated, cycloalkyl groups are
unsubstituted. A "substituted cycloalkyl" group can be substituted
with one or more moieties selected from halo, hydroxy, amino,
alkylamino, nitro, cyano, and alkoxy.
[0014] As used herein, the term "heterocycloalkyl" refers to a
saturated ring system having from 3 to 12 ring members and from 1
to 4 heteroatoms selected from N, O and S. Additional heteroatoms
including, but not limited to, B, Al, Si and P can also be present
in a heterocycloalkyl group. The heteroatoms can be oxidized to
form moieties such as, but not limited to, --S(O)-- and
--S(O).sub.2--. Heterocycloalkyl groups can include any number of
ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, or 4 to 7 ring
members. Any suitable number of heteroatoms can be included in the
heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3,
1 to 4, 2 to 3, 2 to 4, or 3 to 4. Examples of heterocycloalkyl
groups include, but are not limited to, aziridine, azetidine,
pyrrolidine, piperidine, azepane, azocane, quinuclidine,
pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and
1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane
(tetrahydropyran), oxepane, thiirane, thietane, thiolane
(tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine,
isoxazolidine, thiazolidine, isothiazolidine, dioxolane,
dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.
Heterocycloalkyl groups are unsubstituted, but can be described, in
some embodiments as substituted. "Substituted heterocycloalkyl"
groups can be substituted with one or more moieties selected from
halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.
[0015] As used herein, the term "heteroaryl" refers to a monocyclic
or fused bicyclic or tricyclic aromatic ring assembly containing 5
to 16 ring atoms, where from 1 to 5 of the ring atoms are a
heteroatom such as N, O or S. Additional heteroatoms including, but
not limited to, B, Al, Si and P can also be present in a heteroaryl
group. The heteroatoms can be oxidized to form moieties such as,
but not limited to, --S(O)-- and --S(O).sub.2--. Heteroaryl groups
can include any number of ring atoms, such as, 5 to 6, 5 to 8, 6 to
8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ring members. Any suitable
number of heteroatoms can be included in the heteroaryl groups,
such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to
3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have
from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to
8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring
members and from 1 to 4 heteroatoms, or from 5 to 6 ring members
and from 1 to 3 heteroatoms. Examples of heteroaryl groups include,
but are not limited to, pyrrole, pyridine, imidazole, pyrazole,
triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine
(1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole,
isothiazole, oxazole, and isoxazole. Heteroaryl groups are
unsubstituted, but can be described, in some embodiments as
substituted. "Substituted heteroaryl" groups can be substituted
with one or more moieties selected from halo, hydroxy, amino,
alkylamino, nitro, cyano, and alkoxy.
[0016] As used herein, the term "alkoxy" refers to an alkyl group
having an oxygen atom that connects the alkyl group to the point of
attachment: i.e., alkyl-O--. As for the alkyl portion, alkoxy
groups can have any suitable number of carbon atoms, such as
C.sub.1-6 or C.sub.1-4. Alkoxy groups include, for example,
methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy
groups are unsubstituted, but can be described, in some embodiments
as substituted. "Substituted alkoxy" groups can be substituted with
one or more moieties selected from halo, hydroxy, amino,
alkylamino, nitro, cyano, and alkoxy.
[0017] As used herein, the terms "halo" and "halogen" refer to
fluorine, chlorine, bromine and iodine.
[0018] As used herein, the term "pharmaceutically acceptable"
refers to a substance that is compatible with a compound or salt as
described herein, as well as with any other ingredients with which
the compound is formulated. Furthermore, a pharmaceutically
acceptable substance is not deleterious to the recipient of the
substance.
[0019] As used herein, the term "salt" refers to an acid or base
salt of a compound described herein. Pharmaceutically acceptable
salts can be derived, for example, from mineral acids (hydrochloric
acid, hydrobromic acid, phosphoric acid, and the like), organic
acids (acetic acid, propionic acid, glutamic acid, citric acid and
the like), and quaternary ammonium ions. It is understood that the
pharmaceutically acceptable salts are non-toxic. Additional
information on suitable pharmaceutically acceptable salts can be
found in Remington's Pharmaceutical Sciences, 17th ed., Mack
Publishing Company, Easton, Pa., 1985, which is incorporated herein
by reference. The neutral form of a compound may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner.
[0020] As used herein, the term "pharmaceutical composition" refers
to a product comprising a compound or pharmaceutically acceptable
salt described herein, an excipient as defined herein, and other
optional ingredients in specified amounts, as well as any product
which results directly or indirectly from combination of the
specified ingredients in the specified amounts.
[0021] As used herein, the term "excipient" refers to a substance
that aids the administration of an active agent to a subject.
Pharmaceutical excipients include, but are not limited to, binders,
fillers, disintegrants, lubricants, coatings, sweeteners, flavors
and colors. One of skill in the art will recognize that other
excipients can be useful.
[0022] As used herein, the terms "treat," "treating" and
"treatment" refer to any indicia of success in the treatment or
amelioration of a pathology, injury, condition, or symptom related
to hypertrophic cardiomyopathy, including any objective or
subjective parameter such as abatement; remission; diminishing of
symptoms; making the pathology, injury, condition, or symptom more
tolerable to the patient; decreasing the frequency or duration of
the pathology, injury, condition, or symptom; or, in some
situations, preventing the onset of the pathology, injury,
condition, or symptom. Treatment or amelioration can be based on
any objective or subjective parameter; including, e.g., the result
of a physical examination.
III. Compounds and Pharmaceutically Acceptable Salts Thereof
[0023] In one aspect, provided is a compound having the
formula:
##STR00002##
or a pharmaceutically acceptable salt thereof.
[0024] In the above formula, R.sup.1 is a member selected from
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8
cycloalkyl-C.sub.1-C.sub.4 alkyl, 4- to 7-membered
heterocycloalkyl, phenyl, phenyl-C.sub.1-C.sub.4 alkyl, 5- to
6-membered heteroaryl and 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, wherein each R.sup.1 is
optionally substituted with from 1-3 R.sup.a; R.sup.2 is a member
selected from phenyl, phenyl-C.sub.1-C.sub.4 alkyl, 5- to
6-membered heteroaryl and 5- to 6-membered
heteroaryl-C.sub.1-C.sub.4 alkyl, wherein each R.sup.2 is
optionally substituted with from 1-5 R.sup.b; R.sup.3 is a member
selected from C.sub.1-C.sub.4 alkyl, C.sub.3-C.sub.4 cycloalkyl,
and 4- to 7-membered heterocycloalkyl wherein each R.sup.3 is
optionally substituted with from 1-3 R.sup.c; R.sup.4 is H; X is a
member selected from H and halo, and in selected embodiments is
selected from H and F. Each R.sup.a, when present, is independently
selected from halo, CN, hydroxyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, phenyl,
phenyl-C.sub.1-C.sub.4 alkyl, phenyl-C.sub.1-C.sub.4 alkoxy,
phenoxy, --COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1,
--SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein
each R.sup.a1 and R.sup.a2 is independently selected from H,
C.sub.1-C.sub.4 alkyl and phenyl, or optionally R.sup.a1 and
R.sup.a2 when attached to a nitrogen atom are combined to form a 4-
to 6-membered ring. Similarly, each R.sup.b, when present, is
independently selected from halo, CN, hydroxyl, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, phenoxy,
phenyl-C.sub.1-C.sub.4 alkoxy, methylenedioxy,
difluoromethylenedioxy, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, --SO.sub.2NR.sup.b1R.sup.b2,
CONR.sup.b1R.sup.b2, NR.sup.b1R.sup.b2, 5- to 6-membered
heteroaryl, and 5- to 6-membered heterocyclyl optionally
substituted with oxo, wherein each R.sup.b1 and R.sup.b2 is
independently selected from H and C.sub.1-C.sub.4 alkyl or
optionally R.sup.b1 and R.sup.b2 when attached to a nitrogen atom
are combined to form a 4- to 6-membered ring; and each R.sup.c,
when present, is independently selected from halo, hydroxyl and
C.sub.1-C.sub.2 alkoxy.
[0025] In some embodiments, R.sup.1 is selected from
C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8 cycloalkyl, 4- to 7-membered
heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein
each R.sup.1 is optionally substituted with from 1-3 R.sup.a.
R.sup.2 is phenyl, which is optionally substituted with from 1-5
R.sup.b. R.sup.3 is selected from C.sub.1-C.sub.4 alkyl,
C.sub.3-C.sub.4 cycloalkyl, or 4- to 7-membered heterocycloalkyl,
wherein each R.sup.3 is optionally substituted with from 1-2
R.sup.c. R.sup.4 is H, and X is H or F. In some embodiments, each
R.sup.a, when present, is independently halo, CN, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkoxy, --COR.sup.a1, --CO.sub.2R.sup.a1,
--SO.sub.2R.sup.a1, --SO.sub.2NR.sup.a1R.sup.a2, or
--CONR.sup.a1R.sup.a2, wherein each R.sup.a1 and R.sup.a2 is
independently H or C.sub.1-C.sub.4 alkyl. Alternatively, R.sup.a1
and R.sup.a2, when attached to a nitrogen atom, are optionally
combined to form a 4- to 6-membered ring. Each R.sup.b, when
present, is independently halo, CN, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, --SO.sub.2NR.sup.b1R.sup.b2,
CONR.sup.b1R.sup.b2, NR.sup.bR.sup.ba2, 5- to 6-membered
heteroaryl, or 5- to 6-membered heterocyclyl optionally substituted
with oxo, wherein each R.sup.b1 and R.sup.b2 is independently H or
C.sub.1-C.sub.4 alkyl. Alternatively, R.sup.b1 and R.sup.b2, when
attached to a nitrogen atom, are optionally combined to form a 4-
to 6-membered ring. Each R.sup.c, when present, is independently
halo or C.sub.1-C.sub.2 alkoxy.
[0026] In some embodiments, X is H.
[0027] In some embodiments, R.sup.1 is C.sub.3-C.sub.4 alkyl,
C.sub.3-C.sub.8 cycloalkyl, or 4- to 6-membered heterocycloalkyl,
wherein each R.sup.1 is optionally substituted with from 1-2
R.sup.a.
[0028] In some embodiments, R.sup.1 is phenyl or 5- to 6-membered
heteroaryl, wherein each R.sup.1 is optionally substituted with
from 1-3 R.sup.a.
[0029] In some embodiments, R.sup.1 is C.sub.3-C.sub.4 alkyl,
C.sub.3-C.sub.8 cycloalkyl, or 4- to 6-membered
heterocycloalkyl.
[0030] In some embodiments, R.sup.1 is 4- to 6-membered
heterocycloalkyl, optionally substituted with from 1-2 R.sup.a
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
--COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1,
--SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein
each R.sup.a1 and R.sup.a2 is independently H or C.sub.1-C.sub.4
alkyl.
[0031] In some embodiments, R.sup.1 is cyclobutyl, isopropyl,
isobutyl, 1-methoxypropan-2-yl, cyclopentyl, cyclohexyl,
4-tetrahydropyranyl, 1-(methylsulfonyl)piperidin-4-yl,
1-(methoxycarbonyl)piperidin-4-yl, 4,4-difluorocyclohexyl, phenyl,
2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, or
1-methyl-3-pyrazolyl.
[0032] In some embodiments, R.sup.2 is optionally substituted with
from 1-2 R.sup.b.
[0033] In some embodiments, R.sup.2 is phenyl, 3-methylphenyl,
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl,
3,5-difluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,
3-(3-oxazolidin-2-onyl)phenyl, 3-(2-methyl-1-imidazyl)phenyl,
3-(1-pyrazolyl)phenyl, or 3-(1,2,4-triazol-1-yl)phenyl.
[0034] In some embodiments, R.sup.3 is C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxyalkyl, or C.sub.3-C.sub.4 cycloalkyl.
[0035] In some embodiments, R.sup.3 is methyl, ethyl, propyl,
cyclopropyl, cyclobutyl or 2-methoxymethyl.
[0036] In some embodiments, R.sup.3 is methyl.
[0037] The compounds or pharmaceutically acceptable salts described
herein can have any combination of the R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.a, R.sup.a1, R.sup.a2, R.sup.b, R.sup.b1, R.sup.b2,
R.sup.c, and X groups recited above. Selected embodiments recited
for R.sup.2, for example, can be combined with any of the selected
embodiments recited for R.sup.1 which, in turn, can be combined
with any of the selected embodiments recited for R.sup.3.
[0038] In some embodiments, for example, R.sup.1 is C.sub.3-C.sub.8
alkyl; R.sup.3 is C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered
heterocycloalkyl; and R.sup.2 is phenyl. In other embodiments,
R.sup.1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered
heteroaryl which is optionally substituted with C.sub.1-C.sub.4
alkyl, --CO.sub.2R.sup.a1, --SO.sub.2NR.sup.a1R.sup.a2, or
--SO.sub.2R.sup.a1; R.sup.3 is C.sub.3-C.sub.4 cycloalkyl or 4- to
7-membered heterocycloalkyl; and R.sup.2 is phenyl. In still other
embodiments, R.sup.1 is C.sub.3-C.sub.8 cycloalkyl or phenyl,
R.sup.3 is C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered
heterocycloalkyl; and R.sup.2 is phenyl.
[0039] In other embodiments, R.sup.1 is C.sub.3-C.sub.8 alkyl;
R.sup.3 is C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl. In yet
other embodiments, R.sup.1 is 4- to 7-membered heterocycloalkyl or
5- to 6-membered heteroaryl which is optionally substituted with
C.sub.1-C.sub.4 alkyl, --CO.sub.2R.sup.a1, or --SO.sub.2R.sup.a1;
R.sup.3 is C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl. In still
other embodiments, R.sup.1 is C.sub.3-C.sub.8 cycloalkyl or phenyl;
R.sup.3 is C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl.
[0040] In some embodiments, R.sup.1 is C.sub.3-C.sub.8 alkyl;
R.sup.3 is C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered
heterocycloalkyl; and R.sup.2 is phenyl substituted with 1-2
C.sub.1-C.sub.4 alkoxy or halo. In still other embodiments, R.sup.1
is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl
which is optionally substituted with C.sub.1-C.sub.4 alkyl,
--CO.sub.2R.sup.a1, or --SO.sub.2R.sup.a1; R.sup.3 is
C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered heterocycloalkyl;
and R.sup.2 is phenyl substituted with 1-2 C.sub.1-C.sub.4 alkoxy
or halo. In yet other embodiments, R.sup.1 is C.sub.3-C.sub.8
cycloalkyl or phenyl; R.sup.3 is C.sub.3-C.sub.4 cycloalkyl or 4-
to 7-membered heterocycloalkyl; and R.sup.2 is phenyl substituted
with 1-2 C.sub.1-C.sub.4 alkoxy or halo.
[0041] In some embodiments, R.sup.1 is C.sub.3-C.sub.8 alkyl;
R.sup.3 is C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl substituted
with 1-2 C.sub.1-C.sub.4 alkoxy or halo. In other embodiments,
R.sup.1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered
heteroaryl which is optionally substituted with C.sub.1-C.sub.4
alkyl, --CO.sub.2R.sup.a1, or --SO.sub.2R.sup.a1; R.sup.3 is
C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl substituted with 1-2
C.sub.1-C.sub.4 alkoxy or halo. In other embodiments, R.sup.1 is
C.sub.3-C.sub.8 cycloalkyl or phenyl; R.sup.3 is C.sub.1-C.sub.4
alkyl; and R.sup.2 is phenyl substituted with 1-2 C.sub.1-C.sub.4
alkoxy or halo.
[0042] In some embodiments, R.sup.1 is C.sub.3-C.sub.8 alkyl;
R.sup.3 is C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered
heterocycloalkyl; and R.sup.2 is phenyl substituted with 5- to
6-membered heteroaryl or 5- to 6-membered heterocyclyl optionally
substituted with oxo. In other embodiments, R.sup.1 is 4- to
7-membered heterocycloalkyl or 5- to 6-membered heteroaryl which is
optionally substituted with C.sub.1-C.sub.4 alkyl,
--CO.sub.2R.sup.a1, or --SO.sub.2R.sup.a1; R.sup.3 is
C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered heterocycloalkyl;
and R.sup.2 is phenyl substituted with 5- to 6-membered heteroaryl
or 5- to 6-membered heterocyclyl optionally substituted with oxo.
In other embodiments, R.sup.1 is C.sub.3-C.sub.8 cycloalkyl or
phenyl, R.sup.3 is C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered
heterocycloalkyl; and R.sup.2 is phenyl substituted with 5- to
6-membered heteroaryl or 5- to 6-membered heterocyclyl optionally
substituted with oxo.
[0043] In some embodiments, R.sup.1 is C.sub.3-C.sub.8 alkyl;
R.sup.3 is C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl substituted
with 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl
optionally substituted with oxo. In other embodiments, R.sup.1 is
4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl
which is optionally substituted with C.sub.1-C.sub.4 alkyl,
--CO.sub.2R.sup.a1, or --SO.sub.2R.sup.a1; R.sup.3 is
C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl substituted with 5- to
6-membered heteroaryl or 5- to 6-membered heterocyclyl optionally
substituted with oxo. In other embodiments, R.sup.1 is
C.sub.3-C.sub.8 cycloalkyl or phenyl; R.sup.3 is C.sub.1-C.sub.4
alkyl; and R.sup.2 is phenyl substituted with 5- to 6-membered
heteroaryl or 5- to 6-membered heterocyclyl optionally substituted
with oxo.
[0044] In some embodiments, R.sup.1 is C.sub.3-C.sub.8 alkyl;
R.sup.3 is C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered
heterocycloalkyl; and R.sup.2 is phenyl substituted with CN,
C.sub.1-C.sub.4 alkyl, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, --SO.sub.2NR.sup.b1R.sup.b2,
CONR.sup.b1R.sup.b2, or NR.sup.b1R.sup.b2. In other embodiments,
R.sup.1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered
heteroaryl which is optionally substituted with C.sub.1-C.sub.4
alkyl, --CO.sub.2R.sup.a1, or --SO.sub.2R.sup.a1; R.sup.3 is
C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered heterocycloalkyl;
and R.sup.2 is phenyl substituted with CN, C.sub.1-C.sub.4 alkyl,
--COR.sup.b1, --CO.sub.2R.sup.b1, --SO.sub.2R.sup.b1,
CONR.sup.b1R.sup.b2, or NR.sup.b1R.sup.b2. In other embodiments,
R.sup.1 is C.sub.3-C.sub.8 cycloalkyl or phenyl; R.sup.3 is
C.sub.3-C.sub.4 cycloalkyl or 4- to 7-membered heterocycloalkyl;
and R.sup.2 is phenyl substituted with CN, C.sub.1-C.sub.4 alkyl,
--COR.sup.b1, --CO.sub.2R.sup.b1, --SO.sub.2R.sup.b1,
CONR.sup.b1R.sup.b2, or NR.sup.b1R.sup.b2.
[0045] In some embodiments, R.sup.1 is C.sub.3-C.sub.8 alkyl;
R.sup.3 is C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl substituted
with CN, C.sub.1-C.sub.4 alkyl, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, CONR.sup.b1R.sup.b2, or NR.sup.b1R.sup.b2. In
other embodiments, R.sup.1 is 4- to 7-membered heterocycloalkyl or
5- to 6-membered heteroaryl which is optionally substituted with
C.sub.1-C.sub.4 alkyl, --CO.sub.2R.sup.a1, or --SO.sub.2R.sup.a1;
R.sup.3 is C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl substituted
with CN, C.sub.1-C.sub.4 alkyl, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, CONR.sup.b1R.sup.b2, or NR.sup.b1R.sup.b2. In
other embodiments, R.sup.1 is C.sub.3-C.sub.8 cycloalkyl or phenyl;
R.sup.3 is C.sub.1-C.sub.4 alkyl; and R.sup.2 is phenyl substituted
with CN, C.sub.1-C.sub.4 alkyl, --COR.sup.b1, --CO.sub.2R.sup.b1,
--SO.sub.2R.sup.b1, CONR.sup.b1R.sup.b2, NR.sup.b1R.sup.b2, or
--CONR.sup.a1R.sup.a2.
[0046] In some embodiments, R.sup.1 is isopropyl; R.sup.2 is
optionally substituted with 1-2 R.sup.b; and R.sup.3 is methyl.
[0047] In some embodiments, R.sup.1 is 4- to 6-membered
heterocycloalkyl, optionally substituted with from 1-2 R.sup.a
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy,
--COR.sup.a1, --CO.sub.2R.sup.a1, --SO.sub.2R.sup.a1,
--SO.sub.2NR.sup.a1R.sup.a2, and --CONR.sup.a1R.sup.a2, wherein
each R.sup.a1 and R.sup.a2 can independently be H or
C.sub.1-C.sub.4 alkyl; R.sup.2 is optionally substituted with 1-2
R.sup.b; and R.sup.3 is methyl.
[0048] In some embodiments, R.sup.1 is phenyl or 5- to 6-membered
heteroaryl, wherein each R.sup.1 is optionally substituted with
from 1-3 R.sup.a; R.sup.2 is optionally substituted with from 1-2
R.sup.b; and R.sup.3 is methyl.
[0049] X can be H in any of the embodiments set forth above. In
other embodiments, X can be F in any of the embodiments set forth
above. Still further, compounds provided herein with an identified
stereochemistry (indicated as R or S, or with dashed or wedge bond
designations) will be understood by one of skill in the art to be
substantially free of other isomers (e.g., at least 80%, 90%, 95%
up to 100% free of the other isomer).
[0050] In some embodiments, the compound is selected from: [0051]
(S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0052]
(S)-5-fluoro-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H-
,3H)-dione; [0053]
(S)-5-bromo-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dio-
ne; [0054]
(S)-6-((1-(3-chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyri-
midine-2,4(1H,3H)-dione; [0055]
(S)-6-((1-(3,5-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione; [0056]
(S)-6-((cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-
-dione; [0057]
(S)-6-((cyclopropyl(3-methoxyphenyl)methyl)amino)-3-isopropylpyrimidine-2-
,4(1H,3H)-dione; [0058]
(S)-6-((cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)--
dione; [0059]
(S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimi-
dine-2,4(1H,3H)-dione; [0060]
(S)-6-((1-(3-methoxyphenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrim-
idine-2,4(1H,3H)-dione; [0061]
6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H-
)-dione; [0062]
(S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-((1-phenylethyl)amino)pyrimidi-
ne-2,4(1H,3H)-dione; [0063] methyl
(S)-4-(2,6-dioxo-4-((1-phenylethyl)amino)-3,6-dihydropyrimidin-1(2H)-yl)p-
iperidine-1-carboxylate; [0064]
3-((R)-sec-butyl)-6-(((S)-1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1-
H,3H)-dione; [0065]
(S)-6-((1-phenylethyl)amino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;
[0066]
(S)-3-(isoxazol-3-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H-
)-dione; [0067]
(S)-6-((1-(3-(1H-pyrazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2-
,4(1H,3H)-dione; [0068]
(S)-3-isopropyl-6-((1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)--
dione; [0069]
(S)-3-isopropyl-6-((1-(2-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)--
dione; [0070]
(S)-3-isopropyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0071]
(S)-3-isopropyl-5-methyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H-
,3H)-dione; [0072]
(S)-6-((1-(2-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-d-
ione; [0073]
(S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-d-
ione; [0074]
(S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-d-
ione; [0075]
(S)-6-((1-(4-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-d-
ione; [0076]
(S)-5-fluoro-3-isopropyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-d-
ione; [0077]
(S)-5-fluoro-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4-
(1H,3H)-dione; [0078]
(S)-5-fluoro-3-isopropyl-6-((1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,-
4(1H,3H)-dione; [0079]
(S)-6-((1-(2,5-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione; [0080]
(S)-6-((1-(3-bromophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-di-
one; [0081]
(S)-3-ethyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0082]
(S)-3-cyclopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0083]
(S)-6-((1-phenylethyl)amino)-3-(pyridin-2-yl)pyrimidine-2,4(1H,3H)-
-dione; [0084]
(S)-3-(1-methyl-1H-pyrazol-3-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1-
H,3H)-dione; [0085]
(S)-3-(isoxazol-5-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione-
; [0086]
(S)-6-((1-(3-(1H-1,2,4-triazol-1-yl)phenyl)ethyl)amino)-3-isoprop-
ylpyrimidine-2,4(1H,3H)-dione; [0087]
(S)-3-isopropyl-6-((1-(3-(2-methyl-1H-imidazol-1-yl)phenyl)ethyl)amino)py-
rimidine-2,4(1H,3H)-dione; [0088]
(S)-3-isopropyl-6-((1-(3-(2-oxooxazolidin-3-yl)phenyl)ethyl)amino)pyrimid-
ine-2,4(1H,3H)-dione; [0089]
(S)-3-cyclohexyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0090]
(S)-3-phenyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0091]
(S)-3-ethyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0092]
(S)-3-methyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0093]
(S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione;
[0094]
(S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(-
1H,3H)-dione; [0095]
(S)-3-isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0096]
(S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-
-2,4(1H,3H)-dione; [0097]
(R)-3-isopropyl-6-((2,2,2-trifluoro-1-phenylethyl)amino)pyrimidine-2,4(1H-
,3H)-dione; [0098]
3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2-
,4(1H,3H)-dione; [0099]
3-((R)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1-
H,3H)-dione; [0100]
(S)-3-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2-
,4(1H,3H)-dione; [0101]
(S)-2-(1-((1-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)amino)e-
thyl)benzonitrile [0102]
(S)-3-benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0103]
(S)-3-(2,6-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)--
dione; [0104]
(S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione; [0105]
(S)-3-isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3-
H)-dione; [0106]
(S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,-
3H)-dione; [0107]
(S)-6-((1-(4-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)--
dione; [0108]
(R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione; [0109]
(S)-3-(6-methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H-
)-dione; [0110] (S)-3-(2,2-di
fluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0111]
(S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-(2,2,2-trifluoroethyl)-
pyrimidine-2,4(1H,3H)-dione; [0112]
(S)-3-isopropyl-6-((1-(o-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0113]
(S)-3-cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dio-
ne; [0114]
(S)-3-isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)py-
rimidine-2,4(1H,3H)-dione; [0115]
(S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-
-dione; [0116]
(S)-6-((1-(3-(1H-imidazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine--
2,4(1H,3H)-dione; [0117]
(S)-6-((1-phenylethyl)amino)-3-(pyridazin-4-yl)pyrimidine-2,4(1H,3H)-dion-
e; [0118]
(S)-4-((1-phenylethyl)amino)-2H-[1,5'-bipyrimidine]-2,6(3H)-dion-
e; [0119]
(S)-6-((1-phenylethyl)amino)-3-(pyrazin-2-yl)pyrimidine-2,4(1H,3-
H)-dione; [0120]
(S)-3-isopropyl-6-((1-(pyridin-3-yl)ethyl)amino)pyrimidine-2,4(1H,3H)-dio-
ne; [0121]
(S)-3-(1-methyl-1H-pyrazol-4-yl)-6-((1-phenylethyl)amino)pyrimi-
dine-2,4(1H,3H)-dione; [0122]
(S)-3-isopropyl-6-((1-phenylbutyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0123]
6-(((S)-1-phenylethyl)amino)-3-((R)-tetrahydro-2H-pyran-3-yl)pyrim-
idine-2,4(1H,3H)-dione; [0124]
(S)-3-cyclopentyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0125]
(S)-3-isopropyl-6-((2-methyl-1-phenylpropyl)amino)pyrimidine-2,4(1-
H,3H)-dione; [0126]
(S)-3-(4,4-difluorocyclohexyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,-
3H)-dione; [0127]
(S)-3-(pentan-3-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0128]
(S)-3-(1-benzoylpiperidin-4-yl)-6-((1-phenylethyl)amino)pyrimidine-
-2,4(1H,3H)-dione; [0129]
(S)-3-isopropyl-6-((4-phenylbutan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione;
[0130] methyl
(S)-2-(2,6-dioxo-4-((1-phenylethyl)amino)-3,6-dihydropyrimidin-1(2H)-yl)a-
cetate [0131]
(S)-3-isopropyl-6-((1-phenylpropan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione-
; [0132]
3-((S)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyri-
midine-2,4(1H,3H)-dione; [0133]
3-((S)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1-
H,3H)-dione; [0134]
(R)-6-((2-hydroxy-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-d-
ione; [0135]
6-(((S)-1-phenylethyl)amino)-3-((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-
-2,4(1H,3H)-dione; [0136]
6-(((S)-1-phenylethyl)amino)-3-((S)-1,1,1-trifluoropropan-2-yl)pyrimidine-
-2,4(1H,3H)-dione; [0137]
6-(((S)-1-phenylethyl)amino)-3-(4,4,4-trifluorobutan-2-yl)pyrimidine-2,4(-
1H,3H)-dione; [0138]
(S)-6-((1-phenylethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H-
)-dione; [0139]
(S)-3-(tert-butyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0140]
(S)-3-(2-methoxyethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3-
H)-dione; [0141]
6-(((S)-1-phenylpropyl)amino)-3-((S)-1,1,1-trifluoropropan-2-yl)pyrimidin-
e-2,4(1H,3H)-dione; [0142]
3-((R)-1-cyclopropylethyl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,-
3H)-dione; [0143] 3-((S)-1-cyclopropyl
ethyl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;
[0144]
(S)-6-((cyclobutyl(phenyl)methyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dion-
e; [0145]
(S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-isopropylpyri-
midine-2,4(1H,3H)-dione; [0146]
(S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-ethylpyrimidine-2,4(1H-
,3H)-dione; [0147] (S)-6-((1-phenyl
propyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione;
[0148]
(S)-3-(cyclopropylmethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-d-
ione; [0149]
(S)-6-((cyclopropyl(phenyl)methyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidi-
ne-2,4(1H,3H)-dione; [0150]
(S)-6-((cyclobutyl(phenyl)methyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidin-
e-2,4(1H,3H)-dione; [0151]
(S)-3-(1,3-dihydroxypropan-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1-
H,3H)-dione; [0152]
6-(((S)-1-(4-fluorophenyl)propan-2-yl)amino)-3-((S)-1,1,1-trifluoropropan-
-2-yl)pyrimidine-2,4(1H,3H)-dione; [0153]
(S)-6-((1-(3-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)--
dione; [0154]
6-((1-(2-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dion-
e; [0155]
(S)-6-((1-phenylethyl)amino)-3-(1-(trifluoromethyl)cyclopropyl)p-
yrimidine-2,4(1H,3H)-dione; [0156]
(S)-3-(3,5-difluorophenyl)-6-((1-(4-fluorophenyl)propan-2-yl)amino)pyrimi-
dine-2,4(1H,3H)-dione; [0157]
(S)-6-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-isopropylp-
yrimidine-2,4(1H,3H)-dione; [0158]
(S)-6-((1-(2-chlorophenyl)ethyl)amino)-3-isopropyl
pyrimidine-2,4(1H,3H)-dione; [0159]
(S)-3-isopropyl-6-((1-(4-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)--
dione; [0160] (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-ethyl
pyrimidine-2,4(1H,3H)-dione; [0161]
(S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione-
; [0162]
(S)-3-ethyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidi-
ne-2,4(1H,3H)-dione; [0163]
(S)-3-(cyclopropylmethyl)-6-((1-(3-fluorophenyl)ethyl)amino)pyrimidine-2,-
4(1H,3H)-dione; [0164]
(S)-3-(cyclopropylmethyl)-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)py-
rimidine-2,4(1H,3H)-dione; [0165]
(S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-(cyclopropylmethyl)pyrimidine-2,-
4(1H,3H)-dione; [0166]
(S)-5-chloro-6-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-i-
sopropylpyrimidine-2,4(1H,3H)-dione; [0167]
(S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dion-
e; [0168]
(S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H-
,3H)-dione; [0169]
(S)-3-propyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(-
1H,3H)-dione; [0170]
(S)-3-cyclobutyl-6-((1-(4-fluorophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)--
dione; [0171]
(S)-6-((1-(2-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)--
dione; [0172]
(S)-6-((1-(3,4-difluorophenyl)ethyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-d-
ione; [0173]
3-((S)-sec-butyl)-6-(((S)-1-(4-fluorophenyl)ethyl)amino)pyrimidine-2,4(1H-
,3H)-dione; [0174]
(S)-6-((1-(4-fluorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dion-
e; and [0175]
(S)-3-(6-fluoropyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H-
)-dione, or a pharmaceutically acceptable salt of any of the
above.
[0176] In some embodiments, the compound is selected from
##STR00003## ##STR00004##
or a pharmaceutically acceptable salt thereof.
[0177] The compounds or pharmaceutically acceptable salts described
herein (I) can be prepared via any suitable method. Compounds can
be prepared, for example, by the route outlined in FIG. 1. As shown
in FIG. 1A, a pyrimidine trione v can be synthesized via
condensation of a urea iii with a malonate iv. The urea iii can be
prepared via reaction of an amine i with an appropriate cyanate ii.
The pyrimidine trione v is derivatized with a suitable leaving
group (Lg) to provide intermediate vi. The leaving group can be,
but is not limited to, a halogen such as a chloride or iodide. A
halogenated intermediate vi can be prepared from pyrimidine triones
by methods such as those described by Brown (The Chemistry of
Heterocyclic Compounds, The Pyrimidines, John Wiley & Sons,
2009). Intermediates vi can be converted to compounds of formula I
via reaction with amines vii. Certain chiral amines can be prepared
from a ketone or aldehyde ix as shown in FIG. 1B; a sulfinyl imine
xii derived from the ketone or aldehyde can be reacted with a
Gringard reagent xiii to provide a chiral amine vii. One of skill
in the art will appreciate that the compounds described herein can
be prepared via other methods, such as those described by LaRock
(Comprehensive Organic Transformations: A Guide to Functional Group
Preparations, Wiley, 1999).
IV. Compositions
[0178] Also provided is a pharmaceutical composition containing a
compound or pharmaceutically acceptable salt described herein and a
pharmaceutically acceptable excipient. The compositions may be
useful for treating hypertrophic cardiomyopathy in humans and other
subjects.
[0179] The pharmaceutical compositions for the administration of
the compounds or pharmaceutically acceptable salts described herein
may conveniently be presented in unit dosage form and may be
prepared by any of the methods known in the art of pharmacy and
drug delivery. All methods include the step of bringing the active
ingredient into association with a carrier containing one or more
accessory ingredients. In general, the pharmaceutical compositions
are prepared by uniformly and intimately bringing the active
ingredient into association with a liquid carrier or a finely
divided solid carrier or both, and then, if necessary, shaping the
product into the desired formulation. In the pharmaceutical
composition, the active agent is generally included in an amount
sufficient to produce the desired effect upon myocardial
contractility (i.e. to decrease the often supranormal systolic
contractility in HCM) and to improve left ventricular relaxation in
diastole. Such improved relaxation can alleviate symptoms in
hypertrophic cardiomyopathy and other etiologies of diastolic
dysfunction. It can also ameliorate the effects of diastolic
dysfunction causing impairment of coronary blood flow, improving
the latter as an adjunctive agent in angina pectoris and ischemic
heart disease. It can also confer benefits on salutary left
ventricular remodeling in HCM and other causes of left ventricular
hypertrophy due to chronic volume or pressure overload from, e.g.,
valvular heart disease or systemic hypertension.
[0180] The pharmaceutical compositions containing the active
ingredient may be in a form suitable for oral use, for example, as
tablets, troches, lozenges, aqueous or oily suspensions,
dispersible powders or granules, emulsions, hard or soft capsules,
syrups, elixirs, solutions, buccal patch, oral gel, chewing gum,
chewable tablets, effervescent powder and effervescent tablets.
Compositions intended for oral use may be prepared according to any
method known to the art for the manufacture of pharmaceutical
compositions and such compositions may contain one or more agents
selected from the group consisting of sweetening agents, flavoring
agents, coloring agents, antioxidants and preserving agents in
order to provide pharmaceutically elegant and palatable
preparations. Tablets contain the active ingredient in admixture
with non-toxic pharmaceutically acceptable excipients which are
suitable for the manufacture of tablets. These excipients may be
for example, inert diluents, such as cellulose, silicon dioxide,
aluminum oxide, calcium carbonate, sodium carbonate, glucose,
mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate;
granulating and disintegrating agents, for example, corn starch, or
alginic acid; binding agents, for example PVP, cellulose, PEG,
starch, gelatin or acacia, and lubricating agents, for example
magnesium stearate, stearic acid or talc. The tablets may be
uncoated or they may be coated, enterically or otherwise, by known
techniques to delay disintegration and absorption in the
gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a time delay material such as
glyceryl monostearate or glyceryl distearate may be employed. They
may also be coated to form osmotic therapeutic tablets for
controlled release.
[0181] Formulations for oral use may also be presented as hard
gelatin capsules wherein the active ingredient is mixed with an
inert solid diluent, for example, calcium carbonate, calcium
phosphate or kaolin, or as soft gelatin capsules wherein the active
ingredient is mixed with water or an oil medium, for example peanut
oil, liquid paraffin, or olive oil. Additionally, emulsions can be
prepared with a non-water miscible ingredient such as oils and
stabilized with surfactants such as mono-diglycerides, PEG esters
and the like.
[0182] Aqueous suspensions contain the active materials in
admixture with excipients suitable for the manufacture of aqueous
suspensions. Such excipients are suspending agents, for example
sodium carboxymethylcellulose, methylcellulose,
hydroxy-propylmethylcellulose, sodium alginate,
polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or
wetting agents may be a naturally-occurring phosphatide, for
example lecithin, or condensation products of an alkylene oxide
with fatty acids, for example polyoxy-ethylene stearate, or
condensation products of ethylene oxide with long chain aliphatic
alcohols, for example heptadecaethyleneoxycetanol, or condensation
products of ethylene oxide with partial esters derived from fatty
acids and a hexitol such as polyoxyethylene sorbitol monooleate, or
condensation products of ethylene oxide with partial esters derived
from fatty acids and hexitol anhydrides, for example polyethylene
sorbitan monooleate. The aqueous suspensions may also contain one
or more preservatives, for example ethyl, or n-propyl,
p-hydroxybenzoate, one or more coloring agents, one or more
flavoring agents, and one or more sweetening agents, such as
sucrose or saccharin.
[0183] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil,
sesame oil or coconut oil, or in a mineral oil such as liquid
paraffin. The oily suspensions may contain a thickening agent, for
example beeswax, hard paraffin or cetyl alcohol. Sweetening agents
such as those set forth above, and flavoring agents may be added to
provide a palatable oral preparation. These compositions may be
preserved by the addition of an anti-oxidant such as ascorbic
acid.
[0184] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the active
ingredient in admixture with a dispersing or wetting agent,
suspending agent and one or more preservatives. Suitable dispersing
or wetting agents and suspending agents are exemplified by those
already mentioned above. Additional excipients, for example
sweetening, flavoring and coloring agents, may also be present.
[0185] The pharmaceutical compositions described herein may also be
in the form of oil-in-water emulsions. The oily phase may be a
vegetable oil, for example olive oil or arachis oil, or a mineral
oil, for example liquid paraffin or mixtures of these. Suitable
emulsifying agents may be naturally-occurring gums, for example gum
acacia or gum tragacanth, naturally-occurring phosphatides, for
example soy bean, lecithin, and esters or partial esters derived
from fatty acids and hexitol anhydrides, for example sorbitan
monooleate, and condensation products of the said partial esters
with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening and flavoring
agents.
[0186] Syrups and elixirs may be formulated with sweetening agents,
for example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative and
flavoring and coloring agents. Oral solutions can be prepared in
combination with, for example, cyclodextrin, PEG and
surfactants.
[0187] The pharmaceutical compositions may be in the form of a
sterile injectable aqueous or oleagenous suspension. This
suspension may be formulated according to the known art using those
suitable dispersing or wetting agents and suspending agents which
have been mentioned above. The sterile injectable preparation may
also be a sterile injectable solution or suspension in a non-toxic
parenterally-acceptable diluent or solvent, for example as a
solution in 1,3-butane diol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil may be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid find use in the preparation of injectables.
[0188] The compounds or pharmaceutically acceptable salts described
herein may also be administered in the form of suppositories for
rectal administration of the drug. These compositions can be
prepared by mixing the drug with a suitable non-irritating
excipient which is solid at ordinary temperatures but liquid at the
rectal temperature and will therefore melt in the rectum to release
the drug. Such materials include cocoa butter and polyethylene
glycols. Additionally, the compounds or pharmaceutically acceptable
salts can be administered via ocular delivery by means of solutions
or ointments. Still further, transdermal delivery of the subject
compounds or pharmaceutically acceptable salts can be accomplished
by means of iontophoretic patches and the like. For topical use,
creams, ointments, jellies, solutions or suspensions, etc.,
containing the compounds or pharmaceutically acceptable salts
described herein are employed. As used herein, topical application
is also meant to include the use of mouth washes and gargles.
[0189] The compounds or pharmaceutically acceptable salts described
herein may also be coupled to a carrier that is a suitable polymer
for targetable drug carriers. Such polymers can include
polyvinylpyrrolidone, pyran copolymer,
polyhydroxy-propyl-methacrylamide-phenol,
polyhydroxyethyl-aspartamide-phenol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds or pharmaceutically acceptable salts
described herein may be coupled to a carrier that is a
biodegradable polymer useful in achieving controlled release of a
drug, such as polylactic acid, polyglycolic acid, copolymers of
polylactic and polyglycolic acid, polyepsilon caprolactone,
polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacrylates and cross linked or
amphipathic block copolymers of hydrogels. Polymers and
semipermeable polymer matrices may be formed into shaped articles,
such as valves, stents, tubing, prostheses and the like.
V. Methods of Treating Cardiac Disorders
[0190] The mutations that lead to HCM cause significant
perturbations in myosin mechanics. These mutations exert their
effects via distinct mechanisms depending on their locations in the
myosin gene. The well-studied HCM mutations, R403Q and R453C, are
located in different sections of the motor domain and cause
distinct mechanistic perturbations that lead to the common outcome
of increased force production. Without wishing to be bound by any
particular theory, it is believed that the compounds or
pharmaceutically acceptable salts described herein can bind
directly to the mutant sarcomeric proteins and correct for their
aberrant function, either in cis (by affecting the same specific
function) or in trans (by altering a complementary function). As
such, they can provide therapeutic benefit for HCM patients by
counteracting the hypercontractile and/or impaired relaxation
associated with this disease.
[0191] Also provided is a method of treating hypertrophic
cardiomyopathy (HCM) or a cardiac disorder having one or more
pathophysiological features associated with HCM. The method
includes administering to a subject in need thereof an effective
amount of a compound or pharmaceutically acceptable salt described
herein.
[0192] The compounds of the invention or their pharmaceutically
acceptable salts can alter the natural history of HCM and other
diseases rather than merely palliating symptoms. The mechanisms
conferring clinical benefit to HCM patients can extend to patients
with other forms of heart disease sharing similar pathophysiology,
with or without demonstrable genetic influence. For example, an
effective treatment for HCM, by improving ventricular relaxation
during diastole, can also be effective in a broader population
characterized by diastolic dysfunction. The compounds of the
invention or their pharmaceutically acceptable salts can
specifically target the root causes of the conditions or act upon
other downstream pathways. Accordingly, the compounds of the
invention or their pharmaceutically acceptable salts can also
confer benefit to patients suffering from diastolic heart failure
with preserved ejection fraction, ischemic heart disease, angina
pectoris, or restrictive cardiomyopathy. Compounds of the invention
or their pharmaceutically acceptable salts can also promote
salutary ventricular remodeling of left ventricular hypertrophy due
to volume or pressure overload; e.g., chronic mitral regurgitation,
chronic aortic stenosis, or chronic systemic hypertension; in
conjunction with therapies aimed at correcting or alleviating the
primary cause of volume or pressure overload (valve
repair/replacement, effective antihypertensive therapy). By
reducing left ventricular filling pressures the compounds could
reduce the risk of pulmonary edema and respiratory failure.
Reducing or eliminating functional mitral regurgitation and/or
lowering left atrial pressures may reduce the risk of paroxysmal or
permanent atrial fibrillation, and with it reduce the attendant
risk of arterial thromboembolic complications including but not
limited to cerebral arterial embolic stroke. Reducing or
eliminating either dynamic and/or static left ventricular outflow
obstruction may reduce the likelihood of requiring septal reduction
therapy, either surgical or percutaneous, with their attendant
risks of short and long term complications. The compounds or their
pharmaceutically acceptable salts may reduce the severity of the
chronic ischemic state associated with HCM and thereby reduce the
risk of Sudden Cardiac Death (SCD) or its equivalent in patients
with implantable cardioverter-defibrillators (frequent and/or
repeated ICD discharges) and/or the need for potentially toxic
antiarrhythmic medications. The compounds or their pharmaceutically
acceptable salts could be valuable in reducing or eliminating the
need for concomitant medications with their attendant potential
toxicities, drug-drug interactions, and/or side effects. The
compounds or their pharmaceutically acceptable salts may reduce
interstitial myocardial fibrosis and/or slow the progression,
arrest, or reverse left ventricular hypertrophy.
[0193] Depending on the disease to be treated and the subject's
condition, the compounds or pharmaceutically acceptable salts
described herein may be administered by oral, parenteral (e.g.,
intramuscular, intraperitoneal, intravenous, ICV, intracisternal
injection or infusion, subcutaneous injection, or implant), by
implantation (e.g., as when the compound or pharmaceutically
acceptable salt is coupled to a stent device), by inhalation spray,
nasal, vaginal, rectal, sublingual, or topical routes of
administration and may be formulated, alone or together, in
suitable dosage unit formulations containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles
appropriate for each route of administration.
[0194] In the treatment or prevention of conditions which require
improved ventricular relaxation during diastole, an appropriate
dosage level will generally be about 0.001 to 100 mg per kg patient
body weight per day which can be administered in single or multiple
doses. In some embodiments, the dosage level will be about 0.01 to
about 25 mg/kg per day; in some embodiments, about 0.05 to about 10
mg/kg per day. A suitable dosage level may be about 0.01 to 25
mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5
mg/kg per day. Within this range the dosage may be 0.005 to 0.05,
0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. In some embodiments, for
oral administration, the compositions are provided in the form of
tablets containing 1.0 to 1000 milligrams of the active ingredient,
particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0,
150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0,
900.0, and 1000.0 milligrams of the active ingredient for the
symptomatic adjustment of the dosage to the patient to be treated.
The compounds or pharmaceutically acceptable salts may be
administered on a regimen of 1 to 4 times per day, in some
embodiments, once or twice per day.
[0195] It will be understood, however, that the specific dose level
and frequency of dosage for any particular patient may be varied
and will depend upon a variety of factors including the activity of
the specific compound or pharmaceutically acceptable salt employed,
the metabolic stability and length of action of that compound or
pharmaceutically acceptable salt, the age, body weight, hereditary
characteristics, general health, sex and diet of the subject, as
well as the mode and time of administration, rate of excretion,
drug combination, and the severity of the particular condition for
the subject undergoing therapy.
[0196] Compounds and compositions provided herein may be used in
combination with other drugs that are used in the treatment,
prevention, suppression or amelioration of the diseases or
conditions for which compounds and compositions provided herein are
useful. Such other drugs may be administered, by a route and in an
amount commonly used therefor, contemporaneously or sequentially
with a compound or composition provided herein. When a compound or
composition provided herein is used contemporaneously with one or
more other drugs, a pharmaceutical composition containing such
other drugs in addition to the compound or composition provided
herein is preferred. Accordingly, the pharmaceutical compositions
provided herein include those that also contain one or more other
active ingredients or therapeutic agents, in addition to a compound
or composition provided herein. Suitable additional active agents
include, for example: therapies that retard the progression of
heart failure by down-regulating neurohormonal stimulation of the
heart and attempt to prevent cardiac remodeling (e.g., ACE
inhibitors, angiotensin receptor blockers (ARBs), .beta.-blockers,
aldosterone receptor antagonists, or neural endopeptidase
inhibitors); therapies that improve cardiac function by stimulating
cardiac contractility (e.g., positive inotropic agents, such as the
.beta.-adrenergic agonist dobutamine or the phosphodiesterase
inhibitor milrinone); and therapies that reduce cardiac preload
(e.g., diuretics, such as furosemide) or afterload (vasodilators of
any class, including but not limited to calcium channel blockers,
phosphodiesterase inhibitors, endothelin receptor antagonists,
renin inhibitors, or smooth muscle myosin modulators). The weight
ratio of the compound provided herein to the second active
ingredient may be varied and will depend upon the effective dose of
each ingredient. Generally, an effective dose of each will be
used.
VI. Examples
Abbreviations
[0197] aq: aqueous [0198] BBr.sub.3: boron tribromide [0199]
CH.sub.2Cl.sub.2: dichloromethane [0200] CH.sub.3CN: acetonitrile
[0201] CH.sub.3OH: methanol [0202] DIAD: diisopropyl
azodicarboxylate [0203] DIEA: diisopropyl ethylamine [0204] DMF:
dimethyl formamide [0205] DMSO: dimethyl sulfoxide [0206] equiv.:
equivalents [0207] Et.sub.3N: triethylamine [0208] Et.sub.2O:
diethyl ether [0209] EtOH: ethanol [0210] FeSO.sub.4: ferrous
sulfate [0211] h: hour(s) [0212] HCl: hydrogen chloride [0213]
H.sub.2O: water [0214] K.sub.2CO.sub.3: potassium carbonate [0215]
KHSO.sub.4: potassium bisulfate [0216] KNCO: potassium isocyanate
[0217] LiBr: lithium bromide [0218] MgSO.sub.4: magnesium sulfate
[0219] mL: milliliter [0220] MW: microwave (reaction done in
microwave reactor) [0221] NaCl: sodium chloride [0222] NaH: sodium
hydride [0223] NaHCO.sub.3: sodium bicarbonate [0224] NaOEt: sodium
ethoxide [0225] NaOH: sodium hydroxide [0226] NaOMe: sodium
methoxide [0227] Na.sub.2SO.sub.4: sodium sulfate [0228]
NH.sub.4Cl: ammonium chloride [0229] NMP: n-methyl pyrrolidinone
[0230] pH: -log [H.sup.+] [0231] POCl.sub.3: phosphoryl trichloride
[0232] PPTS: pyridinium p-toluenesulfonate [0233] RP-HPLC: reversed
phase high pressure liquid chromatography [0234] RT: room
temperature [0235] SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride
[0236] TEBAC: triethylbenzylammonium chloride [0237] TFA:
trifluoroacetic acid [0238] THF: tetrahydrofuran [0239] TLC: thin
layer chromatography
Example 1. Preparation of
(S)-3-Isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,
4(1H,3H)-dione
##STR00005##
[0240] Compound 1.1. Isopropylurea
[0241] To a stirred solution of isopropylamine (15.3 g, 0.258 mol,
1.0 equiv) in CH.sub.2Cl.sub.2 (200 mL) under argon at 0.degree. C.
was added dropwise trimethylsilyl isocyanate (30 g, 0.26 mol, 1.0
equiv). The resulting mixture was allowed to reach ambient
temperature and stirred overnight. After cooling to 0.degree. C.,
CH.sub.3OH (100 mL) was added dropwise. The resulting solution was
stirred for 2 hours (h) at room temperature and then concentrated
under reduced pressure. The crude residue was recrystallized from
CH.sub.3OH:Et.sub.2O (1:20) to yield 15.4 g (58%) the title
compound as a white solid. LC/MS: m/z (ES+) 103 (M+H).sup.+.
##STR00006##
[0242] Compound 1.2. 1-Isopropyl Barbituric Acid.
[0243] To a stirred solution of 1.1 (14.4 g, 0.14 mol, 1.00 equiv)
in CH.sub.3OH (500 mL) were added dimethyl malonate (19.55 g, 0.148
mol, 1.05 equiv) and sodium methoxide (18.9 g, 0.35 mol, 2.50
equiv). The resulting mixture was stirred overnight at 65.degree.
C. After cooling to ambient temperature and then to 0.degree. C.,
the pH was carefully adjusted to 3 using aqueous concentrated HCl.
The resulting mixture was concentrated under reduced pressure. The
residue was taken up in EtOH (200 mL) and filtered. The filtrate
was concentrated under reduced pressure and the residue was
purified by silica gel column chromatography using
CH.sub.2Cl.sub.2/CH.sub.3OH (20:1) as eluent to yield 16.8 g (50%)
of the title compound as a white solid. LC/MS: m/z (ES+) 171
(M+H).sup.+. .sup.1H-NMR (300 MHz, d.sub.6-DMSO): .delta. 11.19 (s,
1H), 4.83 (m, 1H), 3.58 (s, 2H), 1.32 (d, J=6.0 Hz, 6H).
##STR00007##
Compound 1.3. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione
[0244] To a 100-mL round-bottom flask containing compound 1.2 (11.4
g, 66.99 mmol, 1.00 equiv) under argon were added
triethylbenzylammonium chloride (21.3 g, 93.51 mmol, 1.40 equiv)
and POCl.sub.3 (30 mL). The resulting mixture was stirred overnight
at 50.degree. C. After cooling to room temperature, the mixture was
concentrated under reduced pressure. The residue was dissolved in
CH.sub.2Cl.sub.2 (150 mL) followed by slow addition of H.sub.2O
(100 mL). The phases were separated and the organic layer was
washed with H.sub.2O (100 mL), dried with anhydrous
Na.sub.2SO.sub.4, and concentrated under reduced pressure. The
crude residue was purified by silica gel column chromatography
using EtOAc/petroleum ether (1:1) as eluent to yield 5.12 g (40%)
of the title compound as a light yellow solid. .sup.1H-NMR (300
MHz, d.sub.6-DMSO): .delta. 12.22 (s, 1H), 5.88 (s, 1H), 4.95 (m,
1H), 1.34 (d, J=6.0 Hz, 6H).
##STR00008##
Compound 1. (S)-3-Isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,
4(1H,3H)-dione
[0245] To a solution of
6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 1.0 g, 5.31
mmol) in 1,4-dioxane (20 mL) was added
(S)-.alpha.-methylbenzylamine (Sigma-Aldrich, 1.43 g, 11.7 mmol,
2.2 equiv). The reaction mixture was stirred at 80.degree. C. for
24 h. After cooling to ambient temperature, the mixture was
concentrated under reduced pressure. The residual was taken up in
EtOAc (70 mL) and washed with aqueous 1N HCl (2.times.50 mL) and
brine (40 mL). The organic layer was dried with anhydrous
Na.sub.2SO.sub.4 and then concentrated under reduced pressure to
half the original volume to yield a precipitate. Hexane (20 mL) was
added and the mixture was stirred at room temperature. The
resulting solid was collected by filtration, washed with hexane (20
mL), and dried to yield 1.0 g (69%) of the title compound as a
white solid. LC/MS: m/z (ES+) 274 (M+H).sup.+. .sup.1H-NMR (400
MHz, d.sub.6-DMSO): .delta. 9.77 (s, 1H), 7.32 (m, 4H), 7.24 (m,
1H), 6.50 (d, J=6.8 Hz, 1H), 4.87 (m, 1H), 4.52 (m, 1H), 4.31 (d,
J=6.8 Hz, 1H), 1.37 (m, 3H), 1.24 (m, 6H). .sup.1H NMR (400 MHz,
CD.sub.3OD) .delta. ppm 7.39-7.20 (m, 5H), 5.01 (m, 1H), 4.48 (m,
1H), 1.49 (d, J=6.7 Hz, 3H), 1.36 (m, 6H).
Example 2. Preparation of
(S)-5-Fluoro-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine
[0246] 2,4(1H,3H)-dione (2).
##STR00009##
[0247] To a solution of 1 (80 mg, 0.293 mmol) in acetic acid (2.0
mL) was added selectfluor (104 mg, 0.293 mmol, 1.0 equiv.). The
mixture was stirred at room temperature for 2 h. It was then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography, eluted with 0-50% EtOAc in
hexanes to give 6 mg (7%) of the title compound as a white solid.
LC/MS: m/z (ES+) 292 (M+H).sup.+. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. ppm 7.36-7.24 (m, 5H), 5.04-4.97 (m, 1H),
4.94-4.88 (m, 1H), 1.54 (d, J=8.0 Hz, 3H), 1.39 (m, 6H).
Example 3. Preparation of
(S)-5-Bromo-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dio-
ne (3)
##STR00010##
[0249] To a solution of 1 (55 mg, 0.201 mmol) in acetic acid (1.0
mL) was added N-bromosuccinamide (35 mg, 0.196 mmol). The mixture
was stirred at room temperature for 1 hour. It was then
concentrated under reduced pressure. The residue was purified by a
silica gel column, eluted with 0-40% EtOAc in hexanes to give 52 mg
(74%) of the title compound as a white solid. LC/MS: m/z (ES+) 352,
354 (M+H, bromine pattern).sup.-. .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. ppm 8.96 (br s, 1H), 7.43-7.28 (m, 5H), 5.28 (d, J=7.4 Hz,
1H), 5.14 (m, 1H), 4.87 (m, 1H), 1.62 (d, J=6.7 Hz, 3H), 1.45-1.39
(m, 6H).
Example 4. Preparation of
(S)-6-((1-(3-Chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyrimidine-2,4-
(1H,3H)-dione
##STR00011##
[0251] Compound 4.1.
5-Fluoro-1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione). To a 100 mL
round bottom flask containing a solution of 1.1 (1.31 g, 0.013 mol,
1.00 equiv) in CH.sub.3OH (15 mL) were added diethyl fluoromalonate
(2.41 g, 0.014 mol, 1.05 equiv) and sodium methoxide (1.74 g, 0.032
mol, 2.50 equiv). The reaction flask was equipped with a reflux
condenser and was stirred for 4 h in an oil bath heated at
85.degree. C. The reaction was cooled to 0.degree. C. and was
quenched with careful addition of concentrated HCl, adjusting to
pH=2 with the addition of excess concentrated HCl. The reaction
mixture was concentrated under reduced pressure and the resulting
residue was dried for 18 h under high vacuum to provide 2.65 g of
the title compound (98%). .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. ppm 5.53 (d, J=24.0 Hz, 1H), 4.91 (m, 2H), 1.46 (m,
6H).
##STR00012##
[0252] Compound 4.2.
6-Chloro-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione. To a
100-mL round-bottom flask equipped with a reflux condenser
containing 4.1 (2.65 g, 0.014 mmol, 1.00 equiv) were added
triethylbenzylammonium chloride (4.50 g, 0.019 mmol, 1.40 equiv)
and POCl.sub.3 (25 mL). The reaction mixture was stirred for 4 h at
50.degree. C. and then was cooled to room temperature. The mixture
was concentrated under reduced pressure and the resulting residue
was dissolved in CH.sub.2Cl.sub.2 (50 mL). Water (50 mL) was added
slowly and the layers were separated. The organic layer was washed
a second time with H.sub.2O (100 mL), dried with anhydrous
MgSO.sub.4, and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (silica gel, 30% EtOAc
in hexanes) to yield 2.67 g (93%) of the title compound as a white
solid. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 5.19-5.05 (m,
2H), 1.48 (d, J=7.04 Hz, 6H).
##STR00013##
Compound 4.
(S)-6-((1-(3-Chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyrimidine-2,4-
(1H,3H)-dione
[0253] To a solution of 4.2 (150 mg, 0.70 mmol, 1 equiv) in DMF (2
mL) contained in a heavy wall pressure vessel were added
(S)-3-chloro-.alpha.-methylbenzylamine (150 mg, 0.70 mmol, 1.0
equiv) and proton sponge (190 mg, 0.90 mol, 1.25 equiv). The
pressure vessel was sealed and the reaction mixture was heated to
95.degree. C. for 3 h behind a blast shield. The reaction mixture
was cooled to room temperature and concentrated under reduced
pressure. The resulting residue was purified by preparative RP-HPLC
utilizing a Shimadzu, Prominence LC-20AP system equipped with a
Phenomenex Gemini-NX C18 column (eluting with 10-90%
CH.sub.3CN/H.sub.2O in 30 min., 20 mL/min (both containing 0.1%
TFA)). The fractions containing pure compound were combined and
lyophilized to provide 30 mg (13%) of the title compound as a white
solid. LC/MS: m/z (ES+) 326 (M+H).sup.+. .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm 9.47 (br s, 1H), 7.35-7.27 (m, 3H),
7.22-7.16 (m, 1H), 5.12 (m, 1H), 4.89 (m, 1H), 4.69 (d, J=5.9 Hz,
1H), 1.59 (d, J=6.7 Hz, 3H), 1.43 (m, 6H).
Example 5. Preparation of
(S)-6-((1-(3,5-Difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione
##STR00014##
[0254] Compound 5.1.
((R,E)-N-(3,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide
[0255] To a solution of 3,5-difluorobenzaldehyde (1.00 g, 7.04
mmol, 1.00 equiv) in CH.sub.2Cl.sub.2 (20 mL) were added pyridinium
p-toluenesulfonate (0.089 g, 0.35 mmol, 0.05 equiv),
(R)-(+)-2-methylpropane-2-sulfinamide (0.852 g, 7.03 mmol, 1.00
equiv), and MgSO.sub.4 (4.2 g, 35.00 mmol, 5.00 equiv). The
resulting mixture was stirred overnight at room temperature. The
reaction mixture was filtered and concentrated under reduced
pressure. The resulting residue was purified by flash
chromatography (silica gel, 20, EtOAc in petroleum ether) to
provide 500 mg (29%) of the title compound as a yellow oil.
##STR00015##
Compound 5.2.
(R)-N-((S)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide
[0256] Methylmagnesium bromide (5.17 mL, 3M, 2.00 equiv) was added
dropwise to a solution of 5.1 (1.9 g, 7.75 mmol, 1.00 equiv) in
CH.sub.2Cl.sub.2 (50 mL) under argon at -48.degree. C. The reaction
mixture was warmed to room temperature and stirred overnight. The
reaction was carefully quenched with a saturated aqueous NH.sub.4Cl
solution (20 mL). The layers were separated and the aqueous layer
was further extracted with CH.sub.2Cl.sub.2 (3.times.50 mL). The
combined organic layers were dried over anhydrous MgSO.sub.4 and
concentrated under reduced pressure to provide 1.3 g (64%) of the
title compound as a yellow oil. .sup.1H NMR (300 MHz, CDCl.sub.3):
.delta. ppm 6.92-6.81 (m, 2H), 6.75-6.65 (m, 1H), 4.65-4.55, (m,
1H), 3.46-3.42 (m, 1H), 1.53-1.44 (m, 3H), 1.26-1.22 (m, 9H).
##STR00016##
Compound 5.3. (S)-1-(3,5-Difluorophenyl)ethan-1-amine
hydrochloride
[0257] To a solution of 5.2 (1.3 g, 4.97 mmol, 1.00 equiv) in
CH.sub.3OH (10 mL) was added 4N HCl in 1,4-dioxane (2.67 mL, 2.00
equiv). The reaction mixture was stirred for 0.5 h at room
temperature and then was concentrated under reduced pressure. The
resulting residue was dissolved in CH.sub.3OH (3 mL) and Et.sub.2O
(300 mL) was added. The resulting precipitate was isolated by
filtration to provide 0.80 g (83%) of the title compound. .sup.1H
NMR (300 MHz, D.sub.2O): .delta. ppm 6.98-6.83 (m, 3H), 4.45-4.38
(m, 1H), 1.51-1.48 (d, J=6.9 Hz, 3H).
##STR00017##
Compound 5.
(S)-6-((1-(3,5-Difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione
[0258] Compound 5.3 (50 mg, 0.32 mmol, 1.00 equiv) was dissolved in
1N NaOH (10 mL), and the resulting mixture was stirred at
25.degree. C. After 1 h, the mixture was extracted with EtOAc
(5.times.10 mL). The combined organic layers were dried with
anhydrous Na.sub.2SO.sub.4, filtered, and concentrated under
reduced pressure. The resulting residue and compound 1.3 (35.6 mg,
0.19 mmol, 0.60 equiv) were combined. The mixture was stirred at
100.degree. C. for 18 h, then was cooled to room temperature and
concentrated under reduced pressure. The resulting residue was
purified by preparative RP-HPLC to provide 28 mg (29%) of the title
compound as an off white solid. LC/MS: m/z (ES+) 310 (M+H).sup.+.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 9.83 (s, 1H),
7.06-7.12 (m, 3H), 6.54 (d, J=6.6 Hz, 1H), 4.91-4.82 (m, 1H),
4.54-4.46 (m, 1H), 4.30 (m, 1H), 1.34 (d, J=6.6 Hz, 3H), 1.22 (d,
J=6.9 Hz, 6H).
Example 6. Preparation of
(S)-6-((Cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-
-dione
##STR00018##
[0259] Compound 6.1.
(R,E)-N-benzylidene-2-methylpropane-2-sulfinamide
[0260] The title compound was prepared in the same manner as 5.1
except benzaldehyde (5.0 g, 47.12 mmol, 1.00 equiv) was used in
place of 3,5-difluorobenzaldehyde to provide 2.8 g (28%) of the
title compound. .sup.1H NMR (300 MHz, d.sub.6-DMSO): .delta. ppm
8.62 (s, 1H), 7.89-7.87 (m, 2H), 7.55-7.49 (m, 3H), 1.31 (s,
9H).
##STR00019##
Compound 6.2.
(S)-N-((S)-Cyclopropyl(phenyl)methyl)-2-methylpropane-2-sulfinamide
[0261] The title compound was prepared using a protocol similar to
that used for the preparation of 5.2 except 6.1 (1.0 g, 4.78 mmol,
1.00 equiv) and cyclopropylmagnesium bromide (9.6 mL, IM, 2.00
equiv) were used in place of 5.1 and methylmagnesium bromide to
provide 0.5 g (35%) of the title compound as a yellow oil. .sup.1H
NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 7.36-7.23 (m, 5H),
3.67-3.51 (m, 2H), 1.31 (m, 10H), 0.85-0.15 (m, 4H).
##STR00020##
Compound 6.3. (S)-Cyclopropyl(phenyl)methanamine hydrochloride
[0262] The title compound was prepared using a protocol similar to
that used for the preparation of 5.3 except 6.2 (500 mg, 1.69 mmol,
1.00 equiv) was used in place of 5.2 to provide 220 mg (88%) of the
title compound as a yellow oil. .sup.1H NMR (300 MHz,
d.sub.6-DMSO): .delta. ppm 7.37-7.31 (m, 5H), 3.53 (d, J=10.0 Hz,
1H), 1.37-1.25 (m, 1H), 0.75-0.55 (m, 1H), 0.53-0.31 (m, 2H),
0.25-0.15 (m, 1H).
##STR00021##
[0263] Compound 6.
(S)-6-((Cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-
-dione. The title compound was prepared using a procedure similar
to that used for the preparation of 5 except 6.3 (200 mg, 1.36
mmol, 1.00 equiv) was used instead of 5.3 and 1,4-dioxane was
utilized as a solvent. After concentration under reduced pressure,
purification utilizing a chiral HPLC (Phenomenex Lux 5.mu.
Cellulose-4, 2.12*25, 5 .mu.m column) with an isocratic mixture of
EtOH:Hexane (1:4) as eluent provided 22 mg (5%) of the title
compound as a white solid. LC/MS: m/z (ES+) 300 (M+H).sup.+.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6) .delta. ppm 9.82 (s, 1H),
7.39-7.25 (m, 5H), 7.25-7.32 (m, 1H), 6.72 (m, 1H), 4.90 (m, 1H),
4.22 (s, 1H), 3.78 (m, 1H), 1.27 (m, 6H), 1.57 (m, 1H), 0.60 (m,
1H), 0.56-0.32 (m, 2H).
Example 7. Preparation of
(S)-6-((cyclopropyl(3-methoxyphenyl)methyl)amino)-3-isopropylpyrimidine-2-
,4(1H, 3H)-dione
##STR00022##
[0265] A solution of
6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 50 mg, 0.265
mmol), (S)-cyclopropyl-(3-methoxyphenyl)methylamine (Sigma-Aldrich,
104 mg, 0.587 mmol), and proton sponge (85 mg, 0.397 mmol) in NMP
(0.5 mL) was stirred at 130.degree. C. for 2 h. After cooling to
room temperature, the mixture was purified by preparative RP-HPLC
(Shimadzu, Prominence LC-20AP system equipped with a Phenomenex
Gemini-NX C18 column), eluting with 20-90% CH.sub.3CN in H.sub.2O
(both containing 0.1% TFA). The fractions containing pure compound
were combined and lyophilized to give 10 mg (11%) of the title
compound as a white solid. LC/MS: m/z (ES+) 330 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. ppm 7.26 (t, J=7.8 Hz,
H), 6.92-6.79 (m, 3H), 5.00 (m, 1H), 3.79 (s, 3H), 3.74 (d, J=8.6
Hz, 1H), 1.36 (d, J=7.0 Hz, 6H), 1.23-1.13 (m, 1H), 0.68-0.60 (m,
1H), 0.58-0.50 (m, 1H), 0.50-0.42 (m, 1H), 0.41-0.34 (m, 1H).
Example 8. Preparation of
(S)-6-((Cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)--
dione
##STR00023##
[0266] Compound 8.1.
(S,E)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide
[0267] To a solution of cyclobutanecarbaldehyde (1.0 g, 11.89 mmol,
1.00 equiv) in CH.sub.2Cl.sub.2 (10 mL) were added pyridinium
p-toluenesulfonate (0.143 g, 0.57 mmol, 0.05 equiv),
(S)-(-)-2-methylpropane-2-sulfinamide (1.22 g, 10.07 mmol, 0.85
equiv), and magnesium sulfate (7.14 g, 59.32 mmol, 5.00 equiv). The
resulting mixture was stirred overnight at room temperature. The
reaction mixture was filtered and concentrated under reduced
pressure. The resulting residue was purified by flash
chromatography (silica gel, 30%, EtOAc in petroleum ether) to
provide 2.0 g (900/%) of the title compound as a white solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm 8.08 (d, J=10.8 Hz,
1H), 3.36-3.32 (m, 1H), 2.25-2.16 (m, 4H), 2.03-1.90 (m, 2H), 1.15
(s, 9H).
##STR00024##
Compound 8.2.
(S)-N-((S)-cyclobutyl(phenyl)methyl)-2-methylpropane-2-sulfinamide
[0268] Phenylmagnesium bromide (3M in Et.sub.2O, 15.3 mL, 2.00
equiv) was added dropwise to a solution of 8.1 (4.3 g, 22.96 mmol,
1.00 equiv) in THF (40 mL). The reaction mixture was heated for 3 h
at 65.degree. C. It was then cooled to room temperature and
carefully quenched with a saturated aqueous NH.sub.4Cl solution (30
mL). The resulting mixture was extracted with EtOAc (3.times.30
mL), and the combined organic layers were dried with anhydrous
Na.sub.2SO.sub.4 and concentrated under reduced pressure to provide
5.8 g (95%) of the title compound as a white solid. .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta. 7.30-7.21 (m, 5H), 4.23 (d, J=9.6 Hz,
1H), 2.73-2.68 (m, 1H), 1.95-1.60 (m, 6H), 1.14 (s, 9H).
##STR00025##
Compound 8.3. (S)-Cyclobutyl(phenyl)methanamine hydrochloride
[0269] The title compound was prepared using a procedure similar to
that used for the preparation of 5.3 except 8.2 (5.8 g, 0.022 mol,
1.00 equiv) was used in place of 5.2 to provide 3.20 g (91%) of the
title compound as a white solid. .sup.1H NMR (300 MHz, D.sub.2O):
.delta. ppm 7.36-7.28 (m, 5H), 4.18 (m, 1H), 2.87-2.73 (m, 1H),
2.11-2.01 (m, 1H), 1.90-1.69 (m, 5H).
##STR00026##
Compound 8.
(S)-6-((Cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)--
dione
[0270] Compound 8.3 (0.200 g, 1.24 mmol, 1.00 equiv) was dissolved
in 1N NaOH (10 mL), and was stirred for 1 h at 25.degree. C. The
reaction mixture was extracted with EtOAc (5.times.10 mL). The
combined organic layers were dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated under reduced pressure. The resulting
residue was dissolved in NMP and combined with 1.3 and proton
sponge and heated as described for the preparation of 7. The title
compound (35 mg, 9%) was isolated as a white solid. LC/MS: m/z
(ES+) 314 (M+H).sup.+. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
ppm 7.38-7.26 (m, 5H), 5.08-4.97 (m, 1H), 4.25 (d, J=6.9 Hz, 1H),
2.68-2.58 (m, 1H), 2.19-2.13 (m, 1H), 1.98-1.83 (m, 5H), 1.36 (d,
J=6.9 Hz, 6H).
Example 9. Preparation of
(S)-6-((1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1-
H,3H)-dione
##STR00027##
[0271] Compound 9.1. 1-(tetrahydro-2H-pyran-4-yl)urea
[0272] A mixture of tetrahydro-2H-pyran-4-amine (5.0 g, 49.4 mmol,
1.0 equiv.) and potassium isocyanate (4.0 g, 49.5 mmol, 1.0 equiv.)
was refluxed in H.sub.2O (50 mL) overnight. The reaction was cooled
to room temperature and excess NaCl was added to help saturate the
aqueous layer. The precipitate was isolated by filtration to
provide the desired product (1.28 g, 8.88 mmol). The aqueous layer
was washed with EtOAc (3.times.15 mL) and then was concentrated and
azeotroped with toluene (3.times.100 mL). The resulting solid was
suspended in 1:4 CH.sub.3OH:EtOAc (100 mL) and filtered a total of
four times. The combined organics were concentrated under reduced
pressure and combined with the isolated precipitate to provide 5.01
g (70%) of the title compound. LC/MS: m/z (ES+) 145 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 6.14 (d, J=7.5 Hz,
1H), 5.47 (s, 2H), 3.85 (dt, J=11.6, 3.6 Hz, 2H), 3.65-3.52 (m,
1H), 3.38 (td, J=11.4, 2.2 Hz, 2H), 1.80-1.72 (m, 2H), 1.42-1.27
(m, 2H).
##STR00028##
Compound 9.2.
1-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione
[0273] Compound 9.1 (2.8 g, 19.4 mmol) was dissolved in EtOH (30
mL), and diethyl malonate (2.45 mL, 21.4 mmol, 1.1 equiv.), and
NaOEt (7.55 mL, 23.3 mmol, 1.2 equiv.) were added. The reaction was
stirred at 85.degree. C. overnight, and then was cooled to room
temperature. The reaction mixture was diluted with H.sub.2O (5 mL),
and excess KHSO.sub.4 was added to saturate the aqueous layer. The
reaction mixture was extracted with EtOAc (3.times.15 mL). The
combined organic layers were dried with anhydrous MgSO.sub.4,
filtered and concentrated under reduced pressure. The resulting
residue was purified by flash chromatography (silica gel, 0-25%
CH.sub.3OH in CH.sub.2Cl.sub.2) to provide 1.57 g of a mixture
containing the title compound which was used without further
purification. LC/MS: m/z (ES-) 211 (M-H).sup.-.
##STR00029##
Compound 9.3.
6-chloro-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione
[0274] To a solution of 9.2 (1.57 g, 7.4 mmol, 1 equiv.) in
CH.sub.3CN (15 mL) was added POCl.sub.3 (0.551 mL, 5.9 mmol, 0.8
equiv.). The reaction mixture was stirred at 80.degree. C.
overnight. An additional aliquot of POCl.sub.3 (0.4 equiv.) was
added and the reaction mixture was stirred at 80.degree. C. for 3
h. Additional aliquots of POCl.sub.3 (0.4 equiv.) were added after
3 h and 5 h of stirring at 80.degree. C. The reaction mixture was
then stirred at 90.degree. C. for 1 h. The reaction was cooled to
room temperature, concentrated, swirled with Et.sub.2O (15 mL) and
decanted. The resulting residue was rinsed with Et.sub.2O (15 mL)
and decanted until the Et.sub.2O decanted clear. The resulting
residue was carefully suspended in CH.sub.3OH (10 mL), and
filtered. The filtrate was concentrated to obtain a mixture of
starting material and the title compound (.about.85% pure, 1.6 g).
LC/MS: m/z (ES-) 229 (M-H).sup.-.
##STR00030##
Compound 9.
(S)-6-((1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1-
H,3H)-dione
[0275] A mixture of 9.3 (0.15 g, 0.65 mmol, 1 equiv.) and
(S)-(-)-.alpha.-methylbenzylamine (470 mg, 3.88 mmol, 6.0 equiv.)
was stirred overnight at 90.degree. C. The reaction mixture was
cooled to room temperature and the resulting residue was purified
by preparative RP-HPLC (0-40% CH.sub.3CN in H.sub.2O in 30 min.),
followed by a second purification on a preparatory TLC plate (2000
um) (7% CH.sub.3OH in CH.sub.2Cl.sub.2) to provide 23 mg (11%) of
the title compound. LC/MS: m/z (ES+) 316 (M+H).sup.+. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 10.23 (s, 1H), 7.40-7.32 (m,
4H), 7.31-7.17 (m, 1H), 6.93 (s, 1H), 4.84-4.71 (m, 1H), 4.56-4.43
(m, 1H), 4.35 (s, 1H), 3.93-3.78 (m, 2H), 3.28 (t, J=12.1 Hz, 2H),
2.63-2.39 (m, 2H), 1.40 (d, J=6.7 Hz, 3H), 1.35-1.16 (m, 2H).
Example 10. Preparation of
(S)-6-((1-(3-methoxyphenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrim-
idine-2,4(1H,3H)-dione (10)
##STR00031##
[0277] To a solution of 9.3 (0.58 g, 0.25 mmol) in a mixture of
2-propanol and H.sub.2O (4:1, 1 mL) was added
(S)-1-(3-methoxyphenyl)-ethylamine (0.113 g, 0.75 mmol, 3.0
equiv.). The reaction mixture was heated to 120.degree. C. for 2 h.
After cooling, the reaction mixture was concentrated under reduced
pressure, dissolved in CH.sub.3OH and filtered. The filtrate was
purified by preparative RP-HPLC (20-100% CH.sub.3CN in H.sub.2O in
40 min. at 25 mL/min.) to provide 18 mg (21%) of the title compound
as an off-white solid. LC/MS: m/z (ES+) 346 (M+H).sup.+. .sup.1H
NMR (400 MHz, acetone-d.sub.6) .delta. 8.90 (s, 1H), 7.15 (dd,
J=8.3, 8.1 Hz, 1H), 6.88 (s, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.68 (d,
J=8.1 Hz, 1H), 6.15 (s, 1H), 4.74 (m, 1H), 4.48 (m, 1H), 4.35 (s,
1H), 3.82 (m, 2H), 3.68 (s, 3H), 3.2 (m, 2H), 2.55 (m, 2H) 1.44 (d,
J=6.6 Hz, 3H), 1.15 (m, 2H).
Example 11. Preparation of
6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H-
)-dione
##STR00032##
[0278] Compound 11.1.
6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione
[0279] To a mixture of 6-chloro-uracil (3.0 g, 20.47 mmol, 1
equiv.) and LiBr (1.78 g, 20.5 mmol, 1.0 equiv.) in NMP (70 mL) at
0.degree. C. was added NaH (60% dispersion in mineral oil, 0.82 g,
20.5 mmol, 1.0 equiv.). The reaction mixture was stirred at
0.degree. C. for 10 min, and 2-(trimethylsilyl)ethoxymethyl
chloride (3.75 g, 22.5 mmol, 1.1 equiv.) was slowly added via an
addition funnel. The reaction mixture was stirred overnight at room
temperature and then diluted with EtOAc (150 mL). The mixture was
washed with a saturated aqueous NH.sub.4Cl solution (50 mL),
saturated aqueous NaHCO.sub.3 (50 mL), and brine (50 mL). The
organic layer was dried with anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure to provide 3.2 g (57%) of the
title compound as a white solid. LC/MS: m/z (ES+) 299 (M+Na).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 9.00-8.80 (br-s,
1H), 5.95 (s, 1H), 5.45 (s, 2H)), 3.63 (t, J=7.0 Hz, 2H), 1.48 (t,
J=7.0 Hz, 2H), 0.01 (s, 9H).
##STR00033##
Compound 11.2.
6-chloro-3-(tetrahydrofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyr-
imidine-2,4(1H,3H)-dione
[0280] To a solution of 11.1 (277 mg, 1.0 mmol, 1 equiv.),
3-hydroxytetrahydrofuran (106 mg, 1.2 mmol, 1.2 equiv.), and
triphenylphosphine (320 mg, 1.2 mmol, 1.2 equiv.) in THF (7.5 mL)
at 0.degree. C., was added diisopropyl azodicarboxylate (0.240 g,
1.2 mmol, 1.2 equiv.) dropwise. The reaction mixture was stirred at
room temperature for 30 minutes. The reaction mixture was
concentrated under reduced pressure and the resulting residue was
purified by preparative RP-HPLC (20-100% CH.sub.3CN in H.sub.2O
with 0.1% formic acid buffer in 40 min. at 25 mL/min.) to provide
102 mg (29%) of the title compound. LC/MS: m/z (ES+) 347
(M+H).sup.+. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.92 (s,
1H), 5.58 (m, 1H), 5.41 (s, 2H), 4.20 (m, 1H), 4.00-3.85 (m, 3H),
3.65 (t, J=7.0 Hz, 2H), 2.35-2.20 (m, 1H), 2.20-2.08 (m, 1H), 0.95
(t, 2H), 0.01 (s, 9H); .sup.13C NMR (CDCl.sub.3) .delta. 160.7,
150.7, 145.6, 102.0, 74.8, 68.7, 67.9, 67.5, 51.9, 28.7, 18.0,
0.0.
##STR00034##
Compound 11.3.
6-chloro-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione
[0281] Compound 11.2 (0.50 g, 1.4 mmol, 1.0 equiv.) was dissolved
in trifluoroacetic acid (1 mL). The reaction mixture was stirred at
room temperature for 30 minutes and then was concentrated under
reduced pressure. The resulting residue was purified by preparative
RP-HPLC (10% CH.sub.3CN in H.sub.2O in 40 min. at 25 mL/min.) to
provide 300 mg (96%) of the title compound as a white solid. LC/MS:
m/z (ES+) 217 (M+H).sup.+. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 5.90 (s, 1H), 5.35 (m, 1H), 4.00 (m, 1H), 3.85-3.68 (m,
3H), 2.20 (m, 1H), 2.01 (m, 1H).
##STR00035##
Compound 11.
6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H-
)-dione
[0282] The title compound was prepared using a procedure similar to
that used for the preparation of 9 except 11.3 (22 mg, 0.10 mmol,
1.00 equiv) was used in place of 9.3 to provide 15 mg (50%) of the
title compound as a white solid. LC/MS: m/z (ES+) 302 (M+H).sup.+.
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. ppm 10.50 (1H),
7.50-7.20 (m, 5H), 5.90 (m, 1H), 5.60 (m, 1H), 4.78 (m, 1H), 4.45
(s, 1H), 4.20 (m, 1H), 4.05-3.90 (m, 2H), 3.90-3.80 (m, 1H),
2.45-2.10 (m, 2H), 1.55 (d, J=6.7 Hz, 3H).
Example 12. Preparation of
(S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-(1-phenylethylamino)pyrimidine-
-2,4(1H,3H)-dione
##STR00036##
[0283] Compound 12.1. tert-Butyl
4-(3-benzoylureido)piperidine-1-carboxylate
[0284] To a solution of benzoylisocyanate (4.8 g, 32.6 mmol) in
CH.sub.2Cl.sub.2 (180 mL) at 0.degree. C. was added
4-amino-1-N-boc-piperidine (6.0 g, 30 mmol). The reaction mixture
was stirred at room temperature for 4 h and concentrated. The
residue was treated with Et.sub.2O (100 mL). The precipitate was
filtered and washed with Et.sub.2O to yield 5.70 g (55%) of the
title compound as a white solid. LC/MS: m/z (ES+) 337
(M+H).sup.+.
##STR00037##
Compound 12.2. tert-Butyl 4-ureidopiperidine-1-carboxylate
[0285] To a mixture of 12.1 (5.60 g, 16.1 mmol) in CH.sub.3OH (70
mL) and H.sub.2O (70 mL) was added sodium hydroxide (11.6 g, 290
mmol) portionwise. The reaction mixture was stirred at room
temperature overnight and then refluxed for 1 h. The mixture was
cooled to room temperature and concentrated under reduced pressure
to remove CH.sub.3OH. The precipitate was filtered, washed with
H.sub.2O, and dried to yield 3.2 g (82%) of the title compound as a
white solid. LC/MS: m/z (ES+) 266 (M+Na).sup.+.
##STR00038##
Compound 12.3. tert-Butyl
4-(2,4,6-trioxo-tetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate
[0286] To a mixture of 12.2 (3.63 g, 14.9 mmol), diethylmalonate
(2.6 mL, 16.5 mmol, 1.1 equiv.) and anhydrous ethanol (60 mL) was
added NaOEt (21% in EtOH, 6.6 mL, 17.7 mmol, 1.2 equiv.). The
mixture was refluxed for 14 h and concentrated. The residue was
taken up in H.sub.2O (15 mL) and washed with EtOAc (2.times.30 mL).
The aqueous layer was separated and adjusted to pH=5 with
concentrated. HCl. The precipitate was filtered, washed with
H.sub.2O and dried to give 3.70 g (80%) of the title compound as an
off-white solid. LC/MS: m/z (ES+) 334 (M+Na).sup.+.
##STR00039##
Compound 12.4.
6-chloro-3-(piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione
[0287] To a mixture of 12.3 (2.55 g, 8.19 mmol) and POCl.sub.3 (10
mL, 100.65 mmol) was added H.sub.2O (0.41 mL, 22.78 mmol) dropwise.
The mixture was stirred at 120.degree. C. for 30 min and then
concentrated. The residue was carefully taken up in ice water (20
g). To the mixture was added K.sub.2CO.sub.3 (.about.8.0 g)
portionwise until the pH was .about.7. The precipitate was
filtered, washed with H.sub.2O (20 mL) and EtOAc (50 mL). The
resulting material was dried to yield 1.45 g (77%) of the title
compound as an off-white solid. LC/MS: m/z (ES+) 230
(M+H).sup.+.
##STR00040##
[0288] Compound 12.5.
6-chloro-3-(1-(methylsulfonyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione.
[0289] To a mixture of 12.4 (380 mg, 1.65 mmol, 1.0 equiv.) and
CH.sub.2Cl.sub.2 (8 mL) was added Et.sub.3N (0.70 mL, 4.95 mmol, 3
equiv.) and methanesulfonyl chloride (0.23 mL, 2.5 mmol, 1.5
equiv.). The mixture was stirred at room temperature for 2 h and
then quenched with H.sub.2O (3 mL) to yield precipitate. The
precipitate was filtered and washed with CH.sub.2Cl.sub.2
(3.times.3 mL). The filtrate was concentrated to .about.1.5 mL.
Filtration of a second precipitate was followed by washing with
H.sub.2O (2.times.1 mL) and CH.sub.2Cl.sub.2 (3.times.2 mL). The
precipitates were combined to afford 320 mg (63%) of the title
compound as an off-white solid. LC/MS: m/z (ES+) 308
(M+H).sup.+.
##STR00041##
Compound 12.
(S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-(1-phenylethylamino)pyrimidine-
-2,4(1H,3H)-dione
[0290] A mixture of 12.5 (20 mg, 0.065 mmol) and
(S)-.alpha.-methylbenzylamine (180 mg, 1.5 mmol, 23 equiv.) was
stirred at 125.degree. C. for 1 h. The mixture was concentrated
under reduced pressure, dissolved in CH.sub.3OH and filtered. The
filtrate was purified using preparative RP-HPLC eluting with linear
gradient 20% to 100% CH.sub.3CN in H.sub.2O (0.1% formic acid
buffer) over 40 min to give 16 mg (63%) of the title compound as an
off-white solid. LC/MS: m/z (ES+) 393 (M+H).sup.+. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 9.40 (br s, 1H), 7.35-7.25 (m, 4H),
7.15 (m, 1H), 6.55 (s, 1H), 4.58 (m, 1H), 4.42 (m, 1H), 4.30 (s,
1H), 3.52 (m, 2H), 2.79 (s, 3H), 2.70-2.62 (m, 2H), 2.50-2.48 (m,
2H), 1.48-1.38 (m, 2H), 1.32 (d, J=6.8 Hz, 3H).
Example 13. Preparation of (S)-methyl
4-(2,6-dioxo-4-(1-phenylethylamino)-2,3-dihydropyrimidin-1(6H)-yl)piperid-
ine-1-carboxylate
##STR00042##
[0291] Compound 13.1. Methyl
4-(4-chloro-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)piperidine-1-carboxyl-
ate
[0292] To a mixture of 12.4 (115 mg, 0.5 mmol, 1.0 equiv.) and
CH.sub.2Cl.sub.2 (2 mL) was added Et.sub.3N (0.14 mL, 1.5 mmol, 3.0
equiv.), followed by methyl chloroformate (95 mg, 1.0 mmol, 2.0
equiv.). The mixture was stirred at room temperature for 1 h,
diluted with CH.sub.2Cl.sub.2 (8 mL), washed with a saturated
aqueous NaHCO.sub.3 solution (1 mL), H.sub.2O (1 mL), brine (1 mL),
dried with anhydrous Na.sub.2SO.sub.4 and concentrated to yield 105
mg (73%) of an off-white solid. LC/MS: m/z (ES+) 288
(M+H).sup.+.
##STR00043##
Compound 13. (S)-methyl
4-(2,6-dioxo-4-(l-phenylethylamino)-2,3-dihydropyrimidin-1(6H)-yl)piperid-
ine-1-carboxylate
[0293] A mixture of 13.1 (58 mg, 0.20 mmol) and
(S)-.alpha.-methylbenzylamine (240 mg, 1.5 mmol) was stirred at
120.degree. C. for 0.5 h. The title compound was prepared using a
procedure similar to that used for the preparation of 9 to provide
40 mg (63%) of the title compound as an off-white solid. LC/MS: m/z
(ES+) 373 (M+H).sup.+. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta.
ppm 9.85 (s, 1H), 7.29-7.15 (m, 5H), 5.75 (br s, 1), 4.80 (m, 1H),
4.60 (s, 1H), 4.35 (m, 1H), 4.20-4.00 (m, 2H), 3.58 (s, 3H),
2.80-2.70 (m, 2H), 2.46 (m, 2H), 1.50 (m, 2H), 1.38 (d, J=6.7 Hz,
3H).
Example 14. Preparation of
3-(R)-sec-butyl-6-((S)-1-(3-methoxyphenyl)ethylamino)pyrimidine-2,4(1H,3H-
)-dione
##STR00044##
[0295] Compound 14.1. (R)-1-sec-butylurea. Benzoyl isocyanate (5.36
g, 36.5 mmol, 1.05 equiv.) was dissolved in CH.sub.2Cl.sub.2 (20
mL) and cooled to 0.degree. C. in an ice bath. (R)-butan-2-amine
(2.54 g, 34.7 mmol, 1 equiv.) in CH.sub.2Cl.sub.2 (10 mL) was
carefully added while stirring. The mixture was allowed to stir for
3 h at room temperature. After the reaction was deemed complete,
the mixture was concentrated. The residue was suspended in
Et.sub.2O (20 mL) and filtered. The solid was taken up in a 1:1
mixture of CH.sub.3OH and H.sub.2O (200 mL) followed by the
addition of NaOH (6.9 g, 174 mmol, 5 equiv.). The reaction was
stirred overnight at room temperature. The CH.sub.3OH was
evaporated from the solution and the resulting precipitate (1.66 g,
39%) was collected. LC/MS: m/z (ES+) 117 (M+H).sup.+.
##STR00045##
Compound 14.2. (R)-1-sec-butylpyrimidine-2,4,6(1H,3H,5H)-trione
[0296] Compound 14.1 (1.66 g, 14.3 mmol, 1.0 equiv.) was dissolved
in EtOH (10 mL), and diethyl malonate (1.8 mL, 15.7 mmol, 1.1
equiv.), and NaOEt (5.6 mL, 17.1 mmol, 1.2 equiv.) were added. The
reaction was stirred at 80.degree. C. for 2 h and then cooled to
room temperature. Water (20 mL) was added and then EtOH was removed
by evaporation. KHSO.sub.4 (excess) was added to saturate the
aqueous layer which was then extracted with EtOAc. The combined
organics were dried with anhydrous MgSO.sub.4 and concentrated to
yield 1.6 g (61%) of the title compound as a crude residue which
was used without further purification. LC/MS: m/z (ES-) 183
(M-H).sup.-.
##STR00046##
Compound 14.3.
(R)-3-sec-butyl-6-chloropyrimidine-2,4(1H,3H)-dione
[0297] A mixture of 14.2 (1.6 g, 8.7 mmol, 1 equiv.) and POCl.sub.3
(648 .mu.L, 7.0 mmol, 0.8 equiv.) in CH.sub.3CN (10 mL) was stirred
at 90.degree. C. for 2 h. Additional POCl.sub.3 (0.8 equiv.) was
added and stirred at 90.degree. C. for 3 h. The reaction was cooled
to room temperature, carefully quenched with CH.sub.3OH (10 mL),
stirred for 30 minutes and purified with normal phase HPLC 0-25%
CH.sub.3OH/CH.sub.2Cl.sub.2 followed by a CH.sub.3OH flush. The
product and starting material co-eluted. The mixture was
concentrated, the residue was taken up in CH.sub.3CN (10 mL) and
POCl.sub.3 (648 uL) was added. The reaction was stirred at
90.degree. C. for 3 h and then cooled to room temperature. The
reaction was carefully quenched with CH.sub.3OH (10 mL) and stirred
for 30 minutes. The reaction mixture was purified by normal phase
HPLC with previous condition, concentrated and dried under vacuum
to yield 450 mg (32%) of the title compound as an off-white solid.
LC/MS: m/z (ES-) 201 (M-H).sup.-.
##STR00047##
Compound 14.
3-(R)-sec-butyl-6-((S)-1-(3-methoxyphenyl)ethylamino)pyrimidine-2,4(1H,3H-
)-dione
[0298] A mixture 14.3 (150 mg, 0.74 mmol, 1.0 equiv.) in neat
(S)-1-(3-methoxyphenyl)ethanamine (400 uL) was stirred overnight at
90.degree. C. The reaction was purified using preparative RP-HPLC
on an Agilent system with a gradient of 0-40% CH.sub.3CN in
H.sub.2O over 45 min to yield 13 mg (6%) of the title compound as
an off-white solid. LC/MS: m/z (ES+) 318 (M+H).sup.+. .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 9.79 (s, 1H), 7.28 (t, J=8.1
Hz, 1H), 6.94-6.88 (m, 2H), 6.84 (dd, J=8.2, 1.7 Hz, 1H), 6.51 (d,
J=6.4 Hz, 1H), 4.72-4.59 (m, 1H), 4.47 (m, 1H), 4.35 (s, 1H), 3.76
(s, 3H), 1.98-1.84 (m, 1H), 1.61 (m, 1H), 1.39 (d, J=6.7 Hz, 3H),
1.25 (d, J=6.9 Hz, 3H), 0.70 (t, J=7.4 Hz, 3H).
Example 15. Preparation of
(S)-6-(1-phenylethylamino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione
##STR00048##
[0299] Compound 15.1. 1-(pyridin-3-yl)urea
[0300] Benzoyl isocyanate (3.28 g, 22.3 mmol, 1.05 equiv.) was
taken up in CH.sub.2Cl.sub.2 (30 mL) and cooled to -10.degree. C.
Pyridin-3-amine (2 g, 21.2 mmol, 1 equiv.) was added in portions
while stirring. The mixture was allowed to stir for 3 h at room
temperature. After the reaction was deemed complete, it was
concentrated and then taken up in a 1:1 mixture of CH.sub.3OH and
H.sub.2O (100 mL) followed by the addition of NaOH (4.25 g, 106.3
mmol, 5 equiv.). The reaction was allowed to stir overnight at room
temperature, concentrated to dryness, and then azeotroped three
times with toluene. A mixture of 10% CH.sub.3OH in EtOAc (100 mL)
was added to the solid and stirred for 10 minutes followed by
filtration. The solid was suspended and filtered two additional
times. The combined filtrates were filtered once more to remove any
solids that passed through the filter and concentrated. The residue
was triturated with EtOAc (5 mL) and dried under vacuum to yield
3.5 g of crude material (off-white solid) that was utilized without
further purification. LC/MS: m/z (ES+) 138 (M+H).sup.+.
##STR00049##
Compound 15.2.
1-(pyridin-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione
[0301] Compound 15.1 (3.0 g, 21.8 mmol, 1.0 equiv.) was taken up in
EtOH (20 mL), followed by the addition of diethyl malonate (2.75
mL, 24.1 mmol, 1.1 equiv.), and NaOEt (8.5 mL, 26.3 mmol, 1.2
equiv.). The reaction was stirred at 85.degree. C. overnight and
then cooled to room temperature. Water (100 mL) was added slowly
followed by careful addition of sodium bicarbonate (8 g). The
resulting mixture was washed three times with EtOAc. The aqueous
layer was concentrated to 50 mL and CH.sub.3OH (150 mL) was added.
The precipitate was removed by filtration and the filtrate was
concentrated. The resulting residue was purified flash
chromatography (silica gel, 0-25% CH.sub.3OH/CH.sub.2Cl.sub.2) to
yield 1.70 g (38%) of the title compound as a light yellowish
solid. LC/MS: m/z (ES+) 206 (M+H).sup.+.
##STR00050##
Compound 15.3.
6-chloro-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione
[0302] A mixture of 15.2 (700 mg, 3.41 mmol, 1.0 equiv.) and
POCl.sub.3 (255 .mu.L, 2.7 mmol, 0.8 equiv.) in CH.sub.3CN (10 mL)
was stirred at 90.degree. C. for 2 h. Additional POCl.sub.3 (0.8
equiv) was added and stirring was continued at 90.degree. C. for 2
h. Additional POCl.sub.3 (1.6 equiv.) was added followed by the
careful addition of H.sub.2O (150 ul 2.5 equiv.) The reaction was
stirred overnight at 90.degree. C. After cooling to room
temperature, the mixture was filtered and the solid was carefully
washed with CH.sub.3OH (1 mL). Ethyl acetate (20 mL) was added to
the filtrate and the resulting precipitate was collected by
filtration and dried under vacuum to yield 230 mg (30%) of the
title compound as a light yellowish solid. LC/MS: m/z (ES+) 224
(M+H).sup.+.
##STR00051##
Compound 15.
(S)-6-(1-phenylethylamino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione
[0303] A mixture of 15.3 (100 mg, 0.45 mmol, 1 equiv.) in neat
(S)-(-)-.alpha.-methylbenzylamine (500 uL) was stirred overnight at
100.degree. C. After cooling, the reaction was purified using
preparative RP-HPLC on an Agilent system with a gradient of 0-40'
CH.sub.3CN in H.sub.2O over 45 min., followed by a second
purification on a preparatory TLC plate (2000 um) with 7%
CH.sub.3OH/CH.sub.2Cl.sub.2 to yield 39.5 mg (28%) of the title
compound. LC/MS: m/z (ES+) 309 (M+H).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 11.15 (s, 1H), 8.49 (dd, J=4.8, 1.4 Hz,
1H), 8.34 (d, J=2.4 Hz, 1H), 7.65-7.58 (m, 1H), 7.44 (dd, J=8.1,
4.8 Hz, 1H), 7.37 (m, 5H), 7.26 (m, 1H), 4.61-4.53 (m, 1H), 4.48
(s, 1H), 1.39 (d, J=6.8 Hz, 3H).
Example 16. Preparation of
(S)-3-(Isoxazol-3-yl)-6-(1-phenylethylamino)pyrimidine-2,4(1H,3H)-dione
(16)
##STR00052##
[0305] The title compound was prepared using procedures similar to
those used for the preparation of compound 15 except
isoxazol-3-amine was used in place of pyridin-3-amine. LC/MS: m/z
(ES+) 299 (M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
ppm 8.96 (s, 1H), 7.38 (d, J=3.9 Hz, 4H), 7.28 (dd, J=8.4, 4.3 Hz,
2H), 7.10 (s, 1H), 6.63 (s, 1H), 4.74-4.52 (m, 1H), 4.48 (s, 1H),
1.44 (d, J=6.6 Hz, 3H).
Example 17. Preparation of
(S)-6-((1-(3-(1H-pyvrazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine--
2,4(1H,3H)-dione (17)
##STR00053##
[0307] The title compound was prepared by Ullman coupling (P. E.
Fanta. "The Ullmann Synthesis of Biaryls". Synthesis, 1974, 9-21)
of 35 with 1H-pyrazole in the presence of copper iodide, cesium
carbonate, and trans-N,N'-dimethylcyclohexane-1,2-diamine. LC/MS:
m/z (ES+) 340 (M+H).sup.+. .sup.1H-NMR (400 MHz, CD.sub.3OD):
.delta. ppm 8.26 (s, 1H), 7.70 (m, 2H), 7.66 (m, 1H), 7.51 (m, 1H),
7.34 (m, 1H), 6.55 (s, 1H), 5.05 (m, 1H), 4.62 (m, 1H), 1.58 (d,
J=6.8 Hz, 3H), 1.37 (m, 6H).
Example 18. Preparation of Additional Pyrimidine Dione
Compounds
[0308] The compounds in Table 1 were prepared according to the
examples as described above.
TABLE-US-00001 TABLE 1 Compounds and Analytical Data Compound No.
Observed Mass and/or Structure Ref. Example .sup.1H NMR
##STR00054## 19R 1 274 (M + H).sup.+ .sup.1H-NMR (400 MHz,
CD.sub.3OD): .delta. ppm 7.42-7.22 (m, 5H), 5.06-4.94 (m, 1H), 4.49
(m, 1H), 1.49 (d, J = 7.0 Hz, 3H), 1.36 (m, 6H). ##STR00055## 20R 1
304 (M + H).sup.+ .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm
10.39 (br s, 1H), 7.29-7.23 (m, 1H), 6.88-6.79 (m, 3H), 5.31 (br s,
1H), 5.09 (m, 1H), 4.78 (br s, 1H), 4.48-4.34 (m, 1H), 3.80 (s,
3H), 1.51 (d, J = 7.0 Hz, 3H), 1.44-1.38 (m, 6H). ##STR00056## 21 1
304 (M + H).sup.+ .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. ppm
7.26 (t, J = 7.9 Hz, 1H), 6.92-6.85 (m, 2H), 6.85-6.80 (m, 1H),
5.01 (m, 1H), 4.45 (d, J = 7 0 Hz, 1H), 3.79 (s, 3H), 1.48 (d, J =
7.0 Hz, 3H), 1.37 (d, J = 7.0 Hz, 6H). ##STR00057## 22 1 304 (M +
H).sup.+ .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. ppm 7.29-7.17
(m, 1 H), 7.00 (d, J = 7.4 Hz, 1 H), 6.93 (m, 1 H), 5.05-4.97 (m, 1
H), 4.83 (s, 1 H), 4.80-4.74 (m, 1 H), 3.89 (s, 3 H), l.45 (d, J =
6.7 Hz, 3 H), 1.38- 1.34 (m, 6 H). ##STR00058## 24 1 288 (M +
H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.76 (br
s, 1H), 7.41-7.13 (m, 5H), 6.50 (d, J = 7.0 Hz, 1H), 4.88 (m, 1H),
4.31 (d, J = 2.4 Hz, 1H), 4.24 (m, 1H), 1.83-1.58 (m, 2H),
1.35-1.10 (m, 6H), 0.83 (m, 3H). ##STR00059## 25 1 288 (M +
H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 7.46-7.29
(m, 4H), 7.27-7.21 (m, 1H), 6.27 (d, J = 9.0 Hz, 1H), 6.08 (br s,
1H), 5.13 (m, 1H), 4.98 (m, 1H), 1.78 (s, 3H), 1.46 (m, 3H), 1.29
(m, 6H). ##STR00060## 26 1 292 (M + H).sup.+ .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. ppm 10.45 (br s, 1H), 7.30-7.23 (m, 2H),
7.16-7.01 (m, 2H), 5.13 (dt, J = 13.8, 7.0 Hz, 1H), 4.99 (br s,
1H), 4.74-4.63 (m, 2H), 1.55 (d, J = 6.7 Hz, 3H), 1.43 (m, 6H).
##STR00061## 27 1 292 (M + H).sup.+ .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. ppm 10.28 (br s, 1H), 7.36-7.28 (m, 1H), 7.06
(d, J = 7.8 Hz, 1H), 7.02-6.93 (m, 2H), 5.17-5.04 (m, 1H),
4.95-4.82 (m, 1H), 4.75-4.70 (m, 1H), 4.50-4.40 (m, 1H), 1.53 (d, J
= 7.0 Hz, 3H), 1.46-1.37 (m, 6H). ##STR00062## 28 1 308 (M +
H).sup.+ .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 7.39-7.31
(m, 2H), 7.29-7.23 (m, 2H), 5.01 (m, 1H), 4.50 (q, J = 6.7 Hz, 1H),
1.48 (d, J = 7.0 Hz, 3H), 1.37 (d, J = 7.0 Hz, 6H). ##STR00063## 29
1 304 (M + H).sup.+ .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm
7.38-7.26 (m, 5H), 5.04-4.97 (m, 1H), 4.56 (dd, J = 7.4, 3.9 Hz,
1H), 3.67-3.63 (m, 1H), 3.56-3.51 (m, 1H), 3.37 (s, 3H), 1.36 (m,
6H). ##STR00064## 30 1 292 (M + H).sup.+ .sup.1H-NMR (400 MHz,
CD.sub.3OD): .delta. ppm 7.34 (m, 2H), 7.08 (m, 2H), 5.07-4.95 (m,
1H), 4.50 (q, J = 6.8 Hz, 1H), 1.48 (d, J = 6.7 Hz, 3H), 1.37 (m,
6H). ##STR00065## 31 4 & 5 306 (M + H).sup.+ .sup.1H-NMR (400
MHz, CDCl.sub.3): .delta. ppm 9.70 (br s, 1H), 7.39-7.22 (m, 5H),
5.19- 5.07 (m, 1H), 4.85 (br s, 1H), 4.73-4.61 (m, 1H), 1.88 (dq, J
= 14.3, 7.0 Hz, 2H), 1.45 (m, 6H), 0.96 (t, J = 7.4 Hz, 3H).
##STR00066## 32 4 & 5 310 (M + H).sup.+ .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. ppm 9.89 (br s, 1 H), 7.40-7.29 (m, 1 H),
7.13- 6.95 (m, 3 H), 5.12 (m, 1 H), 5.02-4.87 (m, 1 H), 4.82-4.69
(m, 1 H), 1.59 (d, J = 6.7 Hz, 3 H), 1.42 (m, 6H ), ##STR00067## 33
4 & 5 322 (M + H).sup.+ .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. ppm 9.50 (br s, 1H), 7.30 (dd, J = 9.00, 7.83 Hz, 1H),
6.93-6.90 (m, 3H), 5.19-5.04 (m, 1H), 4.88 (m, 1H), 4.75 (m, 1H),
3.79 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H), 1.43 (d, J = 7.0 Hz, 6H).
##STR00068## 34 6 310 (M + H).sup.+ .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. ppm 9.74 (s, 1H), 7.32-7.24 (m, 2H), 7.21-
7.13 (m, 1H), 6.60 (s, 1H), 4.95-4.86 (m, 1H), 4.69-4.62 (m, 1H),
4.32 (s, 1H), 1.49-1.42 (d, J = 6.6 Hz, 3H), 1.28-1.26 (d, J = 6.9
Hz, 6H). ##STR00069## 35 6 352 (M + H).sup.+ .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. ppm 9.85 (s, 1H), 7.59 (s, 1H), 7.48 (m,
1H), 7.38-7.32 (m, 2H), 6.59 (d, J = 5.4 Hz, 1H), 4.95-4.88 (m,
1H), 4.57-4.50 (m, 1H), 4.36 (s, 1H), 1.41 (d, J = 6.6 Hz, 3H),
1.25 (d, J = 6.9 Hz, 6H). ##STR00070## 36 1 & 5 274 (M +
H).sup.+ 1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 9.96 (br s,
1H), 7.39-7.24 (m, 5H), 6.58 (d, J = 6.6 Hz, 1H), 4.38 (s, 1H),
4.28 (q, J = 6.9 Hz, 1H), 3.65 (q, J = 6.6 Hz, 2H), 1.78-1.66 (m,
2H), 0.99 (t, J = 6.9 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H).
##STR00071## 37 1 & 5 272 (M + H).sup.+ .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 9.83 (s, 1H), 7.37 (m, 4H), 7.26 (m,
1H), 6.52 (m, 1H), 4.50 (m, 1H), 4.33 (s, 1H), 2.37 (m, 1H), 1.41
(d, J = 6.8 Hz, 3H), 0.85 (m, 2H), 0.60 (m, 2H). ##STR00072## 38 15
309 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
10.92 (s, 1H), 8.57-8.42 (m, 1H), 7.85 (ddd, J = 7.8, 7.8, 1.7 Hz,
1H), 7.46- 7.31 (m, 5H), 7.32-7.19 (m, 2H), 7.13 (m, 1H), 4.67-4.52
(m, 1H), 4.41 (s, 1H), 1.39 (d, J = 6.8 Hz, 3H). ##STR00073## 39 15
312 (M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
7.65 (d, J = 2.2 Hz, 1H), 7.41-7.35 (m, 5H), 7.32-7.24 (m, 1H),
6.77 (d, J = 5.9 Hz, 1H), 6.04 (d, J = 2.1 Hz, 1H), 4.63- 4.55 (m,
1H), 4.42 (s, 1H), 3.79 (s, 3H), 1.44 (d, J = 6.7 Hz, 3H).
##STR00074## 40 15 299 (M + H).sup.+ .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 11.07 (s, 1H), 8.93 (s, 1H), 7.43-7.31
(m, 4H), 7.31-7.04 (m, 2H), 6.59 (s, 1H), 4.62 (m, 1H), 4.43 (s,
1H), 1.40 (d, J = 6.7 Hz, 3H). ##STR00075## 41 17 341 (M + H).sup.+
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 10.42 (s, 1H), 8.67
(s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 7.61 (m, 1H), 7.51 (m, 1H),
7.37 (m, 1H), 5.41 (m, 1H), 5.13 (m, 1H), 4.68 (m, 1H), 4.55 (m,
1H), 1.59 (d, J = 6.8 Hz, 3H), 1.44 (m, 6H). ##STR00076## 42 17 354
(M + H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.85
(s, 1H), 7.52 (m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 6.94 (m, 1H),
6.60 (m, 1H), 4.90 (m, 1H), 4.62 (m, 1H), 4.38 (s, 1H), 2.26 (s,
3H), 1.44 (d, J = 9.2 Hz, 3H), 1.28 (d, J = 9.2 Hz, 6H).
##STR00077## 43 17 359 (M + H).sup.+ .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 9.84 (s, 1H), 7.62 (s, 1H), 7.42 (m,
2H), 7.12 (d, J = 7.2 Hz, 1H), 6.61 (bs, 1H), 4.91 (m, 1H),
4.69-4.43 (m, 3H), 4.34 (s, 1H), 4.09 (m, 2H), 1.42 (d, J = 6.8 Hz,
3H), 1.28 (m, 6H). ##STR00078## 44 15 314 (M + H).sup.+ .sup.1H-NMR
(400 MHz, CD.sub.3OD): .delta. ppm 7.28-7.13 (m, 5H), 4.52 (m, 1H),
4.39 (m, 2H), 2.22 (m, 2H), 1.69 (m, 2H), 1.54 (m, 1H), 1.44-1.40
(m, 2H), 1.40 (d, J = 6.7 Hz, 3H), 1.30-1.20 (m, 2H), 1.20- 1.08
(m, 1H). ##STR00079## 45 15 308 (M + H).sup.+ .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. ppm 9.84 (s, 1H), 7.43-7.17 (m, 6H), 7.12 (d,
J = 7.3 Hz, 2H), 7.05 (d, J = 6.8 Hz, 2H), 5.55 (br s, 1H), 4.68
(s, 1H), 4.25 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H). ##STR00080## 46 15
260 (M + H).sup.+ .sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. ppm
7.37-7.30 (m, 4H), 7.10-7.06 (m, 1H), 4.55 (s, 1H), 4.51 (q, J =
6.7 Hz, 1H), 3.81 (q, J = 7.0 Hz, 2H), 1.50 (d, J = 7.0 Hz, 3H),
1.11 (t, J = 7.0 Hz, 3H). ##STR00081## 47 15 246 (M + H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.02 (s, 1H),
7.38-7.30 (m, 4H), 7.26- 7.22 (m, 1H), 6.56 (s, 1H), 4.52 (q, J =
6.7 Hz, 1H), 4.39 (s, 1H), 2.97 (s, 3H) 1.40 (d, J = 6.7 Hz,
3H).
Example 48. Preparation of
(S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione
##STR00082##
[0309] Compound 48.1. 1-propylurea
[0310] To a stirred solution of n-propylamine (2.15 g, 36.5 mmol,
1.00 equiv) in CH.sub.2Cl.sub.2 (35 mL) at 0.degree. C. was added
dropwise trimethylsilyl isocyanate (4.94 g (85% purity), 36.5 mmol,
1.00 equiv). The reaction mixture was stirred at room temperature
for 72 h and was then cooled to 0.degree. C. The chilled mixture
was quenched by the dropwise addition of CH.sub.3OH (10 mL) and was
concentrated under reduced pressure. The resulting solid was
suspended in Et.sub.2O (30 mL) and was filtered. The solid was
further washed with Et.sub.2O (30 mL) and dried to afford 2.0 g
(38%) of the title compound as a white solid.
##STR00083##
Compound 48.2. 1-propylpyrimidine-2,4,6(1H,3H,5H)-trione
[0311] To 48.1 (600 mg, 5.88 mmol, 1.00 equiv) in CH.sub.3OH (1 mL)
was added diethyl malonate (960 mg, 6.0 mmol, 1.02 equiv.) and
sodium methoxide (1 mL, 25% NaOCH.sub.3 in CH.sub.3OH by weight).
The reaction mixture was heated in the microwave reactor at
130.degree. C. for 1 h. The mixture was cooled and the mixture was
carefully adjusted to pH=3 with concentrated HCl. The volatiles
were removed and H.sub.2O was added (10 mL). Solid precipitated and
was filtered. It was further washed with additional H.sub.2O (10
mL) and dried to afford 560 mg (56%) of title compound as a white
solid.
##STR00084##
Compound 48.3. 6-chloro-3-propylpyrimidine-2,4(1H,3H)-dione
[0312] Compound 48.2 (560 mg, 3.30 mmol) and POCl.sub.3 (2 mL) were
added to a heavy wall pressure vessel which was subsequently
sealed. The resulting solution was heated to 70.degree. C. and
stirred for 50 minutes behind a blast shield. The reaction mixture
was cooled and concentrated under reduced pressure. To the
resulting residue was added CH.sub.2Cl.sub.2 (30 mL) which was then
removed under reduced pressure. The addition and evaporation of
CH.sub.2Cl.sub.2 (30 mL) was conducted one additional time and then
the resulting residue was diluted with CH.sub.2Cl.sub.2 (50 mL). To
the organic layer was carefully added a saturated aqueous
NaHCO.sub.3 solution (50 mL). The layers were separated and the
organics were further washed with H.sub.2O (30 mL) and brine (30
mL). The organic layer was concentrated and purified by flash
column chromatography (silica gel, utilizing 10% EtOAc in
CH.sub.2Cl.sub.2) to afford 160 mg (26%) of the title compound as a
white solid.
##STR00085##
Compound 48.
(S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione
[0313] To 48.3 (160 mg, 0.85 mmol, 1.0 equiv.) in 1,4-dioxane (1.5
mL) was added Et.sub.3N (200 .mu.L) and
(S)-.alpha.-methylbenzylamine (235 mg, 1.94 mmol, 2.3 equiv.). The
mixture was heated in a microwave reactor at 130.degree. C. for 2
h. The mixture was cooled and concentrated. The resulting residue
was treated with an 8:3 mixture of H.sub.2O:CH.sub.3CN which
resulted in precipitation. The solid was filtered and successively
washed with H.sub.2O (10 mL) and EtOAc (10 mL). The solid was dried
to give 67 mg (29%) of the title compound as a white solid. LC/MS:
m/z (ES+) 274 (M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 9.92 (br s, 1H), 7.36-7.22 (m, 5H), 6.54 (d, J=7.0 Hz,
1H), 4.50 (quin, J=6.7 Hz, 1H), 4.35 (s, 1H), 3.54 (dd, J=8.0, 6.9
Hz, 2H), 1.42-1.36 (m, 5H), 0.76 (t, J=7.6 Hz, 3H).
Example 49. Preparation of
(S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)--
dione
##STR00086##
[0314] Compound 49.1. 1-(3,5-difluorophenyl)urea
[0315] To a stirred solution of 3,5-difluoroaniline (4.0 g, 31
mmol, 1.00 equiv) in CH.sub.2Cl.sub.2 (50 mL) under argon at room
temperature was added dropwise trimethylsilyl isocyanate (3.56 g,
30.90 mmol, 1.00 equiv). The reaction mixture was stirred overnight
and quenched by the dropwise addition of CH.sub.3OH (50 mL). The
reaction mixture was concentrated under reduced pressure and the
resulting residue was purified by flash chromatography (silica gel,
eluting with CHCl.sub.3/CH.sub.3OH (10:1 to 7:1)) to yield 2.0 g
(38%) of the title compound as a white solid. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 8.96 (s, 1H), 7.16-7.10 (m, 2H),
6.72-6.66 (m, 1H), 6.07 (br s, 2H).
##STR00087##
Compound 49.2.
1-(3,5-difluorophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione
[0316] To a stirred solution of 49.1 (1.6 g, 0.0093 mol, 1.1 equiv)
in CH.sub.3OH (20 mL) were added diethyl malonate (1.4 g, 0.0087
mol, 1.0 equiv) and sodium methoxide (1.25 g, 0.0231 mol, 2.7
equiv). The resulting mixture was stirred overnight at 65.degree.
C. After cooling to ambient temperature, the pH was carefully
adjusted to 5 using aqueous 1N HCl. The resulting solution was
extracted with EtOAc (3.times.50 mL). The organic layers were
combined and concentrated under reduced pressure. The residue was
washed with CH.sub.3OH (50 mL) and the resulting solid was isolated
by filtration to give 700 mg (31%) of the title compound as a white
solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 11.66 (s,
1H), 7.43-7.35 (m, 1H), 7.11-7.08 (m, 2H), 3.77 (s, 2H).
##STR00088##
Compound 49.3.
6-chloro-3-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione
[0317] To a 25-mL round-bottom flask under argon containing 49.2
(740 mg, 3.08 mmol, 1.00 equiv) were added triethylbenzylammonium
chloride (840 mg, 1.20 equiv) and POCl.sub.3 (3 mL). The resulting
solution was stirred for 4 h at 50.degree. C. The reaction cooled
and quenched by the careful addition of water/ice (20 mL). The pH
of the solution was adjusted to 5 with 2N sodium hydroxide. The
resulting solution was extracted with EtOAc (2.times.10 mL) and the
organic layers were combined. The organic layer was washed with
brine (10 mL), dried over anhydrous MgSO.sub.4, filtered, and
concentrated under reduced pressure. This resulted in 500 mg
(crude) of the title compound as a white solid. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 12.60 (br, 1H), 7.38-7.32 (m, 1H),
7.21-7.16 (m, 2H), 6.05 (s, 1H).
##STR00089##
Compound 49.
(S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)--
dione
[0318] To 49.3 (200 mg, 0.77 mmol) was added
(S)-.alpha.-methylbenzylamine (1.5 mL). The resulting solution was
stirred for 2 h at 120.degree. C. The reaction mixture was diluted
with DMF (3 mL) and the crude product (100 mg) was purified by
preparative RP-HPLC with the following conditions: XBridge Prep C18
OBD Column, 5 um, 19*150 mm; mobile phase, H.sub.2O with 0.05% TFA
and CH.sub.3CN (40.0% CH.sub.3CN to 90.0% in 10 min). This resulted
in 21.6 mg (8%) of the title compound as a white solid. LC/MS: m/z
(ES+) 344 (M+H).sup.+. .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.
ppm 10.25 (br s, 1H), 7.38-7.35 (m, 4H), 7.28-7.21 (m, 2H),
7.03-6.98 (m, 2H), 6.76 (d, J=6.9 Hz, 1H), 4.59 (quin, J=6.7 Hz,
1H), 4.50 (d, J=2.0 Hz, 1H), 1.42 (d, J=6.7 Hz, 3H).
Example 50. Preparation of
(S)-3-isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione
##STR00090##
[0319] Compound 50.1.
(R,E)-2-methyl-N-(1-(m-tolyl)ethylidene)propane-2-sulfinamide
[0320] To a stirred solution of 1-(3-methylphenyl)ethanone (1.61 g,
12.0 mmol, 1.00 equiv.) and (R)-(+)-2-methyl-2-propanesulfinamide
(1.94 g, 14 mmol, 1.33 equiv.) in THF (50 mL) was added
Ti(OEt).sub.4 (3.19 g, 14 mmol, 1.17 equiv.) dropwise. The reaction
mixture was stirred for 16 h at 60.degree. C., cooled to room
temperature, and quenched with a saturated aqueous NaHCO.sub.3
solution (50 mL). The layers were separated and the aqueous layer
was further extracted with EtOAc (2.times.100 mL). The combined
organics were concentrated and the resulting residue was purified
by flash chromatography (silica gel, eluting with 0-5% CH.sub.3OH
in CH.sub.2Cl.sub.2) to afford 1.51 g (53%) of the title compound
as a white solid. LC/MS: m/z (ES+) 238 (M+H).sup.+.
##STR00091##
Compound 50.2.
(R)-2-methyl-N-((S)-1-(m-tolyl)ethyl)propane-2-sulfinamide
[0321] To a solution of 50.1 (1.51 g, 6.37 mmol) in THF (30 mL) at
-78.degree. C. under an N.sub.2 atmosphere was added L-selectride
(dropwise, 10 mL, 1.0 M in THF, 10 mmol). The reaction mixture was
warmed to 0.degree. C., stirred for 1 h, and carefully quenched
with a saturated aqueous NH.sub.4Cl solution (30 mL). The layers
were separated and the aqueous layer was further extracted with
EtOAc (2.times.50 mL). The combined organics were concentrated and
the resulting residue was purified by flash chromatography (silica
gel, eluted with 0-5% CH.sub.3OH in CH.sub.2Cl.sub.2) to afford
0.85 g (56%) of the title compound. LC/MS: m/z (ES+) 240
(M+H).sup.+.
##STR00092##
Compound 50.3. (S)-1-(m-tolyl)ethan-1-amine hydrochloride
[0322] To absolute EtOH (10 mL) was added AcCl (1.5 mL, dropwise).
The mixture was stirred for 10 minutes and then was added to 50.2
(0.85 g, 3.56 mmol) in EtOH (3 mL). The reaction mixture was
stirred for 2 h at ambient temperature and was concentrated. The
resulting solid was suspended in Et.sub.2O and filtered. The solid
was washed with additional Et.sub.2O and dried to give 402 mg (66%)
of the title compound as white solid. LC/MS: m/z (ES+) 136
(M+H).sup.+.
##STR00093##
Compound 50.4. (S)-1-(m-tolyl)ethan-1-amine
[0323] To a stirred solution of 50.3 (205 mg, 1.20 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was added MP-carbonate (1.0 g, 3.18
mmol/g). The reaction mixture was stirred at room temperature for 1
h and was then filtered. The solid beads were washed with an
additional 10 mL CH.sub.2Cl.sub.2 and the combined filtrates were
concentrated to give the title compound which was pushed forward
without any purification.
##STR00094##
Compound 50.
(S)-3-isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione
[0324] To 50.4 (presumed .about.1.2 mmol from previous reaction,
2.0 equiv.) in a 0.5 to 2.0 mL microwave tube was added compound
1.3 (110 mg, 0.59 mmol, 1.0 equiv.). The microwave tube was sealed
and heated at 120.degree. C. behind a blast shield for 2.5 h. Upon
cooling (to -60.degree. C.), NMP (2.5 mL) was added to the reaction
mixture. The mixture was sonicated and heated (to .about.60.degree.
C.) until the solid completely dissolved. The resulting solution
was cooled to 40.degree. C. and a 3:1 mixture of
H.sub.2O/CH.sub.3CN (5 mL) was added. A solid precipitated and was
collected through filtration. The light beige solid was
subsequently washed with H.sub.2O and dried to give 97 mg (57%) of
the title compound as a white solid. LC/MS: m/z (ES+) 288
(M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.73
(br s, 1H), 7.22 (t, J=8.0 Hz, 1H), 7.12-7.04 (m, 3H), 6.45 (d,
J=8.0 Hz, 1H), 4.90-4.86 (m, 1H), 4.42 (q, J=6.7 Hz, 1H), 4.31 (d,
J=2.4 Hz, 1H), 2.29 (s, 3H), 1.36 (d, J=6.7 Hz, 3H), 1.27-1.23 (m,
6H).
Example 51. Preparation of
(S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-2,4(1H-
,3H)-dione
##STR00095##
[0325] Compound 51.1.
2-(4-fluorophenyl)-N-methoxy-N-methylacetamide
[0326] To a stirred solution of 2-(4-fluorophenyl)acetic acid (15
g, 97.32 mmol, 1.00 equiv) in CH.sub.2Cl.sub.2 (300 mL) was added
methoxy(methyl)amine hydrochloride (11.1 g, 113.79 mmol, 1.20
equiv), 4-dimethylaminopyridine (12 g, 98.22 mmol, 1.00 equiv),
1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (28.2
g, 147.10 mmol, 1.50 equiv), and DIEA (37.5 g, 290.14 mmol, 3.00
equiv). The resulting solution was stirred at room temperature for
16 h and then diluted with EtOAc (150 mL). The organics were washed
with aqueous 1N HCl (2.times.150 mL) and brine (2.times.150 mL). It
was then dried over anhydrous Na.sub.2SO.sub.4 and concentrated
under reduced pressure. The crude residue was purified by flash
chromatography (silica gel, eluting with EtOAc/petroleum ether
(1:3)). This resulted in 18 g (88%) of the title compound as yellow
oil. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 7.29-7.25 (m,
2H), 7.03-6.99 (m, 2H), 3.75 (s, 2H), 3.65 (s, 3H), 3.21 (s,
3H).
##STR00096##
Compound 51.2. 2-(4-fluorophenyl)acetaldehyde
[0327] To a stirred solution of 51.1 (3 g, 15.21 mmol, 1.00 equiv)
in THF (60 mL) under argon at -10.degree. C. was added LiAlH.sub.4
(1.15 g, 30.30 mmol, 2.00 equiv) in several batches (CAREFUL . . .
EXOTHERMIC REACTION). The resulting solution was stirred for 1 h at
room temperature before being cooled to -10.degree. C. The reaction
was then quenched by the careful addition of a saturated aqueous
NH.sub.4Cl solution (50 mL). The resulting solid was filtered and
the filtrate was extracted with EtOAc (3.times.50 mL). The organic
layers were combined, washed with brine (50 mL), dried with
anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure
to give 2.5 g (crude) of the title compound as a yellow oil.
##STR00097##
Compound 51.3. (S)-1-(4-fluorophenyl)propan-2-amine
hydrochloride
[0328] The title compound was synthesized according to methods
described for the preparation of 5.3, utilizing 51.2 in place of
3,5-difluorobenzaldehyde. LC/MS: m/z (ES+) 154 (M+H).sup.+.
##STR00098##
Compound 51.4. (S)-1-(4-fluorophenyl)propan-2-amine
[0329] To an aqueous solution of 1N NaOH (5 mL) was added 51.3 (300
mg, 1.59 mmol). The resulting mixture was stirred for one hour at
25.degree. C. The resulting solution was extracted with EtOAc
(2.times.10 mL). The organic layer was dried over anhydrous sodium
sulfate and concentrated under reduced pressure to yield 160 mg
(65%) of the title compound. LC/MS: m/z (ES+) 154 (M+H).sup.+.
##STR00099##
Compound 51.
(S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-2,4(1H-
,3H)-dione
[0330] To a stirred solution of 51.4 (160 mg, 1.04 mmol, 2.00
equiv) in NMP (0.5 mL) was added 1.3 (99 mg, 0.52 mmol, 1.00 equiv)
and proton sponge (168 mg, 0.78 mmol, 1.50 equiv). The resulting
solution was stirred for 5 h at 100.degree. C. in an oil bath. The
reaction mixture was concentrated under reduced pressure. The
residue (100 mg) was purified by preparative RP-HPLC to afford 30
mg (19%) of the title compound as gray solid. LC/MS: m/z (ES+) 306
(M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.81
(br s, 1H), 7.27 (dd, J=8.8, 5.6 Hz, 2H), 7.17-7.12 (m, 2H), 5.89
(d, J=7.6 Hz, 1H), 5.00-4.92 (m, 1H), 4.58 (s, 1H), 3.69-3.65 (m,
1H), 2.74 (d, J=6.4 Hz, 2H), 1.31 (d, J=6.8 Hz, 6H), 1.08 (d, J=6.4
Hz, 3H).
Example 52. Preparation of
(R)-3-isopropyl-6-((2,2,2-trifluoro-1-phenylethyl)amino)pyrimidine-2,4(1H-
,3H)-dione (52)
##STR00100##
[0332] To a 0.2-0.5 mL microwave vial was added 1.3 (85 mg, 0.45
mmol) and (R)-2,2,2-trifluoro-1-phenylethan-1-amine (200 uL,
excess). The reaction mixture sealed and heated at 180.degree. C.
in a microwave reactor for 40 minutes. The reaction mixture was
cooled to ambient temperature and then NMP (1 mL) was added to
completely dissolve the solid. Next, a 2:1 H.sub.2O/CH.sub.3CN
mixture (6 mL) was added which resulted in precipitation. The solid
was isolated by filtration, washed with H.sub.2O and dried to give
50 mg (34%) of the title compound as a white solid. LC/MS: m/z
(ES+) 328 (M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
ppm 9.79 (br s, 1H), 7.50-7.40 (m, 5H), 5.66-5.56 (m, 2H),
4.92-4.87 (m, 2H), 1.28-1.25 (m, 6H).
Example 53. Preparation of
3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2-
,4(1H,3H)-dione
##STR00101##
[0333] Compound 53.1. (R)-1-(1-hydroxypropan-2-yl)urea
[0334] To a stirred solution of (R)-(-)-2-amino-1-propanol (0.65 g,
8.68 mmol, 1 equiv.) in CH.sub.2Cl.sub.2 (10 mL) under N.sub.2 at
0.degree. C. was added dropwise trimethylsilyl isocyanate (1.00 g,
8.68 mmol, 1.0 equiv.). The reaction mixture was stirred overnight
while slowly warming to room temperature. After cooling to
0.degree. C., CH.sub.3OH (10 mL) was added dropwise. The resulting
solution was stirred for 2 h at room temperature and was then
concentrated under reduced pressure to provide the title compound
(1.02 g, 99%) as a white solid.
##STR00102##
Compound 53.2. (R)-1-(1-(benzyloxy)propan-2-yl)urea
[0335] To a suspension of sodium hydride (0.52 g, 13.2 mmol, 1.5
equiv.) in THF (10 mL) at 0.degree. C. was added 53.1 (1.02 g, 8.67
mmol, 1 equiv.). The reaction mixture was stirred for 20 minutes at
0.degree. C. under N.sub.2 before benzyl bromide (1.03 mL, 8.67
mmol, 1 equiv.) was added. The reaction mixture was stirred
overnight while slowly warming to room temperature. The reaction
mixture was quenched with H.sub.2O (3 mL) and was extracted into
EtOAc (15 mL), dried with anhydrous Na.sub.2SO.sub.4, filtered, and
concentrated. The resulting residue was purified by flash
chromatography (10% CH.sub.3OH in CH.sub.2Cl.sub.2) to provide 510
mg (28%) of the title compound. LC/MS: m/z (ES+) 209 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 7.42-7.27 (m, 5H),
4.79 (d, J=6.7 Hz, 1H), 4.52 (d, J=2.7 Hz, 2H), 3.91 (s, 1H), 3.51
(dd, J=9.4, 3.9 Hz, 1H), 3.40 (dd, J=9.2, 5.3 Hz, 1H), 1.19 (d,
J=7.0 Hz, 3H).
##STR00103##
Compound 53.3.
(R)-1-(1-(benzyloxy)propan-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione
[0336] To a microwave vial containing 53.2 (0.51 g, 2.42 mmol, 1
equiv.) in CH.sub.3OH (10 mL) was added diethyl malonate (2.55 g,
2.55 mmol, 1.05 equiv.) followed by sodium methoxide (25% wt. soln.
in CH.sub.3OH, 1.31 g, 6.06 mmol, 2.5 equiv.). The vial was capped
and the reaction mixture was heated in a microwave reactor for 15
minutes at 150.degree. C. After cooling to room temperature, the
reaction mixture was quenched with H.sub.2O (2 mL) and the pH was
adjusted to 3 with concentrated HCl. The reaction mixture was
transferred to a round bottom flask and was concentrated under
reduced pressure. The resulting residue was purified by flash
chromatography (5% CH.sub.3OH in CH.sub.2Cl.sub.2) to provide 0.62
g (92%) of the title compound as a white solid. LC/MS: m/z (ES+)
277 (M+H).sup.+. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm
7.99 (s, 1H), 7.38-7.22 (m, 5H), 5.16-5.11 (m, 1H), 4.52 (d, J=12.0
Hz, 1H), 4.45 (d, J=12.0 Hz, 1H), 4.02 (t, J=9.8 Hz, 1H), 3.56 (q,
J=1.57 Hz, 2H), 1.37 (d, J=7.00 Hz, 3H).
##STR00104##
Compound 53.4.
(R)-3-(1-(benzyloxy)propan-2-yl)-6-chloropyrimidine-2,4(1H,3H)-dione
[0337] To a microwave vial containing 53.3 (0.25 g, 0.91 mmol, 1
equiv.) was added triethylbenzylammonium chloride (0.28 g, 1.26
mmol, 1.4 equiv.) and POCl.sub.3 (1 mL). The vial was capped and
the reaction mixture was heated in a microwave reactor for 1 minute
at 130.degree. C. The reaction mixture was transferred to a round
bottom flask and was concentrated under reduced pressure. The
resulting residue was dissolved in CH.sub.2Cl.sub.2 (5 mL) and
water (2 mL) was carefully added. The mixture was stirred for 10
minutes. The layers were separated and the organic layer was dried
with Na.sub.2SO.sub.4, filtered and concentrated under reduced
pressure. The resulting residue was purified by flash
chromatography (silica gel, 5% CH.sub.3OH in CH.sub.2Cl.sub.2) to
provide 150 mg (55%) of the title compound. LC/MS: m/z (ES+) 295
(M+H).sup.+. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 10.27
(s, 1H), 7.36-7.20 (m, 5H), 5.32-5.21 (m, 2H), 4.57 (d, J=12.0 Hz,
1H), 4.48 (d, J=12.0 Hz, 1H), 4.10 (dd, J=10.0, 9.2 Hz, 1H), 1.40
(d, J=7.0 Hz, 3H).
##STR00105##
Compound 53.
3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2-
,4(1H,3H)-dione
[0338] To a microwave vial containing (S)-.alpha.-methylbenzylamine
(1.5 mL) was added 53.4 (0.12 g, 0.42 mmol). The vial was capped
and the reaction mixture was heated in a microwave reactor for 10
minutes at 150.degree. C. After cooling, the reaction mixture was
filtered through a plug of silica gel (10% CH.sub.3OH in
CH.sub.2Cl) and the filtrate was concentrated under reduced
pressure. The resulting residue was dissolved in CH.sub.2Cl.sub.2
(10 mL) and was washed with 100% HCl (5 mL). The organic layer was
dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated to
provide 150 mg (94%) of the title compound. LC/MS: m/z (ES+) 380
(M+H).sup.+. .sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 9.96
(br s 1H), 7.35-7.24 (m, 10H), 4.70 (br s, 1H), 4.53-4.41 (m, 4H),
4.03-3.99 (m, 1H), 3.65-3.61 (m, 1H), 1.49 (d, J=6.7 Hz, 3H), 1.37
(d, J=7.0 Hz, 3H).
Example 54. Preparation of
3-((R)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1-
H,3H)-dione (54)
##STR00106##
[0340] To a solution of 53 (0.10 g, 0.26 mmol, 1 equiv.) in EtOH (2
mL) was added palladium on carbon (10 wt. % loading (dry basis),
matrix activated carbon, wet support, Degussa type, 0.025 g). The
reaction flask was purged with nitrogen and was then fitted with a
H.sub.2(g) balloon. The reaction mixture was evacuated and then
filled with H.sub.2(g). This pump/purge process was repeated three
times and the reaction mixture was stirred for 4 h at room
temperature. After purging with nitrogen, the reaction mixture was
filtered and the filtrate was concentrated under reduced pressure.
The resulting residue was suspended in CH.sub.3CN (2 mL) and the
precipitate was isolated by filtration. The precipitate was
dissolved in CH.sub.2Cl.sub.2: CH.sub.3OH (1:1, 2 mL) and was
filtered through a 0.2 .mu.M PTFE 25 mm filter and was concentrated
under reduced pressure to provide 27 mg (35%) of the title
compound. LC/MS: m/z (ES+) 290 (M+H).sup.+. .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. ppm 9.67 (s, 1H), 7.35-7.24 (m, 5H), 5.64 (d,
J=5.5 Hz, 1H), 5.08-5.04 (m, 1H), 4.66 (s, 1H), 4.42-4.35 (m, 1H),
4.24 (s, 1H), 4.04-3.91 (m, 1H), 3.78-3.68 (m, 1H), 1.50 (d, J=6.70
Hz, 3H), 1.35 (d, J=7.00 Hz, 3H).
Example 55. Preparation of
(S)-3-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2-
,4(1H,3H)-dione
##STR00107##
[0341] Compound 55.1.
(S)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride
[0342] The title compound was synthesized according to methods
described for the preparation of 5.3, utilizing
3-(trifluoromethyl)benzaldehyde in place of
3,5-difluorobenzaldehyde.
##STR00108##
Compound 55.
(S)-3-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2-
,4(1H,3H)-dione
[0343] To a stirred solution of 55.1 (59.8 mg, 0.27 mmol, 1.00
equiv) in DMSO (1.5 mL) under an inert argon atmosphere was added
Et.sub.3N (0.2 mL) and 1.3 (50 mg, 0.27 mmol, 1.00 equiv). The
resulting solution was stirred for 6 h at 120.degree. C. in an oil
bath. After cooling, the mixture was concentrated under reduced
pressure and the resulting residue (75 mg) was purified by
preparative RP-HPLC to give 6.5 mg (7%) of the title compound as a
white solid. LC/MS: m/z (ES+) 342 (M+H).sup.+. .sup.1H-NMR (300
MHz, DMSO-d.sub.6): .delta. ppm 7.78 (s, 1H), 7.74-7.60 (m, 3H),
7.20 (br, 1H), 6.02 (br, 1H), 4.96 (dt, J=10.1, 5.1 Hz, 1H),
4.67-4.64 (m, 1H), 4.36 (s, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.31-1.28
(m, 6H).
Example 56. Preparation of
(S)-3-isopropyl-6-((1-(2-cyanophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-di-
one (56)
##STR00109##
[0345] Intermediate 56.1 was prepared using procedures similar to
those for the preparation of compound 35, utilizing 1.3 and
(S)-1-(2-bromophenyl)ethan-1-amine hydrochloride (synthesized from
the corresponding 2-bromobenzaldehyde using methods described for
example 6.3). To a stirred solution of 56.1 (40 mg, 0.11 mmol, 1.00
equiv,) in DMF (2 mL) was added Zn(CN).sub.2 (20 mg, 0.17 mmol,
1.50 equiv) and tetrakis(triphenylphosphine) palladium (131 mg,
0.11 mmol, 0.20 equiv). CAUTION: CYANIDE CONTAINING REACTION. The
resulting solution was stirred under an argon atmosphere at
100.degree. C. in an oil bath for 2 h. Upon cooling, the reaction
was quenched with a saturated aqueous FeSO.sub.4 solution (5 mL).
The resulting mixture was diluted with EtOAc (20 mL) and washed
with a saturated aqueous FeSO.sub.4 solution (2.times.20 mL). The
organic layer was dried with anhydrous Na.sub.2SO.sub.4, filtered,
and concentrated under reduced pressure. The crude product (5 mg)
was purified by chiral preparative HPLC with the following
conditions: Column, Phenomenex Lux-2 5u Cellulose-2, 30*150 mm
mobile phase, Hexanes and EtOH (hold 50.0% EtOH in 35 min);
resulting in 2.1 mg (6%) of the title compound. LC/MS: m/z (ES+)
299 (M+H).sup.+. .sup.1H-NMR (300 MHz, CD.sub.3CN): .delta. ppm
8.59 (br s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.61-7.56 (m, 1H),
7.48-7.45 (m, 2H), 5.09-4.94 (m, 3H), 1.46 (d, J=6.6 Hz, 3H),
1.34-1.26 (m, 6H).
Example 57. Preparation of
(S)-3-benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione
##STR00110##
[0346] Compound 57.1. 3-ethoxy-3-oxo-1-(1-ethoxy)propan-1-iminium
chloride
[0347] To a stirred solution of ethyl cyanoacetate (5.0 g, 44 mmol)
in anhydrous Et.sub.2O (5 mL) was added absolute EtOH (3 mL). The
reaction mixture was cooled to 0.degree. C. and HCl gas was bubbled
in for 10 minutes. The reaction mixture was warmed to room
temperature and was stirred for 16 h. The white precipitate that
formed was filtered and washed with Et.sub.2O (40 mL) and dried to
give (6.99 g) the title compound as a white solid. LC/MS: m/z (ES+)
160 (M+H).sup.+.
##STR00111##
Compound 57.2. Ethyl
(S,E/Z)-3-amino-3-((1-phenylethyl)amino)acrylate
[0348] To a stirred solution of 57.1 (585 mg, 3.0 mmol) in EtOH (15
mL) was added DIEA (0.8 mL), and (S)-.alpha.-methylbenzylamine (290
mg, 2.4 mmol). The reaction was stirred for 16 h and was
concentrated. The crude was purified by flash column chromatography
(silica gel, eluting with CH.sub.3OH in CH.sub.2Cl.sub.2 (0 to
10%)) to yield 0.57 g (98%) of the title compound as a clear oil.
NMR analysis revealed that the product was a mixture of E/Z
isomers. LC/MS: m/z (ES+) 235 (M+H).sup.+.
##STR00112##
Compound 57.3. Ethyl
(S,Z)-3-(3-benzylureido)-3-((1-phenylethyl)amino)acrylate
[0349] Two reactions were set up in parallel and later combined
since both resulted in formation of product (by HPLC). In the first
reaction, benzyl isocyanate (150 uL, 1.2 mmol) was added to a
stirred solution of 57.2 (143 mg, 0.61 mmol) in CH.sub.3CN (1 mL).
After 10 min., DIEA (300 uL) was added. The reaction was stirred
for an additional 10 min and was quenched with H.sub.2O (12 mL).
Solid precipitated and was removed by filtration. In the second
reaction, benzyl isocyanate (150 uL, 1.2 mmol) was added to a
stirred solution of 57.2 (143 mg, 0.61 mmol) and DIEA (300 uL) in
CH.sub.3CN (1 mL). After 10 min, the reaction mixture was quenched
with H.sub.2O (10 mL). The resulting mixture was diluted with EtOAc
(40 mL) and the layers were separated. To the organic layer was
added the filtrate from first reaction. The layers were separated
and the organics were concentrated to give the title compound which
was utilized without further purification.
##STR00113##
Compound 57.
(S)-3-benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione
[0350] Two reactions were conducted and later combined since both
resulted in formation of product (by HPLC). The first reaction
utilized 1/3 of crude 57.3 in CH.sub.3OH (1 mL). It was heated in a
microwave reactor at 120.degree. C. for 10 min. The remaining 2/3
of crude 57.3 in CH.sub.3OH (2 mL) was heated in a microwave
reactor at 120.degree. C. for 20 min. After cooling to ambient
temperature, the reactions were combined and the CH.sub.3OH was
removed under reduced pressure. A 50/50 mixture of
CH.sub.3CN/H.sub.2O with 0.1% TFA (5 mL) was added to the resulting
residue. Solid precipitated and was filtered. The resulting brown
solid was washed with EtOAc to give 7 mg of the title compound as a
white solid. LC/MS: m/z (ES+) 322 (M+H).sup.+. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 10.05 (br s, 1H), 7.35-7.31 (m,
4H), 7.26-7.16 (m, 6H), 6.61 (d, J=7.0 Hz, 1H), 4.79 (s, 2H), 4.52
(quin, J=6.8 Hz, 1H), 4.42 (d, J=2.3 Hz, 1H), 1.39 (d, J=6.7 Hz,
3H).
Example 58. Preparation of
(S)-3-(2,6-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)--
dione (58)
##STR00114##
[0352] The title compound was synthesized according to a slightly
modified procedure as described in Example 50. Here, 1,4-dioxane
was utilized as a solvent and the reaction was heated at
110.degree. C. for 16 h. The resulting mixture was cooled and
concentrated under reduced pressure. The crude was purified by
preparative RP-HPLC to give 19 mg of the title compound as a white
solid. LC/MS: m/z (ES+) 344 (M+H).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 10.44 (br s, 1H), 7.52-7.42 (m, 2H),
7.39-7.36 (m, 3H), 7.34-7.16 (m, 3H), 6.91 (br s, 1H), 4.65-4.56
(m, 1H), 4.52 (s, 1H), 1.43 (d, J=6.7 Hz, 3H).
Example 59. Preparation of
(S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione
##STR00115##
[0353] Compound 59.1. 2,6-difluorobenzaldehyde
[0354] The title compound was synthesized according to methods
described for the preparation of 51.2. Here, commercially available
2,6-difluorobenzoic acid was utilized instead of
2-(4-fluorophenyl)acetic acid.
##STR00116##
Compound 59.2. (S)-1-(2,6-difluorophenyl)ethan-1-amine
hydrochloride
[0355] The title compound was synthesized according to methods
described for the preparation of 5.3. Here, 59.1 was utilized
instead of 3,5-difluorobenzaldehyde.
##STR00117##
Compound 59.
(S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione
[0356] Reaction of 59.1 with 1.3 was conducted in a similar manner
as the procedure described in Example 51. Here though, the reaction
mixture was heated at 130.degree. C. for 5 h. Analysis of the
reaction mixture via chiral HPLC revealed non-trivial amounts of
the enantiomer. Separation of the enantiomers was performed
utilizing preparative chiral HPLC with an isocratic mixture of
EtOH: Hexane (1:4) as eluent from a Phenomenex Lux-2 5.mu.
Cellulose-2, 30*150 mm column (40 min run). LC/MS: m/z (ES+) 310
(M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.80
(br s, 1H), 7.45-7.41 (m, 1H), 7.18-7.14 (m, 2H), 6.52 (d, J=8.0
Hz, 1H), 4.94-4.88 (m, 1H), 4.79 (quint, J=7.6 Hz, 1H), 4.41 (s,
1H), 1.56 (d, J=6.8 Hz, 3H), 1.30-1.26 (m, 6H).
Example 60. Preparation of
(R)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione (60R)
##STR00118##
[0358] The title compound was generated as a by-product of the
chemistry conducted in Example 59. It was isolated via preparative
chiral HPLC with an isocratic mixture of EtOH:Hexane (1:4) as
eluent from a Phenomenex Lux-2 5.mu. Cellulose-2, 30*150 mm column
(40 min run). LC/MS: m/z (ES+) 310 (M+H).sup.+. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 9.98-9.61 (br, 1H), 7.45-7.41 (m,
1H), 7.18-7.14 (m, 2H), 6.52 (d, J=8.0 Hz, 1H), 4.94-4.88 (m, 1H),
4.79 (quint, J=7.6 Hz, 1H), 4.41 (s, 1H), 1.56 (d, J=6.8 Hz, 3H),
1.30-1.26 (m, 6H).
Example 61. Preparation of
(S)-3-isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3-
H)-dione
##STR00119##
[0359] Compound 61.1.
N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide
[0360] The title compound was synthesized according to methods
described for the preparation of 51.1. Here, commercially available
4-pyridineacetic acid was utilized instead of
2-(4-fluorophenyl)acetic acid.
##STR00120##
Compound 61.2. 1-(pyridin-4-yl)propan-2-one
[0361] To a 250-mL 3-necked round-bottom flask purged and
maintained with an inert atmosphere of argon, was added THF (70 mL)
and N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (7.0 g, 0.039 mol,
1.0 equiv). The mixture was cooled to 0.degree. C. and CH.sub.3MgBr
(3M in THF, 65 mL, 5.0 equiv) was added dropwise. The resulting
solution was warmed to ambient temperature and stirred for 16 h.
The reaction mixture was cooled to 0.degree. C. and quenched by the
addition of saturated NH.sub.4Cl (aq, 100 mL). The resulting
solution was extracted with EtOAc (3.times.200 mL). The organic
layers were combined, dried over anhydrous Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The crude was purified by
flash chromatography (silica gel, CH.sub.2Cl.sub.2/CH.sub.3OH
(20:1)) to yield 2.7 g (51%) of the title compound as yellow oil.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 8.58 (m, 2H), 7.17
(d, J=0.4 Hz, 2H), 3.75 (s, 2H), 2.24 (s, 3H).
##STR00121##
Compound 61.3.
(R)-2-methyl-N-((S)-1-(pyridin-4-yl)propan-2-yl)propane-2-sulfinamide
[0362] The title compound was prepared according to procedures
described in Example 50 utilizing 61.2 in place of
1-(3-methylphenyl)ethanone. Here, the reduction utilizing
L-selectride resulted in isolation of the title compound (61.3)
(20% enantiomeric excess).
##STR00122##
Compound 61.4. (S)-1-(pyridin-4-yl)propan-2-amine
[0363] The title compound was prepared utilizing a two-step
procedure as described in Example 5. First, sulfonamide 61.3 was
converted to the hydrochloride salt by treatment with HCl in
1,4-dioxane (see protocol for Compound 5.3). Subsequent free-basing
of the hydrochloride salt (see protocol for Compound 5) resulted in
the title compound (.about.20% ee).
##STR00123##
Compound 61.
(S)-3-isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3-
H)-dione
[0364] The title compound was prepared according to the protocol
described for 51. Here, the reaction mixture was stirred for at
100.degree. C. for 1 h. The reaction mixture was concentrated under
reduced pressure and the residue (100 mg) was purified by Prep-HPLC
to give 13.1 mg of the title compound as a mixture of enantiomers.
The enantiomers were (13.1 mg) separated by chiral preparative HPLC
with a Chiralpak IC, 2*25 cm, 5 um column, utilizing a isocratic
mixture of EtOH:Hexane (1:3) as eluent (20 min run). This resulted
in 8.2 mg (8%) of the title compound as a light yellow solid.
LC/MS: m/z (ES+) 289 (M+H).sup.+. .sup.1H-NMR (300 MHz,
CD.sub.3OD): .delta. ppm 8.41 (d, J=5.7 Hz, 2H), 7.29 (d, J=6.0 Hz,
2H), 5.06-4.96 (m, 1H), 4.68 (s, 1H), 3.82-3.75 (m, 1H), 2.87-2.83
(m, 2H), 1.36 (d, J=7.2 Hz, 6H), 1.12 (d, J=7.2 Hz, 3H).
Example 62. Preparation of
(S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,-
3H)-dione
##STR00124##
[0365] Compound 62.1.
(S)-2-(1-(4-(methoxy)phenyl)ethyl)isoindoline-1,3-dione
[0366] To phthalimide (1.3 g, 0.0088 mol) in a 2-5 mL microwave
vial was added (S)-1-(4-methoxyphenyl)ethan-1-amine (2.20 mL, 0.015
mol) and K.sub.2CO.sub.3 (1.2 g, 0.0087 mol). The reaction mixture
capped and heated at 160.degree. C. for 2 minutes. The resulting
crude solid was suspended in n-BuOH and was filtered. The filtrate
was put aside. The solid was washed with H.sub.2O and the filtrate
was discarded. The solid was washed with CH.sub.2Cl.sub.2 and the
resulting filtrate was partitioned with H.sub.2O. The organics
(n-BuOH and CH.sub.2Cl.sub.2 layer) were combined and concentrated.
The crude residue was purified by silica gel column chromatography
using CH.sub.2Cl.sub.2 as eluent to yield 1.6 g (64%) of the title
compound. LC/MS: m/z (ES+) 282 (M+H).sup.+.
##STR00125##
Compound 62.2.
(S)-2-(1-(4-hydroxyphenyl)ethyl)isoindoline-1,3-dione
[0367] To a stirred solution of 62.1 (640 mg, 2.28 mmol) in
CH.sub.2Cl.sub.2 (8 mL) at 0.degree. C. was added BBr.sub.3 (1.0 M
in CH.sub.2Cl.sub.2, 3 mL, dropwise). The reaction was allowed to
warm to room temperature over 30 minutes. Significant starting
material remained so the reaction was chilled back to 0.degree. C.
Additional BBr.sub.3 (2 mL, 1.0 M in CH.sub.2Cl.sub.2) was added
and the reaction was allowed to warm to room temperature over 30
minutes. The reaction mixture was poured over 5% NaHCO.sub.3 (aq)
in ice. The layers were separated and the aqueous layer was further
extracted with CH.sub.2Cl.sub.2. The combined organics were washed
with brine, dried with anhydrous Na.sub.2SO.sub.4 and concentrated
to give 500 mg (82%) of the title compound as a white solid. LC/MS:
m/z (ES+) 268 (M+H).sup.+.
##STR00126##
Compound 62.3.
(S)-2-(1-(4-(benzyloxy)phenyl)ethyl)isoindoline-1,3-dione
[0368] To a stirred solution of 62.2 (500 mg, 1.87 mmol) in DMF (10
mL) was added K.sub.2CO.sub.3 (560 mg, 4.05 mmol, 2.17 equiv.) and
benzyl bromide (0.30 mL, 420 mg, 2.45 mmol, 1.3 equiv.). The
reaction was stirred at 120.degree. C. for 5 h. The reaction was
cooled and filtered. Water was added (20 mL) and EtOAc (60 mL) was
utilized to extract product. The organic layer was washed
successively with H.sub.2O, 10% Na.sub.2CO.sub.3 (aq), H.sub.2O,
and brine (2.times.). The organics were dried over anhydrous
MgSO.sub.4 and concentrated. The crude residue was purified by
flash chromatography (silica gel, eluting with CH.sub.2Cl.sub.2) to
yield 480 mg (72%) of the title compound. LC/MS: m/z (ES+) 358
(M+H).sup.+.
##STR00127##
Compound 62.4. (S)-1-(4-(benzyloxy)phenyl)ethan-1-amine
[0369] To a stirred solution of 62.3 (480 mg, 1.34 mmol) in a 70/30
EtOH/H.sub.2O mixture (20 mL) was added N.sub.2H.sub.4H.sub.2O (1.5
mL). The reaction was stirred for 16 h and concentrated. The
resulting material was partitioned between EtOAc and 5%
Na.sub.2CO.sub.3 (aq). The layers were separated and the EtOAc
layer was washed with brine and concentrated to give 280 mg (92%)
of the title compound which was used without further purification.
LC/MS: m/z (ES+) 228 (M+H).sup.+.
##STR00128##
Compound 62.
(S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,-
3H)-dione
[0370] To a 0.5-2.0 mL microwave vial was added 1,4-dioxane (1 mL),
62.4 (280 mg, 1.23 mmol), 1.3 (250 mg, 1.33 mmol) and DIEA (400
uL). The reaction mixture was capped, heated at 135.degree. C. in a
microwave reactor for 1.5 h, allowed to cool, and then
concentrated. The crude reaction mixture was treated with 50/50
CH.sub.3CN/H.sub.2O (0.1% TFA) which led to precipitation. The
solid was isolated by filtration and dried to give 45 mg (10%) of a
white solid. LC/MS: m/z (ES+) 380 (M+H).sup.+. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 9.73 (br, 1H), 7.43-7.29 (m, 5H),
7.23 (d, J=14.5 Hz, 2H), 6.97 (d, J=14.5 Hz, 2H), 6.42 (d, J=7.0
Hz, 1H), 5.06 (s, 2H), 4.93-4.85 (m, 1H), 4.42 (quin, J=6.8 Hz,
1H), 4.32 (d, J=1.6 Hz, 1H), 1.35 (d, J=6.7 Hz, 3H), (m, 1H)
1.27-1.23 (m, 6H).
Example 63. Preparation of
(S)-6-((1-(4-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)--
dione (63)
##STR00129##
[0372] To a stirred solution of 62 (43 mg, 0.11 mmol) in CH.sub.3OH
(20 mL) was added palladium on carbon (50 mg, 10 wt. % loading (dry
basis), matrix activated carbon, wet support, Degussa type). The
vessel was purged with nitrogen followed by hydrogen. The reaction
mixture was stirred under a H.sub.2 atmosphere for 2 h. After
purging the system with nitrogen, the mixture was filtered through
celite and concentrated. The resulting solid was dissolved in 8 mL
CH.sub.3CN and then 20 mL H.sub.2O (0.1% TFA) was added. The
solution was frozen and lyophilized to give 29 mg (90%) of the
title compound as a white solid. LC/MS: m/z (ES+) 290 (M+H).sup.+.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.70 (br, 1H),
9.32 (s, 1H), 7.10 (d, J=8.6 Hz, 2H), 6.71 (d, J=8.6 Hz, 2H), 6.36
(d, J=7.0 Hz, 1H), 4.92-4.85 (m, 1H), 4.37-4.33 (m, 2H), 1.33 (d,
J=6.7 Hz, 3H), 1.27-1.23 (m, 6H).
Example 64. Preparation of
(R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione
##STR00130##
[0373] Compound 64.1.
(R)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione
[0374] To a 2.0-5.0 mL microwave vial was added
(R)-2-amino-2-phenylethan-1-ol (1.53 g, 0.0112 mol) and phthalic
anhydride (1.65 g, 0.0112 mol). The reaction mixture was capped and
heated to 150.degree. C. for 2 minutes in a microwave reactor. The
mixture was cooled and diluted with CH.sub.3CN (2 mL), recapped and
heated in the microwave reactor a second time at 140.degree. C. for
20 minutes. The volatiles were removed under reduced pressure and
the resulting solid was suspended in EtOAc (50 mL). The organic
layer was washed with 5% NaHCO.sub.3 (aq), H.sub.2O, and brine,
dried with anhydrous MgSO.sub.4 and concentrated. The crude residue
was purified by flash chromatography (silica gel, eluting with
CH.sub.3OH in CH.sub.2Cl.sub.2 (0 to 5%) to yield 2.81 g (94%) of
the title compound. LC/MS: m/z (ES+) 268 (M+H).sup.+.
##STR00131##
Compound 64.2.
(R)-2-(2-(benzyloxy)-1-phenylethyl)isoindoline-1,3-dione
[0375] The title compound was made in a similar manner as the
procedure described for 62.3. However, in this case NaH (600/%
dispersion in mineral oil, 1.2 equiv.) was used in place of
K.sub.2CO.sub.3. Specifically, NaH was added at 0.degree. C. and
stirred at room temperature for 45 minutes. The reaction was cooled
back to 0.degree. C. and then benzyl bromide (1.2 equiv.) was
added. A work-up procedure as described for 62.3 followed by flash
chromatography (silica gel, eluting with CH.sub.2Cl.sub.2) yielded
the title compound in 59% yield. LC/MS: m/z (ES+) 358 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 7.84-7.79 (m, 2H),
7.72-7.67 (m, 2H), 7.52-7.48 (m, 2H), 7.37-7.20 (m, 8H), 5.62 (dd,
J=10.2, 5.9 Hz, 1H), 4.63 (t, J=10.2 Hz, 1H), 4.58 (s, 2H),
4.06-4.01 (m, 1H).
##STR00132##
Compound 64.3. (R)-2-(benzyloxy)-1-phenylethan-1-amine
[0376] The title compound was prepared in a similar manner as the
procedure described for 62.4. LC/MS: m/z (ES+) 228 (M+H).sup.+.
.sup.1H-NMR (400 MHz, CDCl.sub.3): .delta. ppm 7.40-7.24 (m, 10H),
4.56 (d, J=2.0 Hz, 2H), 4.25 (dd, J=8.8, 3.7 Hz, 1H), 3.65-3.60 (m,
1H), 3.49-3.44 (m, 1H).
##STR00133##
Compound 64.
(R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3-
H)-dione
[0377] The title compound was prepared in a similar manner as the
procedure described for 62. Here though, the reaction was heated at
140.degree. C. for 1 h. After cooling, the crude reaction mixture
was treated with 50/50 CH.sub.3CN/H.sub.2O (0.1% TFA) which led to
precipitation. LC/MS: m/z (ES+) 380 (M+H).sup.+. .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 10.01 (br, 1H), 7.36-7.26 (m, 10H),
6.62 (d, J=6.7 Hz, 1H), 4.93-4.83 (m, 1H), 4.67-4.62 (m, 1H), 4.50
(dd, J=12.0, 2.0 Hz, 2H), 4.30 (s, 1H), 3.68-3.64 (m, 1H),
3.60-3.55 (m, 1H) 1.27-1.23 (m, 6H).
Example 65. Preparation of
(S)-3-(6-methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H-
)-dione
##STR00134##
[0378] Compound 65.1. 1-(6-methylpyridin-2-yl)urea
[0379] To a 25-mL round-bottom flask purged and maintained with an
inert atmosphere of argon, was added urea (1.48 g, 24.64 mmol, 1.00
equiv) and 6-methylpyridin-2-amine (3 g, 27.74 mmol, 1.00 equiv).
The resulting mixture was stirred for 2 h at 145.degree. C. After
cooling, the crude product (4 g) was purified using CombiFlash:
Column, C18 silica gel; utilizing a mobile phase of CH.sub.3CN:
H.sub.2O=0:100 to CH.sub.3CN: H.sub.2O=50:50 over 40 min. This
resulted in the isolation of 1.2 g (32%) of the title compound as a
white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.07
(s, 1H), 7.56-7.52 (m, 1H), 7.18-7.14 (m, 1H), 6.80-6.75 (m, 1H),
2.36 (s, 3H).
##STR00135##
Compound 65.2.
1-(6-methylpyridin-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione
[0380] The title compound was prepared in a similar manner as the
procedure described for 1.2. Here though, after stirring overnight
at 65.degree. C., the reaction mixture was concentrated under
reduced pressure and the crude product was precipitated from
CH.sub.3OH:Et.sub.2O (1:50). The solid was collected by filtration
and dissolved in CH.sub.3OH (50 mL). The pH value of the solution
was adjusted to 7 with cation ion-exchange resin (Dowex 50WX8-100,
5 g). The solids were filtered and the filtrate was concentrated
under reduced pressure resulting in 0.5 g (29%) of the title
compound as a white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 9.27 (br s, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.17 (d, J=7.6
Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 3.18 (s, 2H), 2.44 (s, 3H).
##STR00136##
Compound 65.3.
6-chloro-3-(6-methylpyridin-2-yl)pyrimidine-2,4(1H,3H)-dione
[0381] To a stirred solution of 65.2 (500 mg, 2.28 mmol, 1.00
equiv) in POCl.sub.3 (5 mL) at 0.degree. C. was added a drop
(.about.20 .mu.L) of H.sub.2O. The resulting solution was warmed to
room temperature, stirred for 30 min., heated to 70.degree. C. and
stirred for 2 h. After cooling, the resulting mixture was
concentrated under reduced pressure. The resulting residue was
carefully dissolved in 10 mL of ice water. The pH was adjusted to 7
with anion ion-exchange resin (activated 201.times.4(711) strong
base styrene anion exchange resin, 20 g) and the solids were
filtered. The filtrate was concentrated under reduced pressure
resulting in 0.2 g (37%) of the title compound as a yellow
solid.
##STR00137##
Compound 65.
(S)-3-(6-methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H-
)-dione
[0382] To a 10-mL round-bottom flask purged and maintained with an
inert atmosphere of argon was added (S)-.alpha.-methylbenzylamine
(0.5 mL) and 65.3 (200 mg, 0.84 mmol, 1.00 equiv). The resulting
solution was stirred for 3 h at 110.degree. C. After cooling, the
resulting mixture was concentrated under vacuum. The residue (100
mg) was purified by preparative RP-HPLC with the following
conditions: Column, XBridge Prep C18 OBD Column, 5 um, 19*150 mm;
mobile phase, H.sub.2O with 0.05% NH.sub.4(HCO.sub.3) and
CH.sub.3CN (15% CH.sub.3CN to 80% in 8 min); This resulted in 28.8
mg (11%) of the title compound as a white solid. LC/MS: m/z (ES+)
323 (M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
7.76 (t, J=7.6 Hz, 1H), 7.39-7.22 (m, 7H), 7.05 (d, J=7.6 Hz, 1H),
6.82 (br, 1H), 4.63-4.59 (m, 1H), 4.46 (s, 1H), 2.43 (s, 3H), 1.44
(d, J=6.4 Hz, 3H).
Example 66. Preparation of
(S)-3-(2,2-difluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-d-
ione
##STR00138##
[0383] Compound 66.1.
6-chloro-3-(2,2-difluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrimi-
dine-2,4(1H,3H)-dione
[0384] To a stirred solution of 11.1 (130 mg, 0.47 mmol) and
Et.sub.3N (0.2 mL) in CH.sub.2Cl.sub.2 (2 mL) at 0.degree. C. was
added 2,2-difluoroethyl trifluoromethanesulfonate (0.10 mL). The
reaction was warmed to room temperature and stirred for 30 minutes.
The mixture was concentrated to give the title compound in a crude
mixture.
##STR00139##
Compound 66.2.
6-chloro-3-(2,2-difluoroethyl)pyrimidine-2,4(1H,3H)-dione
[0385] Crude 65.1 was dissolved in CH.sub.2Cl.sub.2/TFA (1:1, 4 mL)
and stirred for 3 h and concentrated. The resulting material was
treated with 5% NaHCO.sub.3 (aq) until the pH was 7. Ethyl acetate
was added to the mixture and the layers were separated. The aqueous
layer was concentrated. The resulting solid was suspended in
CH.sub.3CN (15 mL) and was remove by filtration. The filtrate was
concentrated to give 52 mg of the title compound.
##STR00140##
[0386] Compound 66.
(S)-3-(2,2-difluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-d-
ione.
[0387] To 66.2 (52 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL) was added
Et.sub.3N (100 uL) and (S)-.alpha.-methylbenzylamine (188 mg, 1.55
mmol). The reaction mixture was heated in a microwave reactor at
100.degree. C. for 32 minutes, cooled to room temperature, and then
concentrated. The resulting residue was dissolved in a 2:3
CH.sub.3CN/H.sub.2O (10 mL) with 2 drops of TFA (.about.40 uL). The
mixture was purified by preparative RP-HPLC to provide 8 mg (11%)
of the title compound as a white solid. LC/MS: m/z (ES+) 296
(M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d6): .delta. ppm 10.20 (br
s, 1H), 7.37-7.32 (m, 4H), 7.26-7.23 (m, 1H), 6.71 (d, J=7.0 Hz,
1H), 6.07 (tt, J=56.0, 4.5 Hz, 1H), 4.54 (quin, J=6.8 Hz, 1H), 4.43
(d, J=2.3 Hz, 1H), 4.02 (td, J=14.3, 4.7 Hz, 2H), 1.40 (d, J=6.7
Hz, 3H).
Example 67. Preparation of
(S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl
amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione
##STR00141##
[0388] Compound 67.1. 2H-1,3-benzodioxole-5-carbaldehyde
[0389] To a stirred solution of 3,4-dihydroxybenzaldehyde (10 g,
72.40 mmol, 1.00 equiv) in DMF (150 mL) was added cesium carbonate
(35.4 g, 108.31 mmol, 1.50 equiv) and dibromomethane (18.7 g,
107.57 mmol, 1.50 equiv). The resulting solution was stirred for 2
h at 110.degree. C. The solution was cooled to room temperature and
the solid was removed by filtration. The filtrate was diluted with
H.sub.2O (300 mL). The resulting solution was extracted with EtOAc
(2.times.300 mL). The organic layers were combined, dried over
sodium sulfate, and concentrated under reduced pressure. The crude
residue was purified by silica gel column chromatography, eluted
with EtOAc/petroleum ether (1:9) to afford 8 g (74%) of the title
compound as a yellow solid. .sup.1H-NMR (300 MHz, CDCl.sub.3):
.delta. ppm 9.81 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.34 (s, 1H),
6.93 (d, J=8.1 Hz, 1H), 6.08 (s, 2H).
##STR00142##
Compound 67.2. (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine
hydrochloride
[0390] The title compound was synthesized according to methods
described for the preparation of 5.3. Here, 67.1 was utilized
instead of 3,5-difluorobenzaldehyde. LC/MS: m/z (ES+) 166
(M+H).sup.+.
##STR00143##
Compound 67.
(S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-(2,2,2-trifluoroethyl)-
pyrimidine-2,4(1H,3H)-dione
[0391] The title compound was synthesized according to methods
described in Example 59. Here, 67.2 was utilized instead
of(S)-1-(2,6-difluorophenyl)ethan-1-amine hydrochloride and
6-chloro-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione was
utilized (synthesized according to methods described in Example 1)
instead of 1.3. LC/MS: m/z (ES+) 358 (M+H).sup.+. .sup.1H-NMR (300
MHz, DMSO-d.sub.6): .delta. ppm 10.27 (br s, 1H), 6.94 (d, J=1.2
Hz, 1H), 6.89-6.82 (m, 3H), 6.72 (d, J=6.9 Hz, 1H), 5.99 (s, 2H),
4.48-4.40 (m, 4H), 1.38 (d, J=6.9 Hz, 3H).
Example 68. Preparation of
(S)-3-isopropyl-6-((1-(o-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione
(68)
##STR00144##
[0393] To a stirred solution of
(1S)-1-(2-methylphenyl)ethan-1-amine (310 mg, 2.29 mmol, 1.50
equiv) in NMP (1 mL) was added proton sponge (491.4 mg, 2.30 mmol,
1.50 equiv) and 1.3 (288 mg, 1.53 mmol, 1.00 equiv). The resulting
solution was stirred for 1 h at 130.degree. C. in an oil bath,
cooled to room temperature, and then diluted with DMSO (2 mL). The
solids were filtered and the filtrate was purified by
Flash-Prep-HPLC with the following conditions: Column: X Bridge
C18, 19*150 mm, 5 um; Mobile Phase A: H.sub.2O/0.05% TFA, Mobile
Phase B: CH.sub.3CN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B
in 10 min. This afforded 50 mg of crude product which was
subsequently separated by chiral preparative HPLC with the
following conditions: Column, Chiralpak IC, 2*25 cm, 5 um; mobile
phase, hexanes and ethanol (9:1, 15 min). This resulted in 35.6 mg
(8%) of the title compound as a white solid. LC/MS: m/z (ES+) 288
(M+H).sup.+. .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 9.76
(br s, 1H), 7.28 (d, J=7.2 Hz, 1H) 7.24-7.14 (m, 3H), 6.48 (d,
J=6.3 Hz, 1H), 4.95-4.86 (m, 1H), 4.60 (quin, J=6.9 Hz, 1H), 4.19
(s, 1H), 2.34 (s, 3H), 1.37 (d, J=6.6 Hz, 3H), 1.27 (d, J=6.9 Hz,
6H).
Example 69. Preparation of
(S)-3-cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione
##STR00145##
[0394] Compound 69.1. 1-cyclobutylurea
[0395] To a stirred solution of cyclobutanamine (40 g, 562.42 mmol,
1.00 equiv) in CH.sub.2Cl.sub.2 (400 mL) at 0.degree. C. was added
trimethylsilyl isocyanate (64.70 g, 561.60 mmol, 1.00 equiv.)
portionwise. The resulting solution was stirred overnight at room
temperature and was quenched by the addition of CH.sub.3OH (80 mL).
The resulting mixture was stirred for 1 h at room temperature and
then concentrated under reduced pressure. The residue was washed
with Et.sub.2O (2.times.100 mL) and filtered, which afforded 53 g
(83%) of the title compound as a white solid. .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. ppm 6.17 (d, J=9.0 Hz, 1H), 5.33 (s, 2H),
3.99-3.91 (m, 1H), 2.16-2.07 (m, 2H), 1.81-1.68 (m, 2H), 1.61-1.45
(m, 2H).
##STR00146##
Compound 69.2. 1-cyclobutylpyrimidine-2,4,6(1H,3H,5H)-trione
[0396] To a stirred solution of sodium methoxide (62.43 g, 1.156
mol, 2.40 equiv) in CH.sub.3OH (500 mL) was added dimethyl malonate
(76.42 g, 0.578 mol, 1.20 equiv) and 69.1 (55 g, 0.48 mol, 1.00
equiv). The resulting solution was heated to 65.degree. C. and
stirred overnight. The reaction was cooled and quenched by the
addition of H.sub.2O (100 mL). The pH of the solution was adjusted
to 1 with concentrated HCl. The resulting mixture was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography with CH.sub.2Cl.sub.2/CH.sub.3OH (20:1) as
eluent to afford 60 g (68%) of the title compound as a white solid.
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 11.20 (s, 1H),
4.95-4.86 (m, 1H), 3.56 (s, 2H), 2.72-2.62 (m, 2H), 2.16-2.09 (m,
2H), 1.78-1.60 (m, 2H).
##STR00147##
Compound 69.3. 6-chloro-3-cyclobutylpyrimidine-2,4(1H,3H)-dione
[0397] To 69.2 (80 g, 0.44 mol, 1.00 equiv) and
triethylbenzylammonium chloride (140.2 g, 0.615 mol, 1.40 equiv)
was added (300 mL). The reaction was stirred for 1 h at 65.degree.
C. and was then concentrated under reduced pressure. The reaction
was quenched by the careful addition of 1 L of water/ice and then
the pH value of the solution was adjusted to 1 with 2N NaOH (aq).
The solid was filtered, washed with CH.sub.3OH (300 mL) and
Et.sub.2O (2.times.300 mL), and dried. This resulted in 78 g (89%0)
of the title compound as a light yellow solid. .sup.1H-NMR (300
MHz, DMSO-d.sub.6): .delta. ppm 12.23 (s, 1H), 5.82 (s, 1H),
5.13-5.01 (m, 1H), 2.87-2.73 (m, 2H), 2.13-2.03 (m, 2H), 1.80-1.56
(m, 2H).
##STR00148##
[0398] Compound 69.
(S)-3-cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.
To a 500-mL round-bottom flask purged and maintained with an inert
atmosphere of argon, was added 69.3 (78 g, 388.79 mmol, 1.00 equiv)
and (S)-.alpha.-methylbenzylamine (150 mL, 2.00 equiv). The
reaction mixture was stirred for 3 h at 120.degree. C. The reaction
mixture was cooled to room temperature, diluted with CH.sub.3OH (1
L) and further cooled to 0.degree. C. The resulting solid was
filtered, washed with Et.sub.2O (2.times.300 mL), and dried under
vacuum to afford 57.25 g (52%) of the title compound as a white
solid. LC/MS: m/z (ES+) 286 (M+H).sup.+. .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 9.94 (br s, 1H), 7.40-7.32 (m, 4H),
7.30-7.26 (m, 1H), 6.40 (br s, 1H), 5.19-5.10 (m, 1H), 4.56-4.49
(m, 1H), 4.35 (s, 1H), 2.91-2.81 (m, 2H), 2.02-1.95 (m, 2H),
1.76-1.58 (m, 2H), 1.42 (d, J=6.8 Hz, 3H).
Example 70. Preparation of
(S)-3-isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2-
,4(1H,3H)-dione
##STR00149##
[0399] Compound 70.1.
(R,E)-2-methyl-N-(2-(trifluoromethyl)benzylidene)propane-2-sulfinamide
[0400] To a 100-mL round-bottom flask purged and maintained with an
inert atmosphere of argon, was added CH.sub.2Cl.sub.2 (50 mL),
2-(trifluoromethyl)benzaldehyde (2.01 g, 11.54 mmol, 1.00 equiv),
(R)-(+)-2-methylpropane-2-sulfinamide (1.68 g, 13.86 mmol, 1.20
equiv), pyridinium p-toluenesulfonate (0.145 g, 0.05 equiv) and
magnesium sulfate (6.93 g, 5.00 equiv). The resulting solution was
stirred for 48 h at 40.degree. C. The mixture was cooled to room
temperature and the solid was filtered. The filtrate was
concentrated under reduced pressure and the resulting residue was
purified by flash column chromatography (silica gel, eluting with
EtOAc/petroleum ether (1:20)). This resulted in 0.96 g (30%) the
title compound as a light yellow solid. LC/MS: m/z (ES+) 278
(M+H).sup.+. .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm
8.82-8.80 (m, 1H), 8.24 (d, J=7.2 Hz, 1H), 7.95-7.80 (m, 3H), 1.22
(s, 9H).
##STR00150##
Compound 70.2.
(R)-2-methyl-N-((1S)-1-(2-(trifluoromethyl)phenyl)-ethyl)propane-2-sulfin-
amide
[0401] To a stirred solution of 70.1 (578 mg, 2.08 mmol, 1.00
equiv) in THF (20 mL) at -50.degree. C. was added 3 M
methylmagnesium bromide in Et.sub.2O (1.4 mL, 4.20 mmol, 2.0 equiv)
dropwise. The resulting solution was stirred at -50.degree. C. for
2.5 h and at room temperature for an additional 10 h. The reaction
was quenched by the addition of a saturated aqueous NH.sub.4Cl
solution (10 mL) and then concentrated under reduced pressure. The
resulting residue was treated with H.sub.2O (50 mL) and extracted
with CH.sub.2Cl.sub.2 (2.times.50 mL). The organic layers were
combined, dried over Na.sub.2SO.sub.4, and concentrated under
reduced pressure. This resulted in 700 mg (60% de) of the title
compound as a yellow solid. LC/MS: m/z (ES+) 294 (M+H).sup.+.
.sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 7.77-7.74 (m, 1H),
7.67-7.60 (m, 2H), 7.43-7.38 (m, 1H), 5.53 (d, J=4.5 Hz, 1H),
4.70-4.60 (m, 1H), 1.42 (d, J=6.6 Hz, 3H), 1.02 (s, 9H).
##STR00151##
Compound 70.3. (S)-1-(2-(trifluoromethyl)phenyl)ethan-1-amine
hydrochloride
[0402] To a stirred solution of 70.2 (700 mg, 2.39 mmol, 1.00
equiv) in CH.sub.3OH (4 mL) was added 4N HCl in 1,4-dioxane (2 mL)
dropwise. The resulting solution was stirred for 1 h at room
temperature and then concentrated under reduced pressure. Solid was
precipitated by the addition of Et.sub.2O (5 mL). The solid was
filtered and dried affording the title compound as a white solid
(0.32 g, 60%).
##STR00152##
Compound 70.4. (S)-1-(2-(trifluoromethyl)phenyl)ethan-1-amine
[0403] To a 50-mL round-bottom flask was added 70.3 (320 mg, 1.43
mmol, 1.00 equiv) and sodium hydroxide (80 mg, 2.00 mmol, 1.40
equiv) in H.sub.2O (20 mL). The resulting solution was stirred for
1 h at room temperature and was then extracted with EtOAc (20 mL).
The organic layer was combined and concentrated under reduced
pressure. This afforded 190 mg (70%) of the title compound as light
yellow oil.
##STR00153##
Compound 70.
(S)-3-isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2-
,4(1H,3H)-dione
[0404] To a 10-mL round-bottom flask purged and maintained with an
inert atmosphere of argon, was added NMP (2 mL), 70.4 (160 mg, 0.85
mmol, 1.00 equiv), 1.3 (160 mg, 0.85 mmol, 1.00 equiv), and proton
sponge (273 mg, 1.28 mmol, 1.5 equiv.). The resulting solution was
stirred for 4 h at 130.degree. C. The crude product (200 mg) was
purified by chiral preparative HPLC with the following conditions:
Column, Phenomenex Lux-2 5u Cellulose-2, 30*150 mm; mobile phase,
Hex-HPLC and ethanol-HPLC (hold 20% ethanol-HPLC in 14 min);
Detector, uv 254/220 nm. 160 mg crude product was obtained. The
obtained material (60 mg) was further purified using chiral
preparative HPLC with following conditions: Column: Phenomenex
Lux-2 5.mu.. Cellulose-2 30*150 mm; Mobile Phase and Gradient:
Hex:EtOH=80:20; Retention Time (Peak 2) (min): 11.106. This
resulted in 30 mg of the title compound as a white solid. LC/MS:
m/z (ES+) 342 (M+H).sup.+. .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 9.84 (br, 1H), 7.78-7.68 (m, 3H), 7.56-7.52 (m, 1H),
6.75 (br s, 1H), 4.93-4.86 (m, 1H), 4.68-4.63 (m, 1H), 4.13 (s,
1H), 1.46 (d, J=6.8 Hz, 3H), 1.25 (d, J=7.2 Hz, 6H).
Example 71. Preparation of
(S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)aminopyrimidine-2,4(1H,3H)--
dione
##STR00154##
[0405] Compound 71.1. 1-(1-methylcyclopropyl)urea
[0406] To a stirred solution of 1-methylcyclopropan-1-amine
hydrochloride salt (429 mg, 3.99 mmol, 1.00 equiv) and
triethylamine (268 mg, 2.65 mmol, 1.00 equiv) in CH.sub.2Cl.sub.2
(6 mL) was added trimethylsilyl isocyanate (366 mg, 3.18 mmol, 1.20
equiv). The resulting mixture was stirred at room temperature
overnight and was quenched by the dropwise addition of CH.sub.3OH
(2 mL) at 0.degree. C. The resulting solution warmed to room
temperature and stirred for an additional 1 h. The resulting
mixture was concentrated under reduced pressure. The crude product
was precipitated from CH.sub.3OH:Et.sub.2O (1:40) affording 300 mg
(66%) of the title compound as a white solid.
##STR00155##
Compound 71.2.
1-(1-methylcyclopropyl)pyrimidine-2,4,6(1H,3H,5H)-trione
[0407] To a stirred solution of 71.1 (320 mg, 2.80 mmol, 1.0 equiv)
in CH.sub.3OH (2 mL) was added sodium methoxide (390 mg, 7.2 mmol,
2.5 equiv) and dimethyl malonate (380 mg, 2.88 mmol, 1.0 equiv).
The resulting solution was stirred overnight at 65.degree. C. After
cooling, the reaction was quenched by the addition of H.sub.2O (100
mL). The pH of the solution was adjusted to 2 with concentrated HCl
and the resulting mixture was concentrated under reduced pressure.
The crude residue was purified by silica gel column chromatography
with EtOAc/petroleum ether (1:3) as eluent. This afforded 100 mg
(20%) of the title compound as a white solid. .sup.1H-NMR (300 MHz,
CDCl.sub.3): .delta. ppm 8.04 (br, 1H), 3.61 (s, 2H), 1.41 (s, 3H),
1.00-, 0.86 (m, 4H).
##STR00156##
Compound 71.3.
6-chloro-3-(1-methylcyclopropyl)pyrimidine-2,4(1H,3H)-dione
[0408] To 71.2 (100 mg, 0.55 mmol, 1.00 equiv) and
triethylbenzylammonium chloride (180 mg, 0.79 mmol, 1.00 equiv) was
added POCl.sub.3 (2 mL). The resulting solution was stirred for 3 h
at 50.degree. C. and then concentrated under reduced pressure. The
residue was carefully quenched by the addition of 10 mL of
water/ice and was extracted with EtOAc (2.times.30 mL). The organic
layers were combined and concentrated under reduced pressure. The
crude residue was purified by silica gel column chromatography with
CH.sub.2Cl.sub.2/CH.sub.3OH (10:1) as eluent to afford 40 mg (36%)
of the title compound as a yellow solid.
##STR00157##
Compound 71.
(S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-
-dione
[0409] To 71.3 (40 mg, 0.20 mmol, 1.00 equiv) was added
(S)-.alpha.-methylbenzylamine (0.5 mL). The reaction mixture was
stirred for 2 h at 130.degree. C. and then was concentrated under
reduced pressure. The resulting residue was purified by preparative
RP-HPLC with the following conditions: Column: X Bridge C18, 19*150
mm, 5 um; Mobile Phase A: H.sub.2O/0.05% TFA, Mobile Phase B:
CH.sub.3CN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10
min. This afforded 15.1 mg (27%) of the title compound as a white
solid. LC/MS: m/z (ES+) 286 (M+H).sup.+. .sup.1H-NMR (300 MHz,
CD.sub.3CN): .delta. ppm 8.41 (br, 1H), 7.42-7.29 (m, 5H), 5.79
(br, 1H), 4.48-4.44 (m, 1H), 4.30 (s, 1H), 1.47 (d, J=6.9 Hz, 3H),
1.27 (s, 3H), 0.87-0.77 (m, 4H).
Example 72. Preparation of Additional Pyrimidine Dione
Compounds
[0410] The compounds in Table 1B were prepared according to the
examples as described above (exemplary methods provided as
`Reference. Ex. No.`)
TABLE-US-00002 Compound No. Observed Mass and/or Structure
Reference Ex. No. .sup.1H NMR ##STR00158## 72 17 340 (M + H).sup.+
.sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 9.89 (br s, 1H),
9.54 (br s, 1H), 8.22 (br s, 1H) 7.82 (br s, 1H), 7.75 (s, 1H)
7.66-7.54 (m, 2H), 7.48 (d, J = 7.5 Hz, 1H), 6.60-6.58 (m, 1H),
4.90-4.83 (m, 1H), 4.55-4.48 (m, 1H), 4.30 (s, 1H), 1.42 (d, J =
6.9 Hz, 3H), 1.27-1.21 (m, 6H). ##STR00159## 73 15 310 (M +
H).sup.+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.20 (m,
1H), 9.04 (br s, 1H), 7.57 (m, 1H), 7.38-7.32 (m, 4H), 7.26-7.21
(m, 1H), 6.76 (m, 1H), 4.69-4.62 (m, 1H), 4.46 (s, 1H), 1.40 (d, J
= 6.8 Hz, 3H). ##STR00160## 74 15 310 (M + H).sup.+ .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 8.56 (m, 1H), 8.49 (m, 1H),
8.37 (m, 1H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 6.68 (m, 1H),
4.71-4.65 (m, 1H), 4.34 (s, 1H), 1.37 (d, J = 6.8 Hz, 3H).
##STR00161## 75 15 310 (M + H).sup.+ .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 8.60 (m, 1H), 8.57 (m, 1H), 8.49 (br s,
1H), 7.39-7.32 (m, 4H), 7.26-7.22 (m, 1H), 6.68 (m, 1H), 4.69-4.64
(m, 1H), 4.41 (s, 1H), 1.39 (d, J = 6.8 Hz, 3H). ##STR00162## 76 5
and 58 275 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
ppm 9.70 (br, 1H), 8.60 (d, J = 2.0 Hz, 1H) 8.50 (dd, J = 4.8, 1.6
Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H),
6.67 (br s, 1H), 4.94-4.88 (m, 1H), 4.62-4.58 (m, 1H), 4.38 (s,
1H), 1.45 (d, J = 6.4 Hz, 3H), 1.30-1.28 (m, 6H). ##STR00163## 77
15 312 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
10.69 (br s, 1H), 7.65 (s, 1H), 7.40-7.20 (m, 7H), 4.52 (quin, J =
6.8 Hz, 1H), 4.40 (s, 1H), 3.30 (br s, 3H), 1.39 (d, J = 7.0 Hz,
3H). ##STR00164## 78 1 302 (M + H)+ .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. ppm 10.58 (br s, 1H), 7.36-7.23 (m, 5H), 5.16
(m, 2H), 4.69 (s, 1H), 4.26 (m, 1H), 1.82-1.71 (m, 2H), 1.44-1.38
(m, 6H), 1.36-1.25 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H). ##STR00165##
79 11 316 (M + H)+ .sup.1H-NMR (400 MHz, CD.sub.3CN): .delta. ppm
7.30-7.20 (m, 4H), 7.16-7.11 (m, 1H), 6.32 (m, 1H), 4.69-4.62 (m,
1H), 4.43 (quin, J = 6.7 Hz, 1H), 4.29 (s, 1H), 4.00 (t, J = 10.5
Hz, 1H), 3.67-3.59 (m, 1H), 3.44-3.40 (m, 1H), 3.14-3.08 (m, 1H),
2.48-2.38 (m, 1H), 1.56-1.45 (m, 3H), 1.38 (d, J = 6.8 Hz, 3H).
##STR00166## 80 1 300 (M + H)+ .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm 9.82 (br s, 1H), 7.41-7.19 (m, 5H), 6.50 (d, J = 6.7
Hz, 1H), 5.05-5.01 (m, 1H), 4.50-4.46 (m, 1H), 4.34 (s, 1H),
2.01-1.84 (m, 2H), 1.83-1.64 (m, 2H), 1.63-1.51 (m, 2H), 1.49-1.34
(m, 5H). ##STR00167## 81 5 302 (M + H).sup.+ .sup.1H-NMR (400 MHz,
CD.sub.3OD): .delta. ppm 7.39-7.35 (m, 2H), 7.30-7.28 (m, 3H),
5.06-5.00 (m, 1H), 4.53 (s, 1H), 4.12 (d, J = 7.2 Hz, 1H),
2.10-2.01 (m, 1H), 1.40-1.37 (m, 6H), 1.02 (d, J = 6.8 Hz, 3H),
0.93 (d, J = 6.8 Hz, 3H). ##STR00168## 82 7 350 (M + H).sup.+
.sup.1H-NMR (400 MHz, CD.sub.3OD): .delta. ppm 7.43-7.33 (m, 4H),
7.30-7.26 (m, 1H), 4.82-4.75 (m, 1H), 4.54-4.49 (m, 2H), 2.74-2.65
(m, 2H), 2.15-2.05 (m, 2H), 1.93-1.79 (m, 2H), 1.61-1.57 (m, 2H),
1.51 (d, J = 6.8 Hz, 3H). ##STR00169## 83 1 302 (M + H).sup.+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.73 (br s, 1H),
7.40-7.22 (m, 5H), 6.50 (d, J = 5.1 Hz, 1H), 4.57-4.44 (m, 2H),
4.34 (br s, 1H), 1.90 (ddd, J = 13.3, 9.8, 7.4 Hz, 2H), 1.61-1.50
(m, 2H), 1.38 (d, J = 6.7 Hz, 3H), 0.74-0.60 (m, 6H). ##STR00170##
84 12 419 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
9.88 (br s, 1H), 7.45-7.41 (m, 3H), 7.37-7.29 (m, 6H), 7.27-7.22
(m, 1H), 6.54 (d, J = 6.7 Hz, 1H), 4.84-4.79 (m, 1H), 4.52-4.47 (m,
1H), 4.36 (d, J = 2.4 Hz, 1H), 3.57 (m, 2H), 3.05 (m, 2H), 2.38 (m,
2H), 1.50 (m, 2H), 1.38 (d, J = 6.7 Hz, 3H). ##STR00171## 85 1 302
(M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.73 (br
s, 1H), 7.31-7.22 (m, 2H), 7.21-7.12 (m, 3H), 5.93 (d, J = 8.2 Hz,
1H), 5.00-4.87 (m, 1H) 4.44 (s, 1H), 4.30 (s, 1H), 3.37-3.31 (m,
1H), 2.65-2.53 (m, 2H), 1.70 (dtd, J = 9.0, 6.9, 6.9, 2.0 Hz, 1H),
1.29 (d, J = 7.0 Hz, 6H), 1.11 (d, J = 6.3 Hz, 3H). ##STR00172## 86
11 304 (M + H).sup.+ .sup.1H-NMR (400 MHz, CD.sub.3OD +
CDCl.sub.3): 7.22-7.15 (m, 2H), 7.13-7.07 (m, 3H), 6.28 (d, J = 6.1
Hz, 1H), 4.44 (s, 1H), 4.38 (s, 2H), 4.30-4.23 (m, 1H), 3.55 (s,
3H), 1.35 (d, J = 6.8 Hz, 3H). ##STR00173## 90 1 288 (M + H)+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.77 (br s, 1H),
7.32-7.26 (m, 2H), 7.23-7.12 (m, 3H), 5.85 (d, J = 7.9 Hz, 1H),
4.97-4.87 (m, 1H), 4.55 (s, 1H), 3.77-3.65 (m, 1H), 2.76-2.68 (m,
2H), 1.27 (d, J = 7.0 Hz, 6H), 1.05 (d, J = 6.7 Hz, 3H).
##STR00174## 91 53 380 (M + H)+ .sup.1H-NMR (400 MHz, CDCl.sub.3):
.delta. ppm 9.77 (br s, 1H), 7.33-7.23 (m, 10H), 5.23 (br s, 1H),
4.67 (br s, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz,
1H), 4.44-4.37 (m, 1H), 4.09 (t, J = 9.2 Hz, 1H), 3.63 (dd, J =
9.8, 5.9 Hz, 1H), 1.48 (d, J = 6.7 Hz, 3H), 1.35 (d, J = 7.0 Hz,
3H). ##STR00175## 92 54 290 (M + H)+ .sup.1H-NMR (400 MHz,
CDCl.sub.3): .delta. ppm 9.68 (s, 1H), 7.41-7.22 (m, 5H), 5.62 (s,
1H), 5.08 (td, J = 7.3, 2.9 Hz, 1H), 4.67 (s, 1H), 4.48-4.35 (m,
1H), 3.98 (dd, J = 11.9, 7.6 Hz, 1H), 3.75 (dd, J = 11.7, 3.1 Hz,
1H), 1.52 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 7.0 Hz, 3H).
##STR00176## 93 1 290 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 10.01 (d, J = 2.0 Hz, 1H), 7.37-7.23 (m, 5H), 6.61 (d,
J = 6.3 Hz, 1H), 5.19 (t, J = 5.1 Hz, 1H), 4.93-4.83 (m, 1H),
4.40-4.33 (m, 1H), 4.24 (d, J = 2.4 Hz, 1H), 3.66 (dt, J = 11.1,
4.7 Hz, 1H), 3.52-3.44 (m, 1H), 1.25 (dd, J = 6.9, 2.2 Hz, 6H).
##STR00177## 94 1 and 50 328 (M + H)+ .sup.1H NMR (400 MHz,
DMSO-d.sub.6 @ 75.degree. C.): .delta. ppm 9.91 (br s, 1H),
7.44-7.23 (m, 5H), 6.58 (br s, 1H), 5.52 (br s, 1H), 4.59-4.51 (m,
1H), 4.46 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.43 (d, J = 7.0
Hz, 3H). ##STR00178## 95 1 and 50 328 (M + H)+ .sup.1H NMR (400
MHz, DMSO-d.sub.6 @ 75.degree. C.): .delta. ppm 9.91 (br s, 1H),
7.44-7.23 (m, 5H), 6.58 (br s, 1H), 5.52 (br s, 1H), 4.59-4.51 (m,
1H), 4.46 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.43 (d, J = 7.0
Hz, 3H). ##STR00179## 99 1 342 (M + H)+ .sup.1H-NMR (400 MHz,
DMSO-d.sub.6 @ 50.degree. C.): .delta. ppm 9.79 (br s, 1H),
7.46-7.23 (m, 5H), 6.51 (d, J = 6.7 Hz, 1H), 5.13 (br s, 1H), 4.50
(quin, J = 6.9 Hz, 1H), 4.37 (s, 1H), 3.15-3.01 (m, 1H), 2.60-2.50
(m, 1H), 1.40 (d, J = 6.7 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H).
##STR00180## 100 1 and 50 314 (M + H)+ .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. ppm 10.32 (br s, 1H), 7.40-7.34 (m, 4H),
7.29-7.25 (m, 1H), 6.81 (d, J = 6.6 Hz, 1H), 4.60-4.54 (m, 1H),
4.49-4.40 (m, 3H), 1.42 (d, J = 6.6 Hz, 3H). ##STR00181## 101 1 and
50 288 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
9.50 (br s, 1H), 7.56-7.44 (m, 4H), 7.38-7.24 (m, 1H), 6.41 (d, J =
6.4 Hz, 1H), 4.45 (q, J = 6.8 Hz, 1H), 4.25 (s, 1H), 1.54 (s, 9H),
1.38 (d, J = 6.8 Hz, 3H). ##STR00182## 102 57 290 (M + H)+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.31 (br s, 1H),
7.35-7.23 (m, 5H), 5.72 (d, J = 4.7 Hz, 1H), 4.67 (s, 1H), 4.40
(quin, J = 6.6 Hz, 1H), 4.05 (t, J = 5.7 Hz, 2H), 3.56 (t, J = 5.7
Hz, 2H), 3.27 (s, 3H), 1.46 (dd, J = 6.7, 1.6 Hz, 3H). ##STR00183##
103 1 and 59 342 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6, @
75.degree. C.): .delta. ppm 9.91 (br s, 1H), 7.37-7.24 (m, 5H),
6.59 (br s, 1H), 5.51 (br s, 1H), 4.45 (br s, 1H), 4.31 (q, J = 6.9
Hz, 1H), 1.83-1.67 (m, 2H), 1.52 (d, J = 7.4 Hz, 3H), 0.86 (t, J =
7.4 Hz, 3H). ##STR00184## 104 1 and 58 300 (M + H)+ .sup.1H-NMR
(400 MHz, DMSO-d.sub.6): .delta. ppm 9.80 (br s, 1H), 7.37-7.31 (m,
4H), 7.27-7.22 (m, 1H), 6.52 (br, 1H), 4.48 (q, J = 6.7 Hz, 1H),
4.32 (br s, 1H), 3.93 (br, 1H), 1.62 (br, 1H), 1.38 (d, J = 6.7 Hz,
3H), 1.33 (d, J = 7.0 Hz, 3H), 0.48-0.41 (m, 1H), 0.27-0.21 (m,
1H), 0.14 (dq, J = 9.4, 4.8 Hz, 1H), 0.02 (m, 1H). ##STR00185## 105
1 and 58 300 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta.
ppm 9.81 (br s, 1H), 7.37-7.30 (m, 4H), 7.26-7.22 (m, 1H), 6.53 (d,
J = 5.9 Hz, 1H), 4.48 (q, J = 6.8 Hz, 1H), 4.32 (d, J = 1.6 Hz,
1H), 3.85 (m, 1H), 1.61 (m, 1H), 1.38 (d, J = 7.0 Hz, 3H), 1.32 (d,
J = 6.7 Hz, 3H), 0.49-0.42 (m, 1H), 0.28-0.22 (m, 1H), 0.17-0.12
(m, 1H), 0.01-(-)0.05, (m, 1H). ##STR00186## 106 8 300 (M + H)+
.sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 9.96 (br s, 1H),
7.36-7.24 (m, 5H), 6.48 (d, J = 6.3 Hz, 1H), 4.40 (s, 1H),
4.36-4.27 (m, 1H), 3.63 (q, J = 6.6 Hz, 2H), 2.67-2.50 (partially
obscured m, 1H) 2.02-1.95 (m, 1H), 1.90-1.78 (m, 4H), 1.66-1.57 (m,
1H), 0.98 (t, J = 6.6 Hz, 3H). ##STR00187## 107 67 and 59 318 (M +
H)+ .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 9.76 (br s,
1H), 6.92 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.80 (dd,
J = 6.0, 1.8 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 5.99 (s, 2H),
4.93-4.88 (m, 1H), 4.41-4.35 (m, 2H), 1.35 (d, J = 6.6 Hz, 3H) 1.28
(d, J = 1.2 Hz, 3H) 1.26 (d, J = 1.2 Hz, 3H). ##STR00188## 108 67
and 59 304 (M + H)+ .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.
ppm 9.93 (br s, 1H), 6.92 (d, J = 1.5 Hz, 1H), 6.87 (d, J = 8.1 Hz,
1H), 6.82-6.79 (m, 1H), 6.48 (d, J = 7.2 Hz, 1H), 5.99 (s, 2H),
4.45-4.39 (m, 2H), 3.65 (q, J = 6.6 Hz, 2H), 1.36 (d, J = 6.9 Hz,
3H) 0.99 (t, J = 6.9 Hz, 3H). ##STR00189## 109 1, 5 and 7 328 (M +
H)+ .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 10.28 (br s,
1H), 7.39-7.24 (m, 5H), 6.81 (d, J = 6.6 Hz, 1H), 4.47-4.33 (m,
4H), 1.80-1.67 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). ##STR00190## 110
1 and 50 286 (M + H)+ .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.
ppm 10.01 (br s, 1H), 7.39-7.33 (m, 4H), 7.30-7.23 (m, 1H), 6.60
(d, J = 6.0 Hz, 1H), 4.52 (q, J = 6.6 Hz, 1H), 4.38 (s, 1H), 3.49
(d, J = 6.9 Hz, 2H), 1.40 (d, J = 6.9 Hz, 3H) 1.08-1.00 (m, 1H),
0.37-0.33 (m, 2H), 0.28-0.23 (m, 2H). ##STR00191## 111 7 and 59 340
(M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.29 (br
s, 1H), 7.37-7.33 (m, 4H), 7.30-7.25 (m, 1H), 6.98 (d, J = 5.6 Hz,
1H), 4.42 (q, J = 9.2 Hz, 2H), 4.35 (d, J = 1.6 Hz, 1H), 3.89-3.85
(m, 1H), 1.24-1.15 (m, 1H) 0.61-0.56 (m, 1H), 0.50-0.33 (m, 3H).
##STR00192## 112 8 and 59 354 (M + H)+ .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 10.27 (br s, 1H), 7.45-7.25 (m, 5H),
6.73 (br s, 1H), 4.46-4.35 (m, 4H), 2.67-2.50 (partially obscured
m, 1H), 2.04-2.01 (m, 1H), 1.90-1.79 (m, 4H), 1.68-1.62 (m, 1H).
##STR00193## 113 15 306 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6
@ 90.degree. C.): .delta. ppm 9.86 (br s, 1H), 7.39-7.31 (m, 4H),
7.29-7.25 (m, 1H), 6.48 (d, J = 6.7 Hz, 1H), 5.00-4.91 (m, 1H),
4.78 (m, 1H), 4.56-4.50 (m, 1H), 4.45-4.38 (m, 2H), 3.76-3.70 (m,
2H), 1.42 (d, J = 7.4 Hz, 3H). ##STR00194## 114 1 and 51 360 (M +
H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6 @ 90.degree. C.): .delta.
ppm 9.86 (br s, 1H), 7.25 (dd, 8.4, 5.7 Hz, 2H), 7.10-7.04 (m, 2H),
5.94 (br s, 1H), 5.52 (br s, 1H), 4.62 (br s, 1H), 3.79-3.71 (m,
1H), 2.76 (d, J = 6.7 Hz, 2H), 1.55 (d, J = 7.0 Hz, 3H), 1.11 (d, J
= 6.3 Hz, 3H). ##STR00195## 115 62 290 (M + H)+ ##STR00196## 116 62
290 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.83
(br s, 1H), 9.68 (br s, 1H), 7.14 (dd, J = 7.4, 1.6 Hz, 1H), 7.05
(td, J = 7.6, 1.6 Hz, 1H), 6.82-6.74 (m, 2H), 6.40 (d, J = 7.0 Hz,
1H), 4.92-4.85 (m, 1H), 4.60 (quin, J = 6.9 Hz, 1H), 4.30 (d, J =
2.4 Hz, 1H), 1.35 (d, J = 6.7 Hz, 3H), 1.27-1.22 (m, 6H).
##STR00197## 117 1 and 59 340 (M + H)+ .sup.1H-NMR (300 MHz,
CDCl.sub.3: .delta. ppm 10.40 (br s, 1H), 7.44-7.26 (m, 5H), 6.13
(br s, 1H), 4.80 (br s, 1H), 4.45 (m, 1H), 1.76-1.52 (m, 5H),
1.35-1.27 (m, 2H). ##STR00198## 118 1 and 51 376 (M + H)+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 10.27 (br s, 1H),
7.29-7.22 (m, 3H), 7.15-7.10 (m, 2H), 7.01 (dd, J = 8.2, 2.3 Hz,
2H), 6.12 (br s, 1H), 4.72 (d, J = 2.0 Hz, 1H), 3.79-3.71 (m, 1H),
2.76 (d, J = 6.7 Hz, 2H), 1.09 (d, J = 6.7 Hz, 3H). ##STR00199##
119 5 and 59 354 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 9.84 (br s, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.38 (d, J =
8.0 Hz, 1H), 7.21 (dd, J = 8.4, 1.2 Hz, 1H), 6.54 (d, J = 6.8 Hz,
1H), 4.90 (q, J = 6.8 Hz, 1H), 4.55-4.52 (m, 1H), 4.34 (d, J = 2.0
Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H) 1.31-1.26 (m, 6H). ##STR00200##
120 5 and 59 308 (M + H)+ .sup.1H-NMR (300 MHz, DMSO-d.sub.6):
.delta. ppm 9.87 (m, 1H), 7.48-7.28 (m, 4H), 6.66 (d, J = 6.6 Hz,
1H), 4.93-4.84 (m, 1H), 4.70 (quin, J = 6.6 Hz, 1H), 4.08 (s, 1H),
1.41 (d, J = 6.6 Hz, 3H), 1.28-1.24 (m, 6H). ##STR00201## 121 5 304
(M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.68 (m,
1H), 7.25-7.21 (m, 2H), 6.91-6.87 (m, 2H), 6.43 (m, 1H), 4.92-4.85
(m, 1H), 4.41 (quin, J = 6.7 Hz, 1H), 4.32 (s, 1H), 3.71 (s, 3H),
1.35 (d, J = 6.7 Hz, 3H), 1.27-1.23 (m, 6H). ##STR00202## 122 7 and
59 286 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
7.38-7.33 (m, 4H), 7.28-7.25 (m, 1H), 6.80 (br s, 1H), 4.24 (s,
1H), 3.82-3.78 (m, 1H), 3.63 (q, J = 6.8 Hz, 2H), 1.17-1.13 (m,
1H), 0.97 (t, J = 6.8 Hz, 3H), 0.59-0.54 (m, 1H), 0.47-0.32 (m,
3H).
##STR00203## 123 1 and 59 294 (M + H)+ .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. ppm 10.00 (br s, 1H), 7.44 (s, 1H),
7.42-7.30 (m, 3H), 6.61 (d, J = 6.6 Hz, 1H), 4.57-4.53 (m, 1H),
4.38 (d, J = 1.8 Hz, 1H), 3.65 (q, J = 6.9 Hz, 2H), 1.39 (d, J =
6.9 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). ##STR00204## 124 1 and 59
328 (M + H) .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 7.75
(s, 1H), 7.72-7.59 (m, 3H), 6.99 (br s, 1H), 4.68-4.62 (m, 1H),
4.38 (s, 1H), 3.65 (q, J = 6.6 Hz, 2H), 1.42 (d, J = 6.6 Hz, 3H),
1.01 (t, J = 4.5 Hz, 3H). ##STR00205## 125 1 and 59 304 (M + H)+
.sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 10.01 (br s, 1H),
7.42 (dd, J = 7.8, 6.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 7.12-7.06
(m, 1H), 6.62 (d, J = 7.2 Hz, 1H), 4.56 (quin, J = 6.9 Hz, 1H),
4.39 (s, 1H), 3.49 (d, J = 6.9 Hz, 2H), 1.40 (d, J = 6.6 Hz, 3H),
1.07-0.99 (m, 1H), 0.37-0.34 (m, 2H), 0.30-0.22 (m, 2H).
##STR00206## 126 1 and 59 354 (M + H)+ .sup.1H-NMR (300 MHz,
CD.sub.3OD): .delta. ppm 7.73-7.50 (m, 4H), 4.63 (q, J = 6.9 Hz,
1H), 3.62 (d, J = 7.2 Hz, 2H), 1.50 (d, J = 6.9 Hz, 3H) 1.17-1.10
(m, 1H), 0.45-0.39 (m, 2H), 0.32-0.26 (m, 2H). ##STR00207## 127 1
and 59 320 (M + H)+ .sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta.
ppm 10.01 (br s, 1H), 7.45 (s, 1H), 7.42-7.30 (m, 3H), 6.64 (d, J =
6.9 Hz, 1H), 4.58-4.53 (m, 1H), 4.39 (s, 1H), 3.50 (d, J = 7.2 Hz,
2H), 1.40 (d, J = 6.6 Hz, 3H) 1.07-1.03 (m, 1H), 0.37-0.31 (m, 2H),
0.25-0.22 (m, 2H). ##STR00208## 128 3 388 (M + H)+ .sup.1H-NMR (400
MHz, DMSO-d.sub.6): .delta. ppm 9.50 (br s, 1H), 7.52-7.22 (m, 3H),
4.87-4.72 (m, 1H), 4.52-4.41 (m, 1H), 1.60-1.48 (m, 3H), 1.41-1.27
(m, 6H). ##STR00209## 129 1 and 59 292 (M + H)+ .sup.1H-NMR (300
MHz, DMSO-d.sub.6): .delta. ppm 10.00 (br s, 1H), 7.40 (dt, J = 7.8
Hz, 0.6 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.09-7.06 (m, 1H), 6.60
(d, J = 6.9 Hz, 1H), 4.46 (q, J = 6.6 Hz, 1H), 4.38 (s, 1H),
3.60-3.55 (m, 2H), 1.47-1.39 (m, 5H), 0.79 (t, J = 7.5 Hz, 3H).
##STR00210## 130 1 and 59 308 (M + H)+ .sup.1H-NMR (300 MHz,
DMSO-d.sub.6): .delta. ppm 10.01 (br s, 1H), 7.44 (t, J = 0.9 Hz,
1H), 7.41-7.38 (m, 1H), 7.34-7.31 (m, 2H), 6.62 (d, J = 5.1 Hz,
1H), 4.55 (q, J = 6.7 Hz, 1H), 4.38 (s, 1H), 3.54 (dd, J = 6.0, 5.7
Hz, 2H), 1.47-1.39 (m, 5H), 0.84 (t, J = 7.5 Hz, 3H). ##STR00211##
131 1 and 59 342 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6):
.delta. ppm 10.05 (br s, 1H), 7.74 (s, 1H), 7.68-7.56 (m, 3H), 6.69
(d, J = 6.4 Hz, 1H), 4.70-4.63 (m, 1H), 4.40 (s, 1H), 3.59-3.54 (m,
2H), 1.49-1.40 (m, 5H), 0.86 (t, J = 6.0 Hz, 3H). ##STR00212## 132
1 304 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
9.85 (br s, 1H), 7.37-7.33 (m, 2H), 7.18-7.13 (m, 2H), 6.52 (d, J =
7.4 Hz, 1H), 5.14-5.05 (m, 1H), 4.50 (quin, J = 6.8 Hz, 1H), 4.31
(s, 1H), 2.84-2.78 (m, 2H), 1.97-1.91 (m, 2H), 1.70-1.54 (m, 2H),
1.36 (t, J = 6.7 Hz, 3H). ##STR00213## 133 1 290 (M + H)+
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.83 (br s, 1H),
9.68 (br s, 1H), 7.14 (dd, J = 7.4, 1.6 Hz, 1H), 7.07-7.03 (m, 1H),
6.81-6.74 (m, 2H), 6.42 (d, J = 7.0 Hz, 1H), 4.92-4.85 (m, 1H),
4.60 (quin, J = 6.8 Hz, 1H), 4.31 (d, J = 2.3 Hz, 1H), 1.35 (d, J =
7.0 Hz, 3H), 1.27-1.22 (m, 6H). ##STR00214## 134 1 296 (M + H)+
.sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. ppm 10.03 (br s, 1H),
7.48-7.39 (m, 2H), 7.23-7.20 (m, 1H), 6.60 (d, J = 5.1 Hz, 1H)
4.58-4.53 (m, 1H), 4.38 (s, 1H), 3.66 (q, J = 5.1 Hz, 2H), 1.39 (d,
J = 5.1 Hz, 3H), 0.99 (t, J = 5.1 Hz, 3H). ##STR00215## 135 1 306
(M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm 9.95 (br
s, 1H), 7.36 (dd, J = 9.0, 5.5 Hz, 2H), 7.18-7.14 (m, 2H), 6.54 (d,
J = 7.0 Hz, 1H) 4.66 (br s, 1H), 4.54-4.49 (m, 1H), 4.34 (s, 1H),
1.97-1.86 (m, 1H), 1.65-1.55 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H),
1.23 (d, J = 6.8 Hz, 3H), 0.70 (t, J = 6.8 Hz, 3H). ##STR00216##
136 1 292 (M + H)+ .sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. ppm
9.95 (br s, 1H), 7.36 (dd, J = 9.0, 5.5 Hz, 2H), 7.18-7.14 (m, 2H),
6.54 (d, J = 7.0 Hz, 1H) 4.56-4.49 (m, 1H), 4.35 (d, J = 2.3 Hz,
1H), 3.57-3.53 (m, 2H), 1.44-1.36 (m, 5H), 0.77 (t, J = 7.4 Hz,
3H). ##STR00217## 137 65 327 (M + H)+ .sup.1H-NMR (400 MHz,
DMSO-d.sub.6): .delta. ppm 10.36 (br s, 1H), 8.09 (q, J = 8.0 Hz,
1H), 7.39-7.35 (m, 4H), 7.30-7.22 (m, 3H), 6.87 (m, 1H), 4.61
(quin, J = 6.8 Hz, 1H), 4.49 (s, 1H), 1.44 (d, J = 6.8 Hz, 3H).
Example 73. Myosin Inhibition Assay
[0411] Small Molecule Agents were Assessed for their Ability to
Inhibit the Enzymatic Activity of bovine cardiac myosin using a
biochemical assay that couples the release of ADP (adenosine
diphosphate) from cardiac myosin to an enzymatic coupling system
consisting of pyruvate kinase and lactate dehydrogenase (PK/LDH)
and monitoring the absorbance decrease of NADH (at 340 nm) as a
function of time. PK converts ADP to ATP (adenosine triphosphate)
by converting PEP (phosphoenolpyruvate) to pyruvate. Pyruvate is
then converted to lactate by LDH by converting NADH (nicotinamide
adenine dinucleotide) to NAD (oxidized nicotinamide adenine
dinucleotide). The source of cardiac myosin was from bovine heart
in the form of skinned myofibrils. Prior to testing small molecule
agents, the bovine myofibrils were assessed for their calcium
responsiveness and the calcium concentration that achieves either a
50% (pCa.sub.50) or 75% (pCa.sub.75) activation of the myofibril
system was chosen as the final condition for assessing the
inhibitory activity of the small molecule agents. All enzymatic
activity was measured in a buffered solution containing 12 mM PIPES
(piperazine-N,N'-bis(2-ethanesulfonic acid), 2 mM magnesium
chloride at pH 6.8 (PM12 buffer). Final assay conditions were 1
mg/mL of bovine cardiac myofibrils, 0.4 mM PK/LDH, 50 uM ATP, 0.1
mg/mL BSA (bovine serum albumin), 10 ppm antifoam, 1 mM DTT, 0.5 mM
NADH, 1.5 mM PEP at the desired free calcium concentration required
to achieve either 50% or 75% activation of the myofibrils.
[0412] A dilution series of compound was created in DMSO such that
the final desired concentration of compound would be achieved in a
volume of 100 .mu.L with a fixed DMSO concentration of 2% (v/v).
Typically 2 .mu.L of the dilution series were added to 96 well
plate to achieve an 8 or 12 point dose response. Following the
addition of 50 .mu.L of a solution containing bovine cardiac
myofibrils, PK/LDH and a solution of calcium (that achieved the
desired activation), the enzymatic reaction was started with the
addition of 50 .mu.L of a solution containing ATP, PEP and NADH.
The reaction progress was followed in a Molecular Devices M5e plate
reader at ambient temperature using clear half area plates. The
plate reader was configured to read absorbance at 340 nm in
kinetics mode for 15 minutes. Data were recorded as the slope of
the absorbance response to time. The slopes of the absorbance
response as a function of time were normalized to slopes on the
plate containing DMSO. This normalized rate was then plotted as a
function of small molecule concentration and the data was fitted to
a four-parameter fit using GraphPad Prism. The midpoint of this
plot is the IC50 and is the concentration at which fifty percent of
the total response is inhibited. Any agent that failed to achieve a
fifty percent inhibition at the highest concentration tested was
reported as an IC50 greater than e highest concentration tested
(ie. IC50>25 uM).
[0413] Selectivity against rabbit skeletal myofibrils was assessed
as described above with the exception that the source of myosin was
that of fast skeletal myosin from rabbit in the form of myofibrils.
Dose responses against rabbit skeletal myofibrils were also
determined as described above.
Example 74. Stereochemical Preference for Activity
[0414] Matched pairs of stereoisomers were tested for their ability
to inhibit myosin activity as described above. The results are
summarized in Table 3. In all cases, the (R) stereoisomer is
significantly less active than the (S) stereoisomer.
Example 75. Cardiomyocyte Contractility Assay
[0415] Contractility of adult rat ventricular myocytes is
determined by edge detection with an IonOptix contractility system.
Aliquots of myocytes in Tyrode buffer (137 mM NaCl, 3.7 mM KCL, 0.5
mM MgCl.sub.2, 1.5 mM CaCl.sub.2, 4 mM HEPES, 11 mM glucose) are
placed in a perfusion chamber (Series 20 RC-27NE; Warner
Instruments), allowed to adhere to the coverslip, and then perfused
with 37.degree. C. Tyrode buffer. Myocytes are filed stimulated at
1 Hz and 10 V. Only myocytes with clear striations, quiescent prior
to pacing, with a cell length of 120-180 microns, a basal
fractional shortening equal to 3-8% of the cell length, and a
contraction velocity greater than 100 microns per second are used
for contractility experiments. To determine the response to
compounds, myocytes are first perfused for 60 seconds with Tyrodes
buffer followed by 5 minutes of compound and a 140 second washout
with Tyrodes buffer. Data is continuously recorded using IonOptix
software. Contractility data is analyzed using Ionwizard software
(IonOptix). For each cell, 10-20 contractility transients were
averaged and compared under basal (no compound) and
compound-treated conditions. Compound activity is measured by
effects on fractional shortening (FS), where fractional shortening
is the ratio of the peak length of the cell at contraction divided
by the basal cell length normalized to 100% for an untreated
cell.
TABLE-US-00003 TABLE 4 Inhibition of Cardiomyocyte Contraction by
Selected Compounds.sup.a Activity Activity ID at 0.3 uM at 1.0 uM 1
++ +++ 2 ++ +++ 12 n.d. ++ 19 n.d. + 27 ++ n.d. 67 n.d. +++ .sup.a+
represents fractional shorting inhibition values less than 33%. ++
represents fractional shorting inhibition values from 33% to 66%.
+++ represents fractional shortening inhibition values greater than
66%.
Example 76. Acute Pharmacodynamic Effect in Rat
[0416] Representative compounds were tested for their ability to
modulate cardiac contractility in rat as a measure of in vivo
target engagement. Fractional shortening, a measure of
contractility, was determined by noting the change in the diameter
of the left ventricle at the end of systole/contraction (LVESd)
relative to diastole/relaxation (LVEDd) and expressing this change
as the ratio FS=(LVEDd-LVESd)/LVEDd. Fed male Sprague-Dawley rats
were lightly anesthetized with isofluorane and baseline fractional
shortening was measured in the parasternal position using
transthoracic echocardiography (TTE). Following this measurement,
animals were recovered and received a single dose of compound (4
mg/kg) by oral gavage. At three hours post-dose, second and third
echocardiograms were collected under light anesthesia to determine
drug effects on contractility. Effects are represented in Table 5
as a percent reduction of baseline fractional shortening.
TABLE-US-00004 TABLE 5 Inhibition of Contractility in Rat by
Selected Compounds.sup.a % Reduction in Fractional ID Shortening 3
h post-dose 1 +++ 45 + 48 +++ 49 +++ 69 + 70 ++ 71 +++ .sup.a+
represents a relative change in fractional shortening less than
15%. ++ represents a relative change in fractional shortening
15-30%. +++ presents a relative change in fractional shortening
greater than 30%.
[0417] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, one of skill in the art will appreciate that
certain changes and modifications may be practiced within the scope
of the appended claims. In addition, each reference provided herein
is incorporated by reference in its entirety to the same extent as
if each reference was individually incorporated by reference. Where
a conflict exists between the instant application and a reference
provided herein, the instant application shall dominate
* * * * *