U.S. patent application number 17/554353 was filed with the patent office on 2022-04-07 for substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diones for treating cardiac diseases.
The applicant listed for this patent is MYOKARDIA, INC.. Invention is credited to Mark Grillo, Brian Kane, Johan Oslob, Fabienne Thompson, Min Zhong.
Application Number | 20220106314 17/554353 |
Document ID | / |
Family ID | 1000006038837 |
Filed Date | 2022-04-07 |
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United States Patent
Application |
20220106314 |
Kind Code |
A1 |
Grillo; Mark ; et
al. |
April 7, 2022 |
SUBSTITUTED 5,6,7,8-TETRAHYDROPYRIDO[2,3-D]PYRIMIDINE-2,4-DIONES
FOR TREATING CARDIAC DISEASES
Abstract
The present disclosure provides novel tetrahydropyran
(THP)-substituted bicyclic pyrimidinedione compounds that are
useful for the treatment of hypertrophic cardiomyopathy (HCM),
conditions associated with left ventricular hypertrophy, conditions
associated with diastolic dysfunction, and/or symptoms associated
thereof. The synthesis and characterization of the compounds is
described, as well as methods for treating HCM and other forms of
heart disease.
Inventors: |
Grillo; Mark; (South San
Francisco, CA) ; Kane; Brian; (San Mateo, CA)
; Oslob; Johan; (Sunnyvale, CA) ; Zhong; Min;
(Palo Alto, CA) ; Thompson; Fabienne; (Paris,
FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MYOKARDIA, INC. |
Brisbane |
CA |
US |
|
|
Family ID: |
1000006038837 |
Appl. No.: |
17/554353 |
Filed: |
December 17, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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17319139 |
May 13, 2021 |
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17554353 |
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16665897 |
Oct 28, 2019 |
11034693 |
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17319139 |
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62752278 |
Oct 29, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 471/04
20130101 |
International
Class: |
C07D 471/04 20060101
C07D471/04 |
Claims
1. A compound having the formula: ##STR00075## or a
pharmaceutically acceptable salt thereof, wherein the subscript n
is 1 or 2; each R.sup.1 is a member selected from the group
consisting of fluoro, chloro, optionally substituted
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-C.sub.4
haloalkyl, optionally substituted C.sub.1-C.sub.4 alkoxy,
optionally substituted C.sub.1-C.sub.4 haloalkoxy, and optionally
substituted C.sub.2-C.sub.4 alkynyl; wherein at least one R.sup.1
is fluoro; and one of R.sup.2a and R.sup.2b is fluoro and the other
of R.sup.2a and R.sup.2b is H.
2. The compound of claim 1, having the formula: ##STR00076## or a
pharmaceutically acceptable salt thereof, wherein the subscript n
is 1 or 2; each R.sup.1 is a member selected from the group
consisting of fluoro, chloro, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
haloalkoxy, and C.sub.2-C.sub.4 alkynyl; wherein at least one
R.sup.1 is fluoro; and one of R.sup.2a and R.sup.2b is fluoro and
the other of R.sup.2a and R.sup.2b is H.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof wherein R.sup.2a is fluoro and R.sup.2b is H or
wherein R.sup.2a is H and R.sup.2b is fluoro.
4. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof wherein R.sup.2a is fluoro, and n is 1.
5. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof wherein R.sup.2a is fluoro, and n is 2.
6. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof wherein R.sup.2b is fluoro, and n is 1.
7. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof wherein R.sup.2b is fluoro, and n is 2.
8. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof wherein n is 1.
9. The compound of claim 1 or 2, having the formula: ##STR00077##
or pharmaceutically acceptable salt thereof, wherein the subscript
n is 1; and the R.sup.1 is a member independently selected from the
group consisting of fluoro, chloro, optionally substituted
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-C.sub.4
haloalkyl, optionally substituted C.sub.1-C.sub.4 alkoxy,
optionally substituted C.sub.1-C.sub.4 haloalkoxy, and optionally
substituted C.sub.2-C.sub.4 alkynyl; and one of R.sup.2a and
R.sup.2b is fluoro and the other of R.sup.2a and R.sup.2b is H.
10. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof wherein n is 1, and having the formula: ##STR00078##
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 or 2, or a pharmaceutically acceptable
salt thereof where n is 2, one R.sup.1 is fluoro and the other may
be selected from the group consisting of fluoro, optionally
substituted C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-4
alkoxy and optionally substituted C.sub.2-C.sub.4 alkynyl.
12. The compound of claim 1 or 2, wherein n is 2, and having the
formula: ##STR00079## or pharmaceutically acceptable salt
thereof.
13. The compound of claim 1 or 2 having the formula: ##STR00080##
or a pharmaceutically acceptable salt thereof, wherein R.sup.1 may
be selected from the group consisting of fluoro, optionally
substituted C.sub.1-C.sub.4 alkyl, optionally substituted
C.sub.1-C.sub.4 alkoxy and optionally substituted C.sub.2-C.sub.4
alkynyl.
14. The compound of any one of claims 1-13, wherein R.sup.1 is
hydroxyalkyl (e.g., hydroxymethyl).
15. The compound of claim 1 or 2, selected from the group
consisting of: ##STR00081## or pharmaceutically acceptable salt of
any of the foregoing.
16. The compound of claim 1 or 2, having the formula: ##STR00082##
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 or 2, having the formula: ##STR00083##
or a pharmaceutically acceptable salt thereof.
18. The compound of claim 1 or 2, having the formula: ##STR00084##
or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 or 2, having the formula: ##STR00085##
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 1 or 2, having the formula: ##STR00086##
or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a compound of any one
of claims 1-20, or a pharmaceutically acceptable salt thereof
optionally, and a pharmaceutically acceptable excipient.
22. The pharmaceutical composition of claim 21, wherein compound
has the formula 1a: ##STR00087##
23. The pharmaceutical composition of claim 21, wherein compound
has the formula 1b: ##STR00088##
24. The pharmaceutical composition of claim 21, wherein compound
has the formula 1c: ##STR00089##
25. The pharmaceutical composition of claim 21, wherein the
compound has the formula Id: ##STR00090##
26. The pharmaceutical composition of claim 21, wherein the
compound is selected from the group consisting of: ##STR00091##
27. A method of treating hypertrophic cardiomyopathy (HCM), or a
cardiac disorder having a pathophysiological feature of HCM,
comprising administering to a subject in need thereof an effective
amount of a compound of any one of claims 1-20, or a
pharmaceutically acceptable salt thereof.
28. A method of treating a disease or disorder selected from the
group consisting of 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 one of claims
1-20, or a pharmaceutically acceptable salt thereof.
29. 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 one of claims
1-20, or a pharmaceutically acceptable salt thereof.
30. 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 one of claims 1-20, 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/or 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).
31. Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
characterized by at least one of: a. a powder X-ray diffraction
pattern having two or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees; b. a DSC thermogram showing
endotherms at about 226.05.degree. C., at about 302.47.degree. C.,
and at about 310.13.degree. C.; or c. an X-ray crystal structure
substantially the same as in FIG. 4.
32. The polymorph of claim 31, characterized by a powder X-ray
diffraction pattern having three or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees.
33. The polymorph of claim 31, characterized by a powder X-ray
diffraction pattern having four or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees.
34. The polymorph of claim 31, characterized by a powder X-ray
diffraction having peaks expressed in degrees
2-theta.+-.0.2.degree. at each of 11.3, 12.4, and 13.3 degrees.
35. The polymorph of claim 43, characterized by a powder X-ray
diffraction having peaks expressed in degrees
2-theta.+-.0.2.degree. at each of 11.3, 12.4, 13.3, 16.5, 17.3,
19.3, 20.4, and 29.5 degrees.
36. The polymorph of claim 31, characterized by melt onsets of
about 221.51.degree. C., about 299.53.degree. C., and about
308.81.degree. C.
37. The polymorph of claim 31, wherein the polymorph has a powder
X-ray diffraction pattern substantially the same as in FIG. 1A.
38. The polymorph of any one of claims 31-37, wherein the Form 1
polymorph is substantially free of other forms of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
39. A pharmaceutical composition comprising a polymorph of any one
of claims 31-38, and a pharmaceutically acceptable excipient.
40. The composition of claim 39, wherein the ratio of the amount of
the Form 1 polymorph to the sum of the amounts of other forms is
equal to or greater than 80:20.
41. The composition of claim 39, wherein the ratio of the amount of
the Form 1 polymorph to the sum of the amounts of other forms is
equal to or greater than 90:10.
42. The composition of claim 39, wherein the ratio of the amount of
the Form 1 polymorph to the sum of the amounts of other forms is
equal to or greater than 95:5.
43. The composition of claim 39, wherein the ratio of the amount of
the Form 1 polymorph to the sum of the amounts of other forms is
equal to or greater than 97:3.
44. The composition of claim 39, wherein the ratio of the amount of
the Form 1 polymorph to the sum of the amounts of other forms is
equal to or greater than 98:2.
45. The composition of claim 39, wherein the ratio of the amount of
the Form 1 polymorph to the sum of the amounts of other forms is
equal to or greater than 99:1.
46. A method of treating hypertrophic cardiomyopathy (HCM), or a
cardiac disorder having a pathophysiological feature of HCM,
comprising administering to a subject in need thereof an effective
amount of a polymorph of any one of claims 31-38, or a
pharmaceutical composition of any one of claims 39-45.
47. 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 polymorph of any one of
claims 31-38, or a pharmaceutical composition of any one of claims
39-45.
48. 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 polymorph of any one claims 31-38, or a
pharmaceutical composition of any one of claims 39-45, 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/or 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).
49. A method of treating a cardiac disease or disorder, comprising
administering to a subject in need thereof an effective amount of a
compound of any one of claims 1-20, or a pharmaceutically
acceptable salt thereof, pharmaceutical composition of any one of
claims 21-26, polymorph of any one claims 31-38, or pharmaceutical
composition of any one of claims 39-45, wherein the cardiac disease
or disorder is selected from the group consisting of diastolic
dysfunction, hypertrophic cardiomyopathy, nHCM, oHCM, heart
failure, HFpEF, HFmREF, valvular disease, Aortic Stenosis, left
ventricular hypertrophy, restrictive cardiomyopathy, inflammatory
cardiomyopathy, Loeffler endocarditis, endomyocardial fibrosis,
infiltrative cardiomyopathy, hemochromatosis, Fabry disease,
glycogen storage disease, congenital heart disease, Tetralogy of
Fallot, left ventricular hypertrophy, angina pectoris, refractory
angina pectoris, and Chagas disease.
50. The method of claim 49, wherein the cardiac disease or disorder
is selected from the group consisting of nHCM, oHCM, HFpEF, HFmREF,
Aortic Stenosis, Loeffler endocarditis, endomyocardial fibrosis,
infiltrative cardiomyopathy, hemochromatosis, Fabry disease,
glycogen storage disease, Tetralogy of Fallot, angina pectoris,
refractory angina pectoris, and Chagas disease.
51. The method of any one of claims 49-50, wherein the compound, or
a pharmaceutically acceptable salt thereof, polymorph, or
pharmaceutical composition is administered as a monotherapy.
52. The method of any one of claims 49-50, wherein the compound, or
a pharmaceutically acceptable salt thereof, polymorph, or
pharmaceutical composition is administered as a combination
therapy, wherein an additional therapeutic agent administered.
53. The method of claim 52, wherein the additional therapeutic
agent is selected from the group consisting of beta adrenergic
blocking agent (beta-blocker), renin-angiotensin-aldosterone system
(RAAS) inhibitor (e.g., an angiotensin converting enzyme (ACE)
inhibitor, an angiotensin receptor antagonist, such as an
angiotensin II receptor blocker), an angiotensin receptor
neprilysin inhibitor (ARNI) (e.g., sacubitril/valsartan), a
mineralocorticoid receptor antagonist (MRA) (e.g., an aldosterone
inhibitor such as a potassium-sparing diuretic such as eplerenone,
spironolactone, or canrenone), a cholesterol lowering drug (e.g., a
statin), a neutral endopeptidase inhibitor (NEPi), a positive
inotropic agent (e.g., digoxin, pimobendane, a beta adrenergic
receptor agonist such as dobutamine, a phosphodiesterase (PDE)-3
inhibitor such as milrinone, or a calcium-sensitizing agent such as
levosimendan), potassium, magnesium, a proprotein convertase
subtilisin kexin-type 9 (PCSK9) inhibitor, a vasodilator (e.g., a
calcium channel blocker, phosphodiesterase inhibitor, endothelin
receptor antagonist, renin inhibitor, or smooth muscle myosin
modulator), a diuretic (e.g., furosemide), an arrhythmia
medication, an anticoagulant (e.g., warfarin), an antithrombotic
agent, an antiplatelet agent, a sodium-glucose cotransporter 2
inhibitor (SGLT2) (e.g., empaglifozin, dapagliflozin,
sotagliflozin) or any combination thereof.
54. The method of claim 53, wherein the angiotensin II receptor
blocker (ARB) is selected from the group consisting of A-81988,
A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698,
candesartan, candesartan cilexetil, CGP-38560 .ANG., CGP-48369,
CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811,
DuP-167, DuP-532, E-4177, elisartan, EMD-66397, EMD-73495,
eprosartan, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803,
EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888,
ICI-D7155, ICI-D8731, irbesartan, isoteoline, KRI-1177, KT3-671,
KW-3433, losartan, LR-B/057, L-158809, L-158978, L-159282,
L-159874, L-161177, L-162154, L-163017, L-159689, L-162234,
L-162441, L-163007, LR-B/081, LR B087, LY-285434, LY-302289,
LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304,
PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin
acetate, S-8307, S-8308, SC-52458, saprisartan, saralasin,
sarmesin, SL-91.0102, tasosartan, telmisartan, UP-269-6, U-96849,
U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360,
X-6803, valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155,
ZD-8731, and zolasartan.
55. The method of claim 53, wherein the ARNI is selected from the
group consisting of sacubitril, valsartan, or a combination of
sacubitril and valsartan (sacubitril/valsartan).
56. The method of claim 53, wherein the SGLT2 is selected from the
group consisting of empaglifozin, dapagliflozin, and
sotagliflozin.
57. The method of claim 52, wherein the additional therapeutic
agent improves cardiovascular conditions in the subject.
58. The method of any one of claims 52, 53, and 57, wherein the
additional therapeutic agent is selected from the group consisting
of a beta blocker, a diuretic, an angiotensin-converting enzyme
(ACE) inhibitor, a calcium channel blocker, an angiotensin II
receptor blocker, a mineralocorticoid receptor antagonist, an ARNI,
a RAAS inhibitor, an arrhythmia medication, and a SGLT2 inhibitor.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. .sctn.
119(e) to U.S. Provisional Application Ser. No. 62/752,278, filed
Oct. 29, 2018, entitled "Tetrahydropyran (THP)-Substituted
Bicyclic-Pyrimidinedione Compounds," which is incorporated herein
by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] 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.
[0003] 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.
[0004] 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 and 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.
[0005] 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. The
present disclosure provides new therapeutic agents and methods that
remedy the long-felt need for improved treatment of HCM and related
cardiac disorders and/or diseases.
BRIEF SUMMARY OF THE INVENTION
[0006] In one aspect, provided is a compound having formula
(I):
##STR00001##
[0007] or a pharmaceutically acceptable salt thereof, wherein
[0008] the subscript n is 1 or 2;
each R.sup.1 is a member selected from the group consisting of
fluoro, chloro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.2-C.sub.4 alkynyl; wherein at least one R.sup.1 is fluoro;
and one of R.sup.2a and R.sup.2b is fluoro and the other of
R.sup.2a and R.sup.2b is H.
[0009] In one aspect, provided is a compound having formula
(I):
##STR00002##
[0010] or a pharmaceutically acceptable salt thereof, wherein
[0011] the subscript n is 1 or 2;
each R.sup.1 is a member selected from the group consisting of
fluoro, chloro, optionally substituted C.sub.1-C.sub.4 alkyl,
optionally substituted C.sub.1-C.sub.4 haloalkyl, optionally
substituted C.sub.1-C.sub.4 alkoxy, optionally substituted
C.sub.1-C.sub.4 haloalkoxy, and optionally substituted
C.sub.2-C.sub.4 alkynyl; wherein at least one R.sup.1 is fluoro;
and one of R.sup.2a and R.sup.2b is fluoro and the other of
R.sup.2a and R.sup.2b is H.
[0012] In another aspect, provided is Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ("Form
1 polymorph"). In another aspect, the Form 1 polymorph is
characterized by at least one of: [0013] a. a powder X-ray
diffraction pattern having two or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees; [0014] b. a DSC thermogram
showing endotherms at about 226.05.degree. C., at about
302.47.degree. C., and at about 310.13.degree. C.; or [0015] c. an
X-ray crystal structure substantially the same as in FIG. 4.
[0016] In another aspect, the disclosure provides a pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof as described herein and
optionally a pharmaceutically acceptable excipient.
[0017] In some aspects, the present disclosure provides a method of
treating a cardiac disease or disorder in a subject in need
thereof, comprising administering to the subject an effective
amount of a compound described herein. In certain aspects,
diastolic dysfunction is a feature of and/or associated with the
cardiac disease or disorder. For instance, the cardiac disease or
disorder may be cardiomyopathy (e.g., hypertrophic cardiomyopathy),
heart failure (e.g., heart failure with preserved ejection
fraction, heart failure with midrange ejection fraction), valvular
disease (e.g., valvular aortic stenosis), congenital heart disease
(e.g., Tetralogy of Fallot), left ventricular hypertrophy, angina
pectoris (e.g., refractory angina pectoris), or Chagas disease.
[0018] In certain aspects, the present disclosure provides methods
of treating a cardiac disease or disorder, comprising administering
to a subject in need thereof an effective amount of a compound as
described herein, or a pharmaceutically acceptable salt thereof,
pharmaceutical composition as described herein, or polymorph as
described herein, wherein the cardiac disease or disorder is
selected from the group consisting of diastolic dysfunction,
hypertrophic cardiomyopathy, nHCM, oHCM, heart failure, HFpEF,
HFmREF, valvular disease, Aortic Stenosis, left ventricular
hypertrophy, restrictive cardiomyopathy, inflammatory
cardiomyopathy, Loeffler endocarditis, endomyocardial fibrosis,
infiltrative cardiomyopathy, hemochromatosis, Fabry disease,
glycogen storage disease, congenital heart disease, Tetralogy of
Fallot, left ventricular hypertrophy, angina pectoris, refractory
angina pectoris, and Chagas disease. In certain aspects, the
cardiac disease or disorder is selected from the group consisting
of nHCM, oHCM, HFpEF, HFmREF, Aortic Stenosis, Loeffler
endocarditis, endomyocardial fibrosis, infiltrative cardiomyopathy,
hemochromatosis, Fabry disease, glycogen storage disease, Tetralogy
of Fallot, angina pectoris, refractory angina pectoris, and Chagas
disease.
[0019] In some aspects, the present disclosure provides methods of
treating a cardiac disease or disorder, comprising administering to
a subject in need thereof an effective amount of a compound as
described herein, or a pharmaceutically acceptable salt thereof,
pharmaceutical composition as described herein, or polymorph as
described herein, wherein the compound, or pharmaceutically
acceptable salt thereof, polymorph, or pharmaceutical composition
is administered as a monotherapy.
[0020] In some aspects, the present disclosure provides methods of
treating a cardiac disease or disorder, comprising administering to
a subject in need thereof an effective amount of a compound as
described herein, or a pharmaceutically acceptable salt thereof,
pharmaceutical composition as described herein, or polymorph as
described herein, wherein the compound, or pharmaceutically
acceptable salt thereof, polymorph, or pharmaceutical composition
is administered as a combination therapy, wherein an additional
therapeutic agent administered. In certain aspects, the additional
therapeutic agent is selected from the group consisting of beta
adrenergic blocking agent (beta-blocker),
renin-angiotensin-aldosterone system (RAAS) inhibitor (e.g., an
angiotensin converting enzyme (ACE) inhibitor, an angiotensin
receptor antagonist, such as an angiotensin II receptor blocker),
an angiotensin receptor neprilysin inhibitor (ARNI) (e.g.,
sacubitril/valsartan), a mineralocorticoid receptor antagonist
(MRA) (e.g., an aldosterone inhibitor such as a potassium-sparing
diuretic such as eplerenone, spironolactone, or canrenone), a
cholesterol lowering drug (e.g., a statin), a neutral endopeptidase
inhibitor (NEPi), a positive inotropic agent (e.g., digoxin,
pimobendane, a beta adrenergic receptor agonist such as dobutamine,
a phosphodiesterase (PDE)-3 inhibitor such as milrinone, or a
calcium-sensitizing agent such as levosimendan), potassium,
magnesium, a proprotein convertase subtilisin kexin-type 9 (PCSK9)
inhibitor, a vasodilator (e.g., a calcium channel blocker,
phosphodiesterase inhibitor, endothelin receptor antagonist, renin
inhibitor, or smooth muscle myosin modulator), a diuretic (e.g.,
furosemide), an arrhythmia medication, an anticoagulant (e.g.,
warfarin), an antithrombotic agent, an antiplatelet agent, a
sodium-glucose cotransporter 2 inhibitor (SGLT2) (e.g.,
empaglifozin, dapagliflozin, sotagliflozin) or any combination
thereof. In some aspects, the additional therapeutic is an
angiotensin II receptor blocker (ARB) which is selected from the
group consisting of A-81988, A-81282, BIBR-363, BIBS39, BIBS-222,
BMS-180560, BMS-184698, candesartan, candesartan cilexetil,
CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194,
DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, E-4177, elisartan,
EMD-66397, EMD-73495, eprosartan, EXP-063, EXP-929, EXP-3174,
EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021,
HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan, isoteoline,
KRI-1177, KT3-671, KW-3433, losartan, LR-B/057, L-158809, L-158978,
L-159282, L-159874, L-161177, L-162154, L-163017, L-159689,
L-162234, L-162441, L-163007, LR-B/081, LR B087, LY-285434,
LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan,
PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458,
saralasin acetate, S-8307, S-8308, SC-52458, saprisartan,
saralasin, sarmesin, SL-91.0102, tasosartan, telmisartan, UP-269-6,
U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472,
WK-1360, X-6803, valsartan, XH-148, XR-510, YM-358, ZD-6888,
ZD-7155, ZD-8731, and zolasartan. In some aspects, the additional
therapeutic is an ARNI which is selected from the group consisting
of sacubitril, valsartan, or a combination of sacubitril and
valsartan (sacubitril/valsartan). In some aspects, the additional
therapeutic is a SGLT2 which is selected from the group consisting
of empaglifozin, dapagliflozin, and sotagliflozin. In some aspects,
the additional therapeutic agent improves cardiovascular conditions
in the subject. In certain aspects, the additional therapeutic
agent is selected from the group consisting of a beta blocker, a
diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a
calcium channel blocker, an angiotensin II receptor blocker, a
mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor,
an arrhythmia medication, and a SGLT2 inhibitor.
[0021] In another aspect, the disclosure provides a method of
preventing or treating a disease or disorder in which diastolic
dysfunction is present or is an important feature, including, but
not limited to, hypertrophic cardiomyopathy (HCM), or a cardiac
disorder having a pathophysiological feature of HCM, or a symptom
thereof. The method includes administering to a subject in need
thereof an effective amount of a compound of formula (I) or
pharmaceutically acceptable salt thereof. In yet another aspect,
the disease is selected from the group consisting of obstructive
HCM, non-obstructive HCM, heart failure with preserved ejection
fraction (HFpEF) (including, but not limited to, diabetic HFpEF)
and hypertension. The disease may be acute, chronic and/or stable.
In yet another aspect, the disease is selected from the group
consisting of Class I HCM, Class II nHCM, Class III nHCM, Class II
oHCM and Class III oHCM.
[0022] In another aspect, the disclosure provides a method of
preventing or treating a disease or disorder selected from the
group consisting of 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 formula (I), or a
pharmaceutically acceptable salt thereof.
[0023] In another aspect, the disclosure provides a method of
preventing or treating a disease or disorder in which left
ventricular hypertrophy due to volume or pressure overload is a
feature of the disease, 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
formula (I), or a pharmaceutically acceptable salt thereof.
[0024] In another aspect, the disclosure provides a method of
preventing or treating hypertrophic cardiomyopathy (HCM) or a
cardiac disorder having a pathophysiological feature associated
with HCM, or symptoms thereof, comprising administering to a
subject in need thereof an effective amount of a compound of
formula (I), 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). The HCM may
be obstructive HCM (oHCM) or non-obstructive HCM (nHCM).
[0025] In another aspect, provided is a pharmaceutical composition
comprising Form 1 polymorph, and a pharmaceutically acceptable
excipient.
[0026] In another aspect, provided is a method of treating
hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a
pathophysiological feature of HCM, comprising administering to a
subject in need thereof an effective amount of Form 1 polymorph, or
a pharmaceutical composition comprising Form 1 polymorph.
[0027] In another aspect, provided is 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 Form 1 polymorph, or a pharmaceutical composition
comprising Form 1 polymorph.
[0028] In another aspect, provided is 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
Form 1 polymorph, or a pharmaceutical composition comprising Form 1
polymorph, 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/or 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
disclosure is intended to include all isotopically labeled analogs
of the compounds of formula (I). Isotopes include those atoms
having the same atomic number but different mass. For example,
isotopes of hydrogen include .sup.2H(D) and .sup.3H(T) and isotopes
of carbon include .sup.13C and .sup.14C. Isotopically labeled
compounds of formula (I) can be prepared according to methods
commonly known in the art. Such compounds have various uses as, but
not limit to, standards and reagents in determining
biological/pharmacological activities. For those stable
isotopically labeled compounds of formula (I), they can also
favorably modulate biological, pharmacological, or pharmacokinetic
properties.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIGS. 1A to 1C show X-ray Powder Diffraction (XRPD) data for
Form 1 polymorph of the compound of Example 1-3 (also referred to
as compound 3).
[0030] FIG. 2 shows Dynamic Scanning Calorimetry (DSC) plot for
Form 1 polymorph of the compound of Example 1-3 (also referred to
as compound 3).
[0031] FIG. 3 shows Thermo Gravimetric Analysis (TGA) for Form 1
polymorph of the compound of Example 1-3 (also referred to as
compound 3).
[0032] FIG. 4 shows crystal structure of Form 1 polymorph of the
compound of Example 1-3 (also referred to as compound 3) obtained
by single crystal X-ray diffraction.
DETAILED DESCRIPTION OF THE INVENTION
[0033] A series of tetrahydropyran (THP)-substituted bicyclic
pyrimidinedione compounds has been found to reduce excess
contractility in hypercontractile states and/or promote cardiac
relaxation in hearts with diastolic dysfunction. Without being
bound by theory, it is believed that these compounds stabilize 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. Preferred compounds of the disclosure have
been optimally designed to have a relatively short half-life in
humans. For instance, certain compounds of the disclosure are
projected to have a half-life of less than 7 days (e.g., less than
5 days, less than 4 days) in humans. The compounds, described
herein, have been designed to have a reduced occurrence of reactive
metabolites upon testing, reduced dependence on polymorphic CYP
enyzmes (such as CYP 2C19) and/or no or reduced risk of CYP
induction (such as CYP3A4 induction). Some other benefits of
compounds of the disclosure relate to selectivity of inhibition of
cardiac myosin as compared to skeletal myosin and/or desirable
time-course of effect intensity in response to administration of a
drug dose. Furthermore, compounds of the disclosure have beneficial
solubility, for example at pH 7.4 a micromolar solubility of over
50, such as over 70. In some cases, the compounds of the disclosure
have a micromolar solubility of over 80, such as over 90. The
compounds can also be used to treat other cardiac disorders.
[0034] The term "about" as used herein is used to describe a range
(e.g., of temperatures, of mass, of weight) and is given its
ordinary meaning in the art, typically referring to the error
associated with an instrument to collect a measurement or reading.
In general, the term "about" when referring to temperature provides
a deviation of 0-2.degree. C.
[0035] 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.2-3, C.sub.2-4 and
C.sub.3-4. For example, C.sub.1-4 alkyl includes, but is not
limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl and tert-butyl. In some instances, alkyl groups are
optionally substituted. In some instances, alkyl groups are
unsubstituted. In some aspects, alkyl groups are substituted. Alkyl
group substituents include, but are not limited to, any of the
substituents described herein, that result in the formation of a
stable moiety. In certain aspects, the substituent may be one or
more hydroxy group. In some such cases, the alkyl group may also be
referred to as a hydroxyalkyl group. As used herein, the term
"hydroxyalkyl" refers to an alkyl group as provided above, wherein
at least one hydrogen atom of the hydrocarbon portion is replaced
by a hydroxy group (--OH). Accordingly, "hydroxyalkyl" refers to,
for example, hydroxymethyl, 2-hydroxyethyl and 2-hydroxypropyl.
[0036] As used herein, the term "alkynyl" refers to an alkyl group
that contains one or more triple bonds in the straight or branched
aliphatic radical. The one or more carbon-carbon triple bonds can
be internal (such as in 2-butynyl) or terminal (such as in
1-butynyl). Examples of alkynyl groups include, without limitation,
ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the
like. Alkynyl groups may be substituted or unsubstituted.
[0037] As used herein, the term "cycloalkyl" refers to a saturated
or partially unsaturated, monocyclic ring containing from 3 or 4
ring atoms, or the number of atoms indicated. Saturated monocyclic
cycloalkyl rings include, for example, cyclopropyl or cyclobutyl.
Cycloalkyl groups can also be partially unsaturated, having one or
more double bonds in the ring. Representative cycloalkyl groups
that are partially unsaturated include cyclobutene. Unless
otherwise stated, cycloalkyl groups are unsubstituted.
[0038] 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 portions, alkoxy
groups can have any suitable number of carbon atoms, such as
C.sub.1-2 or C.sub.1-4. Alkoxy groups include, for example,
methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy,
iso-butoxy, sec-butoxy, tert-butoxy, etc. Alkoxy groups may be
optionally substituted (unsubstituted or substituted).
[0039] As used herein, the terms "halo" and "halogen" refer to
fluorine, chlorine, bromine and iodine.
[0040] As used herein, the terms "haloalkyl" and "haloalkoxy"
refers to the alkyl and alkoxy groups as provided above, wherein at
least one hydrogen atom of the hydrocarbon portion is replaced by a
halogen atom. Additionally, the terms can also refer to a
per-halogenated form of alkyl and alkoxy. Accordingly, "haloalkyl"
refers to, for example, fluoromethyl, difluoromethyl,
trifluoromethyl, 2,2,2-trifluoroethyl, and chloromethyl. Similarly,
"haloalkoxy" refers to, for example, difluoromethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy, and chloromethoxy.
[0041] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example,
"C.sub.1-6 alkyl" is intended to encompass, C.sub.1, C.sub.2,
C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5,
C.sub.1-4, C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4,
C.sub.2-3, C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5,
and C.sub.5-6 alkyl.
[0042] It will be appreciated that the above groups and/or
compounds, as described herein, may be optionally substituted with
any number of substituents or functional moieties. That is, any of
the above groups may be optionally substituted. As used herein the
term "optionally substituted" is contemplated to include
unsubstituted variants and/or substituted variants (i.e.,
"optionally substituted" may be used interchangeably with
"substituted or unsubstituted"). As used herein, the term
"substituted" is contemplated to include all permissible
substituents of organic compounds, "permissible" being in the
context of the chemical rules of valence known to those of ordinary
skill in the art. In general, the term "substituted" whether
preceded by the term "optionally" or not, and substituents
contained in formulas of this disclosure, refer to the replacement
of hydrogen radicals in a given structure with the radical of a
specified substituent. When more than one position in any given
structure may be substituted with more than one substituent
selected from a specified group, the substituent may be either the
same or different at every position. It will be understood that
"substituted" also includes that the substitution results in a
stable compound, e.g., which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
etc. In some cases, "substituted" may generally refer to
replacement of a hydrogen with a substituent as described herein.
However, "substituted," as used herein, does not encompass
replacement and/or alteration of a key functional group by which a
molecule is identified, e.g., such that the "substituted"
functional group becomes, through substitution, a different
functional group. For example, a "substituted phenyl group" must
still comprise the phenyl moiety and cannot be modified by
substitution, in this definition, to become, e.g., a pyridine ring.
In a broad aspect, the permissible substituents include acyclic and
cyclic, branched and unbranched, carbocyclic and heterocyclic,
aromatic and nonaromatic substituents of organic compounds.
Illustrative substituents include, for example, those described
herein. The permissible substituents can be one or more and the
same or different for appropriate organic compounds. For purposes
of this disclosure, the heteroatoms such as nitrogen may have
hydrogen substituents and/or any permissible substituents of
organic compounds described herein which satisfy the valences of
the heteroatoms. Furthermore, this disclosure is not intended to be
limited in any manner by the permissible substituents of organic
compounds. The term "stable," as used herein, preferably refers to
compounds which possess stability sufficient to allow manufacture
and which maintain the integrity of the compound for a sufficient
period of time to be detected and preferably for a sufficient
period of time to be useful for the purposes detailed herein.
[0043] Examples of substituents include, but are not limited to,
halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,
hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,
phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether,
alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,
heterocyclyl, aromatic or heteroaromatic moieties, --CF3, --CN,
aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy,
heteroarylalkyl, heteroaralkoxy, azido, amino, halide, alkylthio,
nitrido, acylalkyl, carboxy esters, -carboxamido, acyloxy,
aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl,
arylamino, aralkylamino, alkylsulfonyl, -carboxamidoalkylaryl,
-carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-,
aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl,
arylalkyloxyalkyl, and the like.
[0044] As used herein, the term "pharmaceutically acceptable"
refers to to those compounds, materials, compositions, and/or
dosage forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio. A pharmaceutically acceptable substance may be
compatible with a compound of formula (I), as well as with any
other ingredients with which the compound is formulated.
[0045] As used herein, the term "salt" refers to an acid or base
salt of a compound of formula (I). Pharmaceutically acceptable
salts can be derived, for example, from mineral acids (e.g.,
hydrochloric acid, hydrobromic acid, phosphoric acid, and the
like), organic acids (e.g., 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.
[0046] Certain aspects of the present compounds may contain one or
more basic functional groups and, thus, are capable of forming
pharmaceutically-acceptable salts with pharmaceutically-acceptable
acids. In such cases, the pharmaceutically-acceptable salts may be
relatively non-toxic, inorganic and organic acid addition salts of
compounds of the present disclosure. These salts can be prepared in
situ in the administration vehicle or the dosage form manufacturing
process, or by separately reacting a purified compound of the
disclosure in its free base form with a suitable organic or
inorganic acid, and isolating the salt thus formed during
subsequent purification. Non-limiting examples of salts include the
hydrobromide, hydrochloride, sulfate, bisulfate, phosphate,
nitrate, acetate, valerate, oleate, palmitate, stearate, laurate,
benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, napthylate, mesylate, glucoheptonate,
lactobionate, and laurylsulphonate salts and the like. (See, for
example, Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977,
66, 1-19)
[0047] The pharmaceutically acceptable salts of the compounds,
described herein, include the nontoxic salts or quaternary ammonium
salts of the compounds, e.g., from non-toxic organic or inorganic
acids. For example, such nontoxic salts include those derived from
inorganic acids such as hydrochloride, hydrobromic, sulfuric,
sulfamic, phosphoric, nitric, and the like; and the salts prepared
from organic acids such as acetic, propionic, succinic, glycolic,
stearic, lactic, malic, tartaric, citric, ascorbic, palmitic,
maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic,
sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isothionic, and the
like.
[0048] In some cases, the compounds of the present disclosure may
contain one or more acidic functional groups and, thus, are capable
of forming pharmaceutically-acceptable salts with
pharmaceutically-acceptable bases. In such cases, the
pharmaceutically-acceptable salts may be relatively non-toxic,
inorganic and organic base addition salts of compounds of the
present disclosure. These salts can likewise be prepared in situ in
the administration vehicle or the dosage form manufacturing
process, or by separately reacting the purified compound in its
free acid form with a suitable base, such as the hydroxide,
carbonate or bicarbonate of a pharmaceutically-acceptable metal
cation, with ammonia, or with a pharmaceutically-acceptable organic
primary, secondary or tertiary amine. Non-limiting examples of
alkali or alkaline earth salts include the lithium, sodium,
potassium, calcium, magnesium, and aluminum salts and the like.
Non-limiting examples of organic amines useful for the formation of
base addition salts include ethylamine, diethylamine,
ethylenediamine, ethanolamine, diethanolamine, piperazine and the
like.
[0049] Additional information on suitable pharmaceutically
acceptable salts can be found in Remington's Pharmaceutical
Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985 and
Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66,
1-19, which are incorporated herein by reference.
[0050] 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. The parent form of the
compound may differ from the various salt forms in certain physical
properties, such as solubility in polar solvents.
[0051] Certain compounds of the present disclosure possess
asymmetric carbon atoms (chiral centers) or double bonds; the
racemates, diastereomers, geometric isomers, regioisomers and
individual isomers (e.g., separate enantiomers) are all intended to
be encompassed within the scope of the present disclosure. When a
stereochemical depiction is shown, it is meant to refer to the
compound in which one of the isomers is present and substantially
free of other isomers. `Substantially free of` other isomers
indicates that at least about 80% of the disclosed isomer should be
present, based on a molar amount of all isomeric forms of the
disclosed isomer present, more preferably at least about 90%, such
as about 95% or more. The depicted isomer may be present in an
amount of at least about 99%. For example, when a disclosed isomer
is provided in a pharmaceutical composition, the composition may
comprise at least about 99% of said disclosed isomer in the
pharmaceutical composition, based on a total molar amount of all
isomeric forms of the disclosed compound present in the
pharmaceutical composition (including the disclosed isomeric form
and all other isomeric forms).
[0052] As used herein, the term "pharmaceutical composition" refers
to a product comprising a mixture of the compound of formula (I)
and one or more other chemical components. The pharmaceutical
composition may comprise an excipient as defined herein, and/or
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.
[0053] As used herein, the term "excipient" refers to a substance
that aids the administration of an active agent to a subject.
Pharmaceutical excipients useful in the present disclosure 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 in
the present disclosure.
[0054] 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 a disease or disorder (for example a cardiac disorder having a
pathophysiological feature of HCM), 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; or decreasing the frequency or duration
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.
[0055] As used herein, the terms "prevent," "preventing," or
"prevention" refers to a prophylactic treatment of a subject who
does not and did not have a pathology, injury, condition, or
symptom related to a disease or disorder (for example a cardiac
disorder having a pathophysiological feature of HCM) but is at risk
of developing the pathology, injury, condition, or symptom or who
was with a pathology, injury, condition, or symptom, is not with
the pathology, injury, condition, or symptom, but is at risk of
regression of the pathology, injury, condition, or symptom. In
certain aspects, the subject is at a higher risk of developing the
pathology, injury, condition, or symptom or at a higher risk of
regression of the pathology, injury, condition, or symptom than an
average healthy member of a population. In some aspects, preventing
refers to the prevention of the onset of the pathology, injury,
condition, or symptom.
[0056] An "effective amount" or a "pharmaceutically effective
amount" is an amount sufficient to accomplish a stated purpose
(e.g. achieve the effect for which it is administered, treat a
disease, reduce enzyme activity, reduce one or more symptoms of a
disease or condition, reduce viral replication in a cell). An
example of an "effective amount" is an amount sufficient to
contribute to the treatment, or reduction of a symptom or symptoms
of a disease, which could also be referred to as a "therapeutically
effective amount." A "reduction" of a symptom or symptoms (and
grammatical equivalents of this phrase) means decreasing of the
severity or frequency of the symptom(s), or elimination of the
symptom(s).
[0057] A "subject" to which administration is contemplated refers
to a human (i.e., male or female of any age group, e.g., pediatric
subject (e.g., infant, child, or adolescent) or adult subject
(e.g., young adult, middle-aged adult, or senior adult)) or
non-human animal. A "patient" refers to a human subject in need of
treatment of a disease.
[0058] Hypertrophic cardiomyopathy (HCM) is identified clinically
as unexplained left ventricular (LV) hypertrophy in the absence of
known causes such as pressure overload, systemic diseases, or
infiltrative processes. One phenotypic hallmark of HCM is
myocardial hypercontractility accompanied by reduced LV compliance,
reflected clinically as reduced ventricular chamber size, often
supranormal ejection fraction, increased wall thickness, and
diastolic dysfunction. Some of the symptoms and signs that HCM
patients have include, but are not limited to, shortness of breath
(especially during exercise), chest pain (especially during
exercise), fainting (especially during or just after exercise),
sensation of rapid, fluttering or pounding heartbeats, and heart
murmur.
[0059] Obstructive HCM (oHCM), also known as hypertrophic
obstructive cardiomyopathy (HOCM), refers to HCM in the presence of
left ventricular outflow tract obstruction (LVOT).
[0060] Non-obstructive HCM (nHCM) refers to HCM without outflow
tract obstruction at rest or upon provocation.
[0061] Heart failure refers to a clinical syndrome that a patient's
heart is unable to provide an adequate supply of blood to the body.
For some people with heart failure, the heart has difficulty
pumping enough blood to support other organs in the body. For
others, they may have a hardening and stiffening of the heart
muscle itself, which blocks or reduces blood flow to the heart.
Heart failure can affect the right or left side of the heart, or
both at the same time. It can be either an acute (short-term) or
chronic (ongoing) condition. Symptoms of heart failure include, but
are not limited to, excessive fatigue, sudden weight gain, a loss
of appetite, persistent coughing, irregular pulse, heart
palpitations, abdominal swelling, shortness of breath, leg and
ankle swelling, protruding neck veins and edema.
[0062] Heart failure with preserved ejection fraction (HFpEF), also
called diastolic heart failure or diastolic failure refers to heart
failure when the heart's ejection fraction is normal (e.g., equal
to or greater than 50 percent). Often, heart muscle contracts
normally but the ventricles do not relax as they should during
ventricular filling, leading to reduced stroke volume.
[0063] Stable Diastolic Heart Failure refers to patients with
disastolic heart failure who are not having an acute worsening of
symptoms. These patients have impaired diastolic function, wherein
symptoms can be controlled or stabilized using available
therapies.
[0064] Diastolic dysfunction refers to abnormal diastole function.
Abnormal diastolic function includes impaired left ventricle
relaxation, filling, diastolic distensibility, or stiffness. These
traits can be measured using echocardiography. Further determining
factors for diagnosing diastolic dysfunction using echocardiography
are described in J Am Soc Echocardiogr. 29(4):277-314 (2016), the
contents of which are incorporated by reference. Left ventricle
stiffness can be measured by cardiac magnetic resonance. Cardiac
magnetic resonance is used to determine peak filling rate, time to
peak filling, and peak diastolic strain rate. Subjects with
diastolic dysfunction may also display increased levels of
biomarkers in the blood. For example, brain natriuretic peptide
(BNP) or N-terminal-pro-brain natriuretic peptide (NT-pro BNP) are
present at elevated levels in the blood of individuals with
diastolic dysfunction.
[0065] Diastolic dysfunction is present or an important feature of
a series of diseases including, but not limited to, hypertrophic
cardiomyopathy (HCM), heart failure with preserved ejection
fraction (HFpEF)--including both disorders of active relaxation and
disorders of chamber stiffness (e.g., diabetic HFpEF); ischemic
cardiomyopathy, cardiac transplant allograft vasculopathy,
restrictive cardiomyopathy (e.g., genetic mutations in one or more
sarcomeric protein), inflammatory cardiomyopathy (e.g., Loefilers
and EMF), infiltrative cardiomyopathy (e.g., amyloid, sarcoid and
XRT), storage diseases (e.g., hemochromatosis, Fabry and glycogen
storage disease, congenital heart disease (e.g.,
pressure-overloaded RV, Tetrology of Fallot (e.g., diastolic
dysfunction pre-op and early post-op), and valvular heart disease
(e.g., aortic stenosis).
[0066] Class I HCM refers to HCM which is Class I according to the
New York Heart Association (NYHA).
[0067] Class II-III nHCM Refers to nHCM which is Class II or Class
III according to the NYHA
[0068] Class II-III oHCM Refers to oHCM which is Class II or Class
III according to the NYHA
[0069] NYHA Class I refers to a classification wherein a patient or
subject has no limitation of physical activity and ordinary
physical activity does not cause undue fatigue, palpitation,
dyspnea (shortness of breath).
[0070] NYHA Class II refers to a classification wherein a patient
or subject has slight limitation of physical activity, is
comfortable at rest, and ordinary physical activity results in
fatigue, palpitation, dyspnea (shortness of breath).
[0071] NYHA Class III refers to a classification wherein a patient
or subject has marked limitation of physical activity, is
comfortable at rest, and less than ordinary activity causes
fatigue, palpitation, or dyspnea.
[0072] NYHA Class IV refers to a classification wherein a patient
or subject is unable to carry on any physical activity without
discomfort with symptoms of heart failure at rest, and if any
physical activity is undertaken, discomfort increases
[0073] As used herein "Valsalva gradient" refers to the pressure
gradient across LVOT in an individual while this individual is
performing a Valsalva maneuver.
III. COMPOUNDS
[0074] In one aspect, provided herein is a compound having formula
(I):
##STR00003## [0075] or a pharmaceutically acceptable salt thereof,
wherein [0076] the subscript n is 1 or 2; [0077] each R.sup.1 is a
member independently selected from the group consisting of fluoro,
chloro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.2-C.sub.4 alkynyl; wherein at least one R.sup.1 is fluoro;
and one of R.sup.2a and R.sup.2b is fluoro and the other of
R.sup.2a and R.sup.2b is H. [0078] R.sup.2a may be fluoro. R.sup.2b
may be fluoro. R.sup.2a may be fluoro when n is 1. R.sup.2a may be
fluoro when n is 2. R.sup.2b may be fluoro when n is 1. R.sup.2b
may be fluoro when n is 2.
[0079] In one aspect, provided herein is a compound having formula
(I):
##STR00004## [0080] or a pharmaceutically acceptable salt thereof,
wherein [0081] the subscript n is 1 or 2; [0082] each R.sup.1 is a
member independently selected from the group consisting of fluoro,
chloro, optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 haloalkyl, optionally substituted
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.1-C.sub.4
haloalkoxy, and optionally substituted C.sub.2-C.sub.4 alkynyl;
wherein at least one R.sup.1 is fluoro; and one of R.sup.2a and
R.sup.2b is fluoro and the other of R.sup.2a and R.sup.2b is H.
[0083] R.sup.2a may be fluoro. R.sup.2b may be fluoro. R.sup.2a may
be fluoro when n is 1. R.sup.2a may be fluoro when n is 2. R.sup.2b
may be fluoro when n is 1. R.sup.2b may be fluoro when n is 2.
[0084] A pharmaceutically acceptable salt of such compounds of
formula (I) is also provided.
[0085] In certain aspects, the compound of formula (I) may have the
formula:
##STR00005## [0086] or a pharmaceutically acceptable salt thereof,
wherein the subscript n is 1; and [0087] the R.sup.1 is a member
independently selected from the group consisting of fluoro, chloro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy, and C.sub.2-C.sub.4 alkynyl;
and one of R.sup.2a and R.sup.2b is fluoro and the other of
R.sup.2a and R.sup.2b is H.
[0088] In certain aspects, the compound of formula (I) may have the
formula:
##STR00006## [0089] or a pharmaceutically acceptable salt thereof,
wherein the subscript n is 1; and [0090] the R.sup.1 is a member
independently selected from the group consisting of fluoro, chloro,
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 haloalkyl, optionally substituted
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.1-C.sub.4
haloalkoxy, and optionally substituted C.sub.2-C.sub.4 alkynyl; and
one of R.sup.2a and R.sup.2b is fluoro and the other of R.sup.2a
and R.sup.2b is H.
[0091] In some instances, n of the compound of formula (I) is 1.
The compound of formula (I) may have the formula:
##STR00007##
One of R.sup.2a and R.sup.2b is fluoro and the other of R.sup.2a
and R.sup.2b is H.
[0092] A pharmaceutically acceptable salt of such compounds of
formula (Ib) is also provided.
[0093] In some instances, n of the compound of formula (I) is 2. In
some instances where n is 2, one R.sup.1 is fluoro and the other
may be selected from the group consisting of fluoro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.2-C.sub.4
alkynyl; optionally fluoro, methyl, methoxy and ethynyl
(--C.ident.CH), optionally methyl, methoxy and ethynyl
(--C.ident.CH).
[0094] In some instances, n of the compound of formula (I) is 2. In
some instances where n is 2, one R.sup.1 is fluoro and the other
may be selected from the group consisting of fluoro, optionally
substituted C.sub.1-C.sub.4 alkyl, optionally substituted
C.sub.1-C.sub.4 alkoxy, and optionally substituted C.sub.2-C.sub.4
alkynyl; optionally fluoro, methyl, methoxy and ethynyl
(--C.ident.CH), optionally methyl, methoxy and ethynyl
(--C.ident.CH).
[0095] The compound of formula (I) may have the formula:
##STR00008## [0096] One of R.sup.2a and R.sup.2b is fluoro and the
other of R.sup.2a and R.sup.2b is H; and [0097] each R.sup.1 is a
member independently selected from the group consisting of fluoro,
chloro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.2-C.sub.4 alkynyl.
[0098] The compound of formula (I) may have the formula:
##STR00009## [0099] One of R.sup.2a and R.sup.2b is fluoro and the
other of R.sup.2a and R.sup.2b is H; and [0100] each R.sup.1 is a
member independently selected from the group consisting of fluoro,
chloro, optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 haloalkyl, optionally substituted
C.sub.1-C.sub.4 alkoxy, optionally substituted C.sub.1-C.sub.4
haloalkoxy, and optionally substituted C.sub.2-C.sub.4 alkynyl.
[0101] In some instances, for formula (I) one R.sup.1 is fluoro and
the other may be selected from the group consisting of fluoro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, and C.sub.2-C.sub.4
alkynyl; optionally fluoro, methyl, methoxy and ethynyl
(--C.ident.CH), optionally methyl, methoxy and ethynyl
(--C.ident.CH).
[0102] In some instances, for formula (I) one R.sup.1 is fluoro and
the other may be selected from the group consisting of fluoro,
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 alkoxy, and optionally substituted
C.sub.2-C.sub.4 alkynyl. In some instances, for formula (I) one
R.sup.1 is fluoro and the other may be selected from the group
consisting of optionally fluoro, methyl, methoxy and ethynyl
(--C.ident.CH), optionally methyl, methoxy and ethynyl
(--C.ident.CH). In some instances, for formula (I) one R.sup.1 is
fluoro and the other is a hydroxy substituted alkyl. In some
instances, for formula (I) one R.sup.1 is fluoro and the other is
hydroxymethyl.
[0103] A pharmaceutically acceptable salt of such compound of
formula (Ic) is also provided.
[0104] The compound of formula (I) may have the formula:
##STR00010## [0105] R.sup.1 may be selected from the group
consisting of fluoro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, and C.sub.2-C.sub.4 alkynyl; optionally fluoro, methyl,
methoxy and ethynyl (--C.ident.CH), optionally methyl, methoxy and
ethynyl (--C.ident.CH); and [0106] one of R.sup.2a and R.sup.2b is
fluoro and the other of R.sup.2a and R.sup.2b is H.
[0107] The compound of formula (I) may have the formula:
##STR00011## [0108] R.sup.1 may be selected from the group
consisting of fluoro, optionally substituted C.sub.1-C.sub.4 alkyl,
optionally substituted C.sub.1-C.sub.4 alkoxy, and optionally
substituted C.sub.2-C.sub.4 alkynyl; optionally fluoro, methyl,
methoxy and ethynyl (--C.ident.CH), optionally methyl, methoxy and
ethynyl (--C.ident.CH); and [0109] one of R.sup.2a and R.sup.2b is
fluoro and the other of R.sup.2a and R.sup.2b is H. In certain
aspects, R.sup.1 is hydroxymethyl.
[0110] A pharmaceutically acceptable salt of such compound of
formula (Id) is also provided.
[0111] The compound of formula (I) may have the formula:
##STR00012##
In certain aspects, one of R.sup.2a and R.sup.2b is fluoro and the
other of R.sup.2a and R.sup.2b is H.
[0112] A pharmaceutically acceptable salt of such compound of
formula (Ie) is also provided.
[0113] The compound of formula (I) may have the formula:
##STR00013##
In some aspects, of R.sup.2a and R.sup.2b is fluoro and the other
of R.sup.2a and R.sup.2b is H. A pharmaceutically acceptable salt
of such compound is also provided.
[0114] The compound of formula (I) may be of the formula:
##STR00014##
or a pharmaceutically acceptable salt thereof.
[0115] The compound may be:
##STR00015##
or a pharmaceutically acceptable salt thereof.
[0116] The compound may be:
##STR00016##
or a pharmaceutically acceptable salt thereof.
[0117] The compound disclosed above, or a pharmaceutically
acceptable salt thereof, may be provided (e.g. in a pharmaceutical
composition) substantially free of other isomers at the carbon atom
bearing the phenyl ring (i.e. having an absolute configuration
differing from that disclosed and depicted herein). The compound,
or a pharmaceutically acceptable salt thereof, may, alternatively
or additionally, be provided substantially free of other isomers at
the carbon atom bearing fluoro adjacent the carbon atom bearing the
phenyl ring. For example, when provided in a pharmaceutical
composition, the composition may be substantially free of other
isomers at the carbon atom bearing the phenyl ring. Similarly, the
composition may, alternatively or additionally, be substantially
free of other isomers at the carbon atom bearing fluoro adjacent
the carbon atom bearing the phenyl ring. In some aspects,
substantially free refers an enantiomeric excess (ee) of
.gtoreq.95%, .gtoreq.98%, .gtoreq.99%, or 100% at the carbon atom
bearing the phenyl ring. In some aspects, substantially free refers
an ee of .gtoreq.95%, .gtoreq.98%, .gtoreq.99%, or 100% at the
carbon atom bearing fluoro adjacent the carbon atom bearing the
phenyl ring. In some aspects, substantially free refers a
diastereomeric excess (de) of .gtoreq.95%, .gtoreq.98%,
.gtoreq.99%, or 100%.
[0118] In another aspect, provided herein is Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. Form 1
polymorph is characterized by at least one of:
a. a powder X-ray diffraction pattern having two or more peaks
expressed in degrees 2-theta.+-.0.2.degree. and selected from 11.3,
12.4, 13.3, 16.5, 17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4,
28.2, 29.5, 31.5, 32.9, 34.3, 35.5, and 38.8 degrees; b. a DSC
thermogram showing endotherms at about 226.05.degree. C., at about
302.47.degree. C., and at about 310.13.degree. C.; or c. an X-ray
crystal structure substantially the same as in FIG. 4. In another
aspect, Form 1 polymorph is characterized by a powder X-ray
diffraction pattern having three or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees. In some aspects, Form 1
polymorph is characterized by a powder X-ray diffraction pattern
having four or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees. In some aspects, Form 1
polymorph is characterized by a powder X-ray diffraction having
peaks expressed in degrees 2-theta.+-.0.2.degree. at each of 11.3,
12.4, and 13.3 degrees. In another aspect, Form 1 polymorph is
characterized by a powder X-ray diffraction having peaks expressed
in degrees 2-theta.+-.0.2.degree. at each of 11.3, 12.4, 13.3,
16.5, 17.3, 19.3, 20.4, and 29.5 degrees. In another aspect, Form 1
polymorph is characterized by melt onsets of about 221.51.degree.
C., about 299.53.degree. C., and about 308.81.degree. C. In some
aspects, Form 1 polymorph has a powder X-ray diffraction pattern
substantially the same as in FIG. 1A. In some aspects, Form 1
polymorph is substantially free of other forms of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
[0119] The compounds of formula (I) can be prepared via any
suitable method. Compounds can be prepared, for example, by the
route outlined in in the Examples below. One of skill in the art
will appreciate that the compounds of formula (I) can be prepared
using other synthetic methods, including transformations as
described in, for example, Larock (Comprehensive Organic
Transformations: A Guide to Functional Group Preparations, Wiley,
1999, which is incorporated herein by reference).
[0120] In another aspect, provided herein is a pharmaceutical
composition containing a compound of formula (I) or a
pharmaceutically acceptable salt thereof. The pharmaceutical
composition may comprise a pharmaceutically acceptable excipient.
The compositions are useful for treating conditions, such as
hypertrophic cardiomyopathy in humans and other subjects. In some
aspects, the pharmaceutical composition further comprises an
additional agent. Exemplary non-limiting additional agents include
agents 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); agents 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/or agents 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). In certain aspects, the
additional agent in the pharmaceutical composition is a
cardiovascular medication. In further aspects, additional exemplary
therapeutic agents include a beta adrenergic blocking agent
(beta-blocker), renin-angiotensin-aldosterone system (RAAS)
inhibitor (e.g., an angiotensin converting enzyme (ACE) inhibitor,
an angiotensin receptor antagonist, such as an angiotensin II
receptor blocker), an angiotensin receptor neprilysin inhibitor
(ARNI) (e.g., sacubitril/valsartan), a mineralocorticoid receptor
antagonist (MRA) (e.g., an aldosterone inhibitor such as a
potassium-sparing diuretic such as eplerenone, spironolactone, or
canrenone), a cholesterol lowering drug (e.g., a statin), a neutral
endopeptidase inhibitor (NEPi), a positive inotropic agent (e.g.,
digoxin, pimobendane, a beta adrenergic receptor agonist such as
dobutamine, a phosphodiesterase (PDE)-3 inhibitor such as
milrinone, or a calcium-sensitizing agent such as levosimendan),
potassium or magnesium, a proprotein convertase subtilisin
kexin-type 9 (PCSK9) inhibitor, a vasodilator (e.g., a calcium
channel blocker, phosphodiesterase inhibitor, endothelin receptor
antagonist, renin inhibitor, or smooth muscle myosin modulator), a
diuretic (e.g., furosemide), an arrhythmia medication, an
anticoagulant (e.g., warfarin), an antithrombotic agent, an
antiplatelet agent, or any combination thereof. Suitable
angiotensin II receptor blockers (ARBs) may include, e.g., A-81988,
A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698,
candesartan, candesartan cilexetil, CGP-38560A, CGP-48369,
CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811,
DuP-167, DuP-532, E-4177, elisartan, EMD-66397, EMD-73495,
eprosartan, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803,
EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888,
ICI-D7155, ICI-D8731, irbesartan, isoteoline, KRI-1177, KT3-671,
KW-3433, losartan, LR-B/057, L-158809, L-158978, L-159282,
L-159874, L-161177, L-162154, L-163017, L-159689, L-162234,
L-162441, L-163007, LR-B/081, LR B087, LY-285434, LY-302289,
LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304,
PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin
acetate, S-8307, S-8308, SC-52458, saprisartan, saralasin,
sarmesin, SL-91.0102, tasosartan, telmisartan, UP-269-6, U-96849,
U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360,
X-6803, valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155,
ZD-8731, and zolasartan. In particular aspects, the additional
therapeutic agent may be an ARNI such as sacubitril/valsartan
(Entresto.RTM.) or a sodium-glucose cotransporter 2 inhibitor
(SGLT2), such as empaglifozin (e.g., Jardiance.RTM.), dapagliflozin
(e.g., Farxiga.RTM.), or sotagliflozin. In some aspects, the
subject is administered an additional medication for improving
cardiovascular conditions in the subject. The additional medication
may be, e.g., a beta blocker, a diuretic, an angiotensin-converting
enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin
II receptor blocker, a mineralocorticoid receptor antagonist, an
ARNI, a RAAS inhibitor, or an arrhythmia medication. In particular
aspects, the additional medication is an ANRI such as
sacubitril/valsartan or an SGLT2 inhibitor.
[0121] In another aspect, provided herein is a pharmaceutical
composition comprising Form 1 polymorph. In some aspects, the
pharmaceutical composition comprises a pharmaceutically acceptable
excipient. In some aspects, provided herein is a pharmaceutical
composition, wherein the ratio of the amount of the Form 1
polymorph to the sum of the amounts of other forms is equal to or
greater than 80:20. In another case, the ratio of the amount of the
Form 1 polymorph to the sum of the amounts of other forms is equal
to or greater than 90:10. In certain aspects, the ratio of the
amount of the Form 1 polymorph to the sum of the amounts of other
forms is equal to or greater than 95:5. In some cases, the ratio of
the amount of the Form 1 polymorph to the sum of the amounts of
other forms is equal to or greater than 97:3. In certain cases, the
ratio of the amount of the Form 1 polymorph to the sum of the
amounts of other forms is equal to or greater than 98:2. In some
cases, the ratio of the amount of the Form 1 polymorph to the sum
of the amounts of other forms is equal to or greater than 99:1.
[0122] In some aspects, the pharmaceutical composition comprising
Form 1 polymorph further comprises an additional agent. Exemplary
non-limiting additional agents include agents 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); agents 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/or agents 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).
In certain aspects, the additional agent in the pharmaceutical
composition is a cardiovascular medication. In further aspects,
additional exemplary therapeutic agents include a beta adrenergic
blocking agent (beta-blocker), renin-angiotensin-aldosterone system
(RAAS) inhibitor (e.g., an angiotensin converting enzyme (ACE)
inhibitor, an angiotensin receptor antagonist, such as an
angiotensin II receptor blocker), an angiotensin receptor
neprilysin inhibitor (ARNI) (e.g., sacubitril/valsartan), a
mineralocorticoid receptor antagonist (MRA) (e.g., an aldosterone
inhibitor such as a potassium-sparing diuretic such as eplerenone,
spironolactone, or canrenone), a cholesterol lowering drug (e.g., a
statin), a neutral endopeptidase inhibitor (NEPi), a positive
inotropic agent (e.g., digoxin, pimobendane, a beta adrenergic
receptor agonist such as dobutamine, a phosphodiesterase (PDE)-3
inhibitor such as milrinone, or a calcium-sensitizing agent such as
levosimendan), potassium or magnesium, a proprotein convertase
subtilisin kexin-type 9 (PCSK9) inhibitor, a vasodilator (e.g., a
calcium channel blocker, phosphodiesterase inhibitor, endothelin
receptor antagonist, renin inhibitor, or smooth muscle myosin
modulator), a diuretic (e.g., furosemide), an arrhythmia
medication, an anticoagulant (e.g., warfarin), an antithrombotic
agent, an antiplatelet agent, or any combination thereof. Suitable
angiotensin II receptor blockers (ARBs) may include, e.g., A-81988,
A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698,
candesartan, candesartan cilexetil, CGP-38560A, CGP-48369,
CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811,
DuP-167, DuP-532, E-4177, elisartan, EMD-66397, EMD-73495,
eprosartan, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803,
EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888,
ICI-D7155, ICI-D8731, irbesartan, isoteoline, KRI-1177, KT3-671,
KW-3433, losartan, LR-B/057, L-158809, L-158978, L-159282,
L-159874, L-161177, L-162154, L-163017, L-159689, L-162234,
L-162441, L-163007, LR-B/081, LR B087, LY-285434, LY-302289,
LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304,
PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin
acetate, S-8307, S-8308, SC-52458, saprisartan, saralasin,
sarmesin, SL-91.0102, tasosartan, telmisartan, UP-269-6, U-96849,
U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360,
X-6803, valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155,
ZD-8731, and zolasartan. In particular aspects, the additional
therapeutic agent may be an ARNI such as sacubitril/valsartan
(Entresto.RTM.) or a sodium-glucose cotransporter 2 inhibitor
(SGLT2), such as empaglifozin (e.g., Jardiance.RTM.), dapagliflozin
(e.g., Farxiga.RTM.), or sotagliflozin. In some aspects, the
subject is administered an additional medication for improving
cardiovascular conditions in the subject. The additional medication
may be, e.g., a beta blocker, a diuretic, an angiotensin-converting
enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin
II receptor blocker, a mineralocorticoid receptor antagonist, an
ARNI, a RAAS inhibitor, or an arrhythmia medication. In particular
aspects, the additional medication is an ANRI such as
sacubitril/valsartan or an SGLT2 inhibitor.
[0123] The pharmaceutical compositions for the administration of
the compounds of formula (I) or their pharmaceutically acceptable
salts or polymorphs provided 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 compound of formula (I), or pharmaceutically
acceptable salt thereof, into association with a carrier containing
one or more accessory ingredients. In general, the pharmaceutical
compositions are prepared by uniformly and intimately bringing the
compound of formula (I), or pharmaceutically acceptable salt
thereof, 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 compound of formula (I), or pharmaceutically acceptable salt
thereof, is generally included in an amount sufficient to produce
the desired effect upon myocardial contractility (e.g., to decrease
the often supranormal systolic contractility in HCM) and/or to
improve left ventricular relaxation in diastole. Such improved
relaxation can alleviate symptoms in hypertrophic cardiomyopathy
and/or other etiologies of diastolic dysfunction. The
pharmaceutical compositions can, alternatively or additionally,
ameliorate the effects of diastolic dysfunction causing impairment
of coronary blood flow, thereby improving the latter as an
adjunctive agent in angina pectoris and/or ischemic heart disease.
The pharmaceutical compositions can, alternatively or additionally,
confer benefits on salutary left ventricular remodeling in HCM
and/or other causes of left ventricular hypertrophy due to chronic
volume or pressure overload from, e.g., valvular heart disease
and/or systemic hypertension.
[0124] The pharmaceutical compositions containing the compound of
formula (I), or pharmaceutically acceptable salt or polymorph
thereof, 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 compound of formula (I), or
pharmaceutically acceptable salt thereof, 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.
[0125] Pharmaceutical compositions for oral use may also be
presented as gelatin capsules, such as hard gelatin capsules
wherein the compound of formula (I), or pharmaceutically acceptable
salt thereof or polymorph, is mixed with an inert solid diluent,
for example, calcium carbonate, calcium phosphate or kaolin, or as
soft gelatin capsules wherein the compound of formula (I), or
pharmaceutically acceptable salt thereof, 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.
[0126] Aqueous suspensions contain the compound of formula (I), or
pharmaceutically acceptable salt or polymorph thereof, 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.
[0127] Oily suspensions may be formulated by suspending the
compound of formula (I), or pharmaceutically acceptable salt or
polymorph thereof, 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.
[0128] Dispersible powders and granules suitable for preparation of
an aqueous suspension by the addition of water provide the compound
of formula (I), or pharmaceutically acceptable salt or polymorph
thereof, 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.
[0129] The pharmaceutical compositions provided 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.
[0130] 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.
[0131] 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.
[0132] The compounds of formula (I) or their pharmaceutically
acceptable salts or polymorph provided 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 can be administered via ocular delivery by means of
solutions or ointments. Still further, transdermal delivery of the
subject compounds 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 their
pharmaceutically acceptable salts provided herein are employed. As
used herein, topical application is also meant to include the use
of mouth washes and gargles.
[0133] The compounds of formula (I) or their pharmaceutically
acceptable salts or polymorph provided 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 of formula (I) or their pharmaceutically
acceptable salts provided 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.
[0134] 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 of formula (I)
or their pharmaceutically acceptable salts provided 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.
[0135] Accordingly, the disclosure provides 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 provided herein, or a pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof. The method includes
administering to a subject in need thereof an effective amount of a
compound provided herein, or a pharmaceutical composition
comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
[0136] The disclosure also provides a method of treating
hypertrophic cardiomyopathy (HCM) or a cardiac disorder. The method
includes administering to a subject in need thereof an effective
amount of a compound provided herein, or a pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof. The method includes
administering to a subject in need thereof an effective amount of
Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, or a
pharmaceutical composition comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
[0137] Diastolic dysfunction is present or an important feature of
a series of diseases including, but not limited to, hypertrophic
cardiomyopathy (HCM), heart failure with preserved ejection
fraction (HFpEF)--including both disorders of active relaxation and
disorders of chamber stiffness (e.g., diabetic HFpEF); ischemic
cardiomyopathy, cardiac transplant allograft vasculopathy,
restrictive cardiomyopathy (e.g., genetic mutations in one or more
sarcomeric protein), inflammatory cardiomyopathy (e.g., Loeflers
and EMF), infiltrative cardiomyopathy (e.g., amyloid, sarcoid and
XRT), storage diseases (e.g., hemochromatosis, Fabry and glycogen
storage disease, congenital heart disease (e.g.,
pressure-overloaded RV, Tetrology of Fallot (e.g., diastolic
dysfunction pre-op and early post-op), and valvular heart disease
(e.g., aortic stenosis).
[0138] The present disclosure provides methods of treating a
cardiac disease or disorder in a subject in need thereof,
comprising administering to the subject an effective amount of a
compound, or salt thereof, or the Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
described herein. In some aspects, diastolic dysfunction is a
feature of and/or associated with the cardiac disease or disorder.
For instance, the cardiac disease or disorder may be cardiomyopathy
(e.g., hypertrophic cardiomyopathy), heart failure (e.g., heart
failure with preserved ejection fraction, heart failure with
midrange ejection fraction), valvular disease (e.g., valvular
aortic stenosis), congenital heart disease (e.g., Tetralogy of
Fallot), left ventricular hypertrophy, angina pectoris (e.g.,
refractory angina pectoris), or Chagas disease. In certain aspects,
a normal or preserved ejection fraction (e.g., ejection fraction of
greater than or equal to about 50%) is a feature of the cardiac
disease or disorder. In some such cases, features of the cardiac
disease or disorder include a normal or preserved ejection fraction
and diastolic dysfunction. For instance, a subject in need of
treatment for the cardiac disease or disorder (e.g., HCM, HFpEF,
valvular aortic stenosis) may have diastolic dysfunction and an
ejection fraction of greater than or equal to about 50%. In certain
aspects, a moderate ejection fraction (e.g., ejection fraction of
between about 40% and about 50%) is a feature of the cardiac
disease or disorder. In some such cases, a subject in need of
treatment for the cardiac disease or disorder may have a moderate
ejection fraction and diastolic dysfunction. For example, a subject
in need of treatment for the cardiac disease or disorder (e.g.,
heart failure with midrange ejection fraction) may have diastolic
dysfunction and an ejection fraction of between about 40% and about
50%.
[0139] In some aspects, methods for treating diastolic dysfunction
in a subject in need thereof are provided. In some aspects, the
method comprises administering an effective amount of a compound of
Formula (I), or salt thereof, or the Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to the
subject. In some instances, the diastolic dysfunction is left
ventricular diastolic dysfunction, right ventricular diastolic
dysfunction, or both. The diastolic dysfunction may be chronic,
stable, or acute. In some aspects, the subject in need of treatment
for diastolic dysfunction may be suffering from one or more
diseases or disorders selected from the group consisting of
hypertrophic cardiomyopathy (e.g., oHCM, nHCM), restrictive
cardiomyopathy, heart failure (e.g., HFpEF, diabetic HFpEF,
HFmrEF), infiltrative cardiomyopathy (e.g., due to amyloidosis,
sarcoidosis, and/or X-ray therapy), inflammatory cardiomyopathy
(e.g., Loeffler endocarditis, endomyocardial fibrosis),
hemochromatosis, Fabry disease, glycogen storage disease,
congenital heart disease (e.g., Tetralogy of Fallot), valvular
heart disease (e.g., aortic stenosis), left ventricular hypertrophy
(e.g., due to mitral regurgitation, aortic stenosis, aortic
regurgitation, and/or chronic systemic hypertension), hypertension
(e.g., chronic, systemic), Chagas disease, and angina pectoris
(e.g., refractory angina pectoris). In certain aspects, the subject
in need of treatment for diastolic dysfunction may be suffering
from one or more diseases or disorders selected from the group
consisting of hypertrophic cardiomyopathy (e.g., oHCM, nHCM), heart
failure (e.g., HFpEF, diabetic HFpEF, HFmrEF), valvular heart
disease (e.g., aortic stenosis), congenital heart disease (e.g.,
Tetralogy of Fallot), and left ventricular hypertrophy (e.g., due
to mitral regurgitation, aortic stenosis, aortic regurgitation,
and/or chronic systemic hypertension). In some aspects, the subject
in need of treatment for diastolic dysfunction may have undergone
one or more surgical procedure. For instance, the subject may have
undergone valve replacement surgery (e.g., surgical aortic valve
replacement, transcatheter aortic valve replacement) and/or
corrective surgery for a congenital heart disease, such as
Tetralogy of Fallot. In some aspects, the subject in need of
treatment for diastolic dysfunction may an artificial heart valve
(e.g., artificial aortic valve). In some cases, the subject in need
of treatment for diastolic dysfunction has post-operative diastolic
dysfunction. For instance, the subject may have post-operative
diastolic dysfunction (e.g., right ventricular diastolic
dysfunction) after corrective surgery for a congenital disorder
(e.g., Tetralogy of Fallot). In some instances, the subject in need
of treatment for diastolic dysfunction has a normal or preserved
ejection fraction. In other instances, the subject in need of
treatment for diastolic dysfunction has a moderate ejection
fraction.
[0140] In some aspects, methods for treating a cardiomyopathy
(e.g., hypertrophic) in a subject in need thereof are provided. In
certain aspects, the method comprises administering an effective
amount of a compound of Formula (I), or salt thereof, or the Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to the
subject. Non-limiting examples of cardiomyopathies that may be
treated using the compounds described herein include hypertrophic
cardiomyopathy (e.g., obstructive cardiomyopathy, non-obstructive
cardiomyopathy), restrictive cardiomyopathy, infiltrative
cardiomyopathy (e.g., with diastolic dysfunction), and inflammatory
cardiomyopathy (e.g., with diastolic dysfunction). In some aspects,
the cardiomyopathy is hypertrophic cardiomyopathy. In some
instances, the hypertrophic cardiomyopathy is nHCM. The method may
comprise administering an effective amount of a compound of Formula
(I), or salt thereof, or the Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to a
subject in need of treatment for nHCM. The subject in need of
treatment for nHCM may have NYHA class II, III, or IV heart
failure. In other instances, the hypertrophic cardiomyopathy is
oHCM. The method may comprise administering an effective amount of
a compound of Formula (I), or salt thereof, or the Form 1 polymorph
of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to a
subject in need of treatment for oHCM. The subject in need of
treatment for oHCM may have NYHA class II, III, or IV heart
failure.
[0141] In some aspects, the cardiomyopathy is restrictive
cardiomyopathy. The method may comprise administering an effective
amount of a compound of Formula (I), or salt thereof, or the Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to a
subject in need of treatment for restrictive cardiomyopathy. In
some aspects, the restrictive cardiomyopathy may be due to, e.g.,
one or more mutations (e.g., gene mutation) in a sarcomeric
protein. In some aspects, the cardiomyopathy is infiltrative
cardiomyopathy. The infiltrative cardiomyopathy may be due to
amyloidosis, sarcoidosis, and/or X-ray therapy. In some instances,
a feature of the infiltrative cardiomyopathy may be diastolic
dysfunction. The method of treating infiltrative cardiomyopathy may
comprise administering an effective amount of a compound of Formula
(I), or salt thereof, or the Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to a
subject in need thereof. In some aspects, the cardiomyopathy is
inflammatory cardiomyopathy. Non-limiting examples of inflammatory
cardiomyopathy include Loeffler endocarditis and endomyocardial
fibrosis. In some instances, a feature of the inflammatory
cardiomyopathy may be diastolic dysfunction. The method of treating
inflammatory cardiomyopathy may comprise administering an effective
amount of a compound of Formula (I), or salt thereof, or the Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to a
subject in need thereof.
[0142] In some aspects, methods for treating heart failure (e.g.,
HFpEF, HFmrEF) in a subject in need thereof are provided. The
method comprises administering an effective amount of a compound of
Formula (I), or salt thereof, or the Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to the
subject. The heart failure may be left-sided heart failure,
right-sided heart failure, or both. The heart failure may be
chronic, stable, or acute. The subject in need of treatment for
heart failure may have NYHA class II, III, or IV heart failure.
Non-limiting examples of heart failure that may be treated using
the compounds described herein include HFpEF, diabetic HFpEF, and
HFmrEF. In some aspects, the heart failure is HFpEF. In some
instances, the subject in need of treatment for HFpEF may have
normal or elevated contractility (e.g., as measured by
echocardiogram). In some cases, the subject in need of treatment
for HFpEF may have an abnormal global longitudinal strain (e.g.,
less than -15%). In certain aspects, the subject in need of
treatment for HFpEF may suffer from diabetes (type I, type II)
and/or valvular disease (e.g., aortic stenosis). In some instances,
the subject in need of treatment for HFpEF may have an artificial
valve (e.g., aortic valve) due to valvular disease (e.g., aortic
stenosis). A method of treating HFpEF (e.g., diabetic HFpEF) in a
subject in need thereof may comprise administering an effective
amount of a compound of Formula (I), or salt thereof, or the Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to the
subject. In some instances, the heart failure is HFmrEF. The method
may comprise administering an effective amount of a compound of
Formula (I), or salt thereof, or the Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to a
subject in need of treatment for HFmrEF. The subject in need of
treatment for HFmrEF may have NYHA class II, III, or IV heart
failure.
[0143] In some aspects, methods for treating left ventricular
hypertrophy in a subject in need thereof are provided. The method
comprises administering an effective amount of a compound of
Formula (I), or salt thereof, or the Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to the
subject. In some aspects, the subject in need of treatment for left
ventricular hypertrophy has an abnormal left ventricular wall
thickness. The left ventricular wall thickness in the subject may
be greater than normal, but less than a diagnostic criterion for
hypertrophic cardiomyopathy. For example, the subject in need of
treatment for left ventricular hypertrophy may have a left
ventricular wall thickness of greater than about 10 mm (e.g.,
greater than about 11 mm) and less than about 15 mm (e.g., less
than or equal to about 14 mm, less than or equal to about 13 mm).
In some aspects, the subject in need of treatment for left
ventricular hypertrophy has left ventricular hypertrophy in the
absence of hypertrophic cardiomyopathy. In certain aspects, the
subject in need of treatment for left ventricular hypertrophy may
suffer from hypertension (e.g., chronic and/or systemic). In some
aspects, the left ventricular hypertrophy may be due to, e.g.,
chronic mitral regurgitation, chronic aortic regurgitation, chronic
aortic stenosis, and/or chronic systemic hypertension.
[0144] Further determining factors for diagnosing diastolic
dysfunction using echocardiography are described in J Am Soc
Echocardiogr. 29(4):277-314 (2016), the contents of which are
incorporated herein for all purposes.
[0145] Subjects in need of treatment for diastolic dysfunction
include subjects from a patient population having non-obstructive
hypertrophic cardiomyopathy (nHCM), or subjects having heart
failure with preserved ejection fraction (HFpEF). Subjects in need
of treatment for diastolic dysfunction include subjects who exhibit
left ventricle stiffness as measured by echocardiography or left
ventricle stiffness as measured by cardiac magnetic resonance.
[0146] In some aspects, the subject in need thereof is from a
patient population having HFpEF.
[0147] The disclosure also provides a method of treating a disease
or disorder selected from the group consisting of diastolic heart
failure (for example 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 formula (I), or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
[0148] The compounds of formula (I) may be administered as a
monotherapy or combination therapy. In combination therapy, a
compound of formula (I) is used in combination with an additional
therapy regimen, e.g., a standard of care (SOC) therapy for the
subject's cardiac condition or other therapy useful for treating
the relevant disease or disorder. The additional therapeutic agent
may be administered by a route and in an amount commonly used for
said agent or at a reduced amount, and may be administered
simultaneously, sequentially, or concurrently with a compound of
formula (I).
[0149] In certain aspects, a compound of formula (I) is
administered on top of the SOC for a condition of diastolic
dysfunction, such as diastolic heart failure. In further aspects,
the subject is given, in addition to the compound of formula (I),
another therapeutic agent such as a beta-blocker, a RAAS inhibitor
(e.g., an angiotensin converting enzyme (ACE) inhibitor, an
angiotensin receptor antagonist such as an angiotensin II receptor
blocker), an angiotensin receptor neprilysin inhibitor (ARNI)
(e.g., sacubitril/valsartan), a mineralocorticoid receptor
antagonist (e.g., an aldosterone inhibitor such as a
potassium-sparing diuretic such as eplerenone, spironolactone, or
canrenone), a cholesterol lowering drug (e.g., a statin), a neutral
endopeptidase inhibitor (NEPi), a positive inotropic agent (e.g.,
digoxin, pimobendane, a beta adrenergic receptor agonist such as
dobutamine, a phosphodiesterase (PDE)-3 inhibitor such as
milrinone, or a calcium-sensitizing agent such as levosimendan),
potassium or magnesium, a proprotein convertase subtilisin
kexin-type 9 (PCSK9) inhibitor, a vasodilator (e.g., a calcium
channel blocker, phosphodiesterase inhibitor, endothelin receptor
antagonist, renin inhibitor, or smooth muscle myosin modulator), a
diuretic (e.g., furosemide), an arrhythmia medication, an
anticoagulant (e.g., warfarin), an antithrombotic agent, an
antiplatelet agent, or any combination thereof.
[0150] Suitable ARBs may include, e.g., A-81988, A-81282, BIBR-363,
BIBS39, BIBS-222, BMS-180560, BMS-184698, candesartan, candesartan
cilexetil, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996,
CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, E-4177,
elisartan, EMD-66397, EMD-73495, eprosartan, EXP-063, EXP-929,
EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056,
HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan,
isoteoline, KRI-1177, KT3-671, KW-3433, losartan, LR-B/057,
L-158809, L-158978, L-159282, L-159874, L-161177, L-162154,
L-163017, L-159689, L-162234, L-162441, L-163007, LR-B/081, LR
B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875,
ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647,
RWJ-38970, RWJ-46458, saralasin acetate, S-8307, S-8308, SC-52458,
saprisartan, saralasin, sarmesin, SL-91.0102, tasosartan,
telmisartan, UP-269-6, U-96849, U-97018, UP-275-22, WAY-126227,
WK-1492.2K, YM-31472, WK-1360, X-6803, valsartan, XH-148, XR-510,
YM-358, ZD-6888, ZD-7155, ZD-8731, and zolasartan. In particular
aspects, the additional therapeutic agent may be an ARNI such as
sacubitril/valsartan (Entresto.RTM.) or a sodium-glucose
cotransporter 2 inhibitor (SGLT2) such as empaglifozin (e.g.,
Jardiance.RTM.), dapagliflozin (e.g., Farxiga.RTM.), or
sotagliflozin. In some aspects, the subject is administered an
additional medication for improving cardiovascular conditions in
the subject. The additional medication may be, e.g., a beta
blocker, a diuretic, an angiotensin-converting enzyme (ACE)
inhibitor, a calcium channel blocker, an angiotensin II receptor
blocker, a mineralocorticoid receptor antagonist, an ARNI, a RAAS
inhibitor, or an arrhythmia medication. In particular aspects, the
additional medication is an ANRI such as sacubitril/valsartan or an
SGLT2 inhibitor. In yet another aspect, a subject being treated for
heart failure with a compound of formula (I) is also being treated
with an ARNI, a beta blocker, and an MRA.
[0151] The disclosure also provides a method of treating a disease
or disorder selected from the group consisting of diastolic heart
failure (for example 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 Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione The
disclosure also provides a method of treating a disease or disorder
selected from the group consisting of diastolic heart failure (for
example 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 pharmaceutical composition comprising Form 1 polymorph
of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
[0152] The Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione may be
administered as a monotherapy or combination therapy. In
combination therapy, Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione is used
in combination with an additional therapy regimen, e.g., a standard
of care (SOC) therapy for the subject's cardiac condition or other
therapy useful for treating the relevant disease or disorder. The
additional therapeutic agent may be administered by a route and in
an amount commonly used for said agent or at a reduced amount, and
may be administered simultaneously, sequentially, or concurrently
with Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. In
certain aspects, Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione is
administered on top of the SOC for a condition of diastolic
dysfunction, such as diastolic heart failure. In further aspects,
the subject is given, in addition to Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione,
another therapeutic agent such as a beta-blocker, a RAAS inhibitor
(e.g., an angiotensin converting enzyme (ACE) inhibitor, an
angiotensin receptor antagonist such as an angiotensin II receptor
blocker), an angiotensin receptor neprilysin inhibitor (ARNI)
(e.g., sacubitril/valsartan), a mineralocorticoid receptor
antagonist (e.g., an aldosterone inhibitor such as a
potassium-sparing diuretic such as eplerenone, spironolactone, or
canrenone), a cholesterol lowering drug (e.g., a statin), a neutral
endopeptidase inhibitor (NEPi), a positive inotropic agent (e.g.,
digoxin, pimobendane, a beta adrenergic receptor agonist such as
dobutamine, a phosphodiesterase (PDE)-3 inhibitor such as
milrinone, or a calcium-sensitizing agent such as levosimendan),
potassium or magnesium, a proprotein convertase subtilisin
kexin-type 9 (PCSK9) inhibitor, a vasodilator (e.g., a calcium
channel blocker, phosphodiesterase inhibitor, endothelin receptor
antagonist, renin inhibitor, or smooth muscle myosin modulator), a
diuretic (e.g., furosemide), an arrhythmia medication, an
anticoagulant (e.g., warfarin), an antithrombotic agent, an
antiplatelet agent, or any combination thereof. Suitable ARBs are
provided herein (vide supra). In particular aspects, the additional
therapeutic agent may be an ARNI such as sacubitril/valsartan
(Entresto.RTM.) or a sodium-glucose cotransporter 2 inhibitor
(SGLT2) such as empaglifozin (e.g., Jardiance.RTM.), dapagliflozin
(e.g., Farxiga.RTM.), or sotagliflozin. In some aspects along with
administration of Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, the
subject is administered an additional medication for improving
cardiovascular conditions in the subject. The additional medication
may be, e.g., a beta blocker, a diuretic, an angiotensin-converting
enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin
II receptor blocker, a mineralocorticoid receptor antagonist, an
ARNI, a RAAS inhibitor, or an arrhythmia medication. In particular
aspects, the additional medication is an ANRI such as
sacubitril/valsartan or an SGLT2 inhibitor. In yet another aspect,
a subject being treated for heart failure with Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione is also
being treated with an ARNI, a beta blocker, and an MRA.
[0153] The disclosure also provides a method of treating a disease
or disorder characterized by left ventricular hypertrophy (for
example 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, combined 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 formula (I), or a
pharmaceutically acceptable salt thereof. The disclosure also
provides a method of treating a disease or disorder characterized
by left ventricular hypertrophy (for example 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, combined 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 pharmaceutical
composition comprising a compound of formula (I) or a
pharmaceutically acceptable salt thereof.
[0154] The disclosure also provides a method of treating a disease
or disorder characterized by left ventricular hypertrophy (for
example 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, combined 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 Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The
disclosure also provides a method of treating a disease or disorder
characterized by left ventricular hypertrophy (for example 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, combined 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 pharmaceutical
composition comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.
[0155] The disclosure also provides a method of treating
hypertrophic cardiomyopathy (HCM), or a cardiac disorder (for
example 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 formula (I), or a
pharmaceutically acceptable salt thereof, combined with (1)
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); (2) 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/or (3) 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).
[0156] The disclosure also provides a method of treating
hypertrophic cardiomyopathy (HCM), or a cardiac disorder (for
example a cardiac disorder having a pathophysiological feature
associated with HCM), comprising administering to a subject in need
thereof an effective amount of a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof, combined with (1) 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); (2) 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/or (3) 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).
[0157] The disclosure also provides a method of treating
hypertrophic cardiomyopathy (HCM), or a cardiac disorder (for
example a cardiac disorder having a pathophysiological feature
associated with HCM), comprising administering to a subject in need
thereof an effective amount of Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione,
combined with (1) 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); (2)
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/or (3) 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).
[0158] The disclosure also provides a method of treating
hypertrophic cardiomyopathy (HCM), or a cardiac disorder (for
example a cardiac disorder having a pathophysiological feature
associated with HCM), comprising administering to a subject in need
thereof an effective amount of a pharmaceutical composition
comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione,
combined with (1) 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); (2)
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/or (3) 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).
[0159] The disclosure also provides a compound of formula (I) or
pharmaceutically acceptable salt thereof, for use as a medicament.
The disclosure also provides a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof, for use as a medicament. The disclosure
also provides Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use
as a medicament. The disclosure also provides a pharmaceutical
composition comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use as a medicament.
[0160] The disclosure also provides a compound of formula (I) or
pharmaceutically acceptable salt thereof for use in the treatment
of hypertrophic cardiomyopathy, or a cardiac disorder (for example
a cardiac disorder having a pathophysiological feature of HCM). The
disclosure also provides a pharmaceutically acceptable salt
thereof, for use in the treatment of hypertrophic cardiomyopathy,
or a cardiac disorder (for example a cardiac disorder having a
pathophysiological feature of HCM). The disclosure also provides
Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use in the treatment of hypertrophic cardiomyopathy, or a cardiac
disorder (for example a cardiac disorder having a
pathophysiological feature of HCM). The disclosure also provides a
pharmaceutical composition comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use in the treatment of hypertrophic cardiomyopathy, or a cardiac
disorder (for example a cardiac disorder having a
pathophysiological feature of HCM).
[0161] The disclosure also provides a compound of formula (I) or
pharmaceutically acceptable salt thereof, for use in the treatment
of a disease or disorder selected from the group consisting of
diastolic heart failure (for example heart failure with preserved
ejection fraction), ischemic heart disease, angina pectoris, and
restrictive cardiomyopathy. The disclosure also provides a compound
of a pharmaceutical composition comprising a compound of formula
(I) or a pharmaceutically acceptable salt thereof, for use in the
treatment of a disease or disorder selected from the group
consisting of diastolic heart failure (for example heart failure
with preserved ejection fraction), ischemic heart disease, angina
pectoris, and restrictive cardiomyopathy. The disclosure also
provides Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use in the treatment of a disease or disorder selected from the
group consisting of diastolic heart failure (for example heart
failure with preserved ejection fraction), ischemic heart disease,
angina pectoris, and restrictive cardiomyopathy. The disclosure
also provides a pharmaceutical composition comprising Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use in the treatment of a disease or disorder selected from the
group consisting of diastolic heart failure (for example heart
failure with preserved ejection fraction), ischemic heart disease,
angina pectoris, and restrictive cardiomyopathy.
[0162] The disclosure also provides a compound of formula (I) or
pharmaceutically acceptable salt thereof, for use in the treatment
of disease or disorder characterized by left ventricular
hypertrophy (for example 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; wherein the compound is for use in combination with
therapies aimed at correcting or alleviating the primary cause of
volume or pressure overload, including valve repair/replacement or
effective antihypertensive therapy. The disclosure also provides a
pharmaceutical composition comprising a compound of formula (I) or
a pharmaceutically acceptable salt thereof, for use in the
treatment of disease or disorder characterized by left ventricular
hypertrophy (for example 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; wherein the compound is for use in combination with
therapies aimed at correcting or alleviating the primary cause of
volume or pressure overload, including valve repair/replacement or
effective antihypertensive therapy. The disclosure also provides
Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4--
yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use in the treatment of disease or disorder characterized by left
ventricular hypertrophy (for example 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; wherein the compound
is for use in combination with therapies aimed at correcting or
alleviating the primary cause of volume or pressure overload,
including valve repair/replacement or effective antihypertensive
therapy. The disclosure also provides a pharmaceutical composition
comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use in the treatment of disease or disorder characterized by left
ventricular hypertrophy (for example 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; wherein the compound
is for use in combination with therapies aimed at correcting or
alleviating the primary cause of volume or pressure overload,
including valve repair/replacement or effective antihypertensive
therapy.
[0163] The disclosure also provides a compound of formula (I) or
pharmaceutically acceptable salt thereof, for use in the treatment
of hypertrophic cardiomyopathy (HCM), or a cardiac disorder (for
example a cardiac disorder having a pathophysiological feature
associated with HCM), wherein the compound is for use in
combination with (1) 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); (2)
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/or (3) 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 disclosure also provides a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof, for use in the treatment of hypertrophic
cardiomyopathy (HCM), or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature associated with HCM),
wherein the compound is for use in combination with (1) 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); (2) 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/or
(3) 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).
[0164] The disclosure also provides Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use in the treatment of hypertrophic cardiomyopathy (HCM), or a
cardiac disorder (for example a cardiac disorder having a
pathophysiological feature associated with HCM), wherein the
compound is for use in combination 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/or 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 disclosure also provides a pharmaceutical
composition comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
use in the treatment of hypertrophic cardiomyopathy (HCM), or a
cardiac disorder (for example a cardiac disorder having a
pathophysiological feature associated with HCM), wherein the
compound is for use in combination 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/or 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).
[0165] The disclosure also provides a use of a compound of formula
(I) or pharmaceutically acceptable salt thereof, for the
manufacture of a medicament. The disclosure also provides a use of
a pharmaceutical composition comprising a compound of formula (I)
or a pharmaceutically acceptable salt thereof, for the manufacture
of a medicament. The disclosure also provides a use of Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the
manufacture of a medicament. The disclosure also provides a use of
a pharmaceutical composition comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the
manufacture of a medicament.
[0166] The disclosure also provides a use of a compound of formula
(I) or pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of hypertrophic
cardiomyopathy, or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature of HCM). The
disclosure also provides a use of a pharmaceutical composition
comprising a compound of formula (I) or a pharmaceutically
acceptable salt thereof, for the manufacture of a medicament for
the treatment of hypertrophic cardiomyopathy, or a cardiac disorder
(for example a cardiac disorder having a pathophysiological feature
of HCM). The disclosure also provides a use of Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
the manufacture of a medicament for the treatment of hypertrophic
cardiomyopathy, or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature of HCM). The
disclosure also provides a use of a pharmaceutical composition
comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
the manufacture of a medicament for the treatment of hypertrophic
cardiomyopathy, or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature of HCM).
[0167] The disclosure also provides a use of a compound of formula
(I) or pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of a disease or
disorder selected from the group consisting of diastolic heart
failure (for example heart failure with preserved ejection
fraction), ischemic heart disease, angina pectoris, and restrictive
cardiomyopathy. The disclosure also provides a use of a
pharmaceutical composition comprising a compound of formula (I) or
a pharmaceutically acceptable salt thereof, for the manufacture of
a medicament for the treatment of a disease or disorder selected
from the group consisting of diastolic heart failure (for example
heart failure with preserved ejection fraction), ischemic heart
disease, angina pectoris, and restrictive cardiomyopathy. The
disclosure also provides a use of Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
the manufacture of a medicament for the treatment of a disease or
disorder selected from the group consisting of diastolic heart
failure (for example heart failure with preserved ejection
fraction), ischemic heart disease, angina pectoris, and restrictive
cardiomyopathy. The disclosure also provides a use of a
pharmaceutical composition comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
the manufacture of a medicament for the treatment of a disease or
disorder selected from the group consisting of diastolic heart
failure (for example heart failure with preserved ejection
fraction), ischemic heart disease, angina pectoris, and restrictive
cardiomyopathy.
[0168] The disclosure also provides a use of a compound of formula
(I) or pharmaceutically acceptable salt thereof for the manufacture
of a medicament for the treatment of left ventricular hypertrophy
(for example 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. The disclosure also provides a use of a pharmaceutically
acceptable salt thereof, for the manufacture of a medicament for
the treatment of left ventricular hypertrophy (for example 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. The disclosure also provides
a use of Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the
manufacture of a medicament for the treatment of left ventricular
hypertrophy (for example 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. The disclosure also provides a use of a pharmaceutical
composition comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
the manufacture of a medicament for the treatment of left
ventricular hypertrophy (for example 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.
[0169] The disclosure also provides a use of a compound of formula
(I) or pharmaceutically acceptable salt thereof for the manufacture
of a medicament for the treatment of hypertrophic cardiomyopathy
(HCM), or a cardiac disorder (for example a cardiac disorder having
a pathophysiological feature associated with HCM), 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/or 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 disclosure also provides a
use of a pharmaceutical composition comprising a compound of
formula (I) or a pharmaceutically acceptable salt thereof, for the
manufacture of a medicament for the treatment of hypertrophic
cardiomyopathy (HCM), or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature associated with HCM),
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/or 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).
[0170] The disclosure also provides a use of Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the
manufacture of a medicament for the treatment of hypertrophic
cardiomyopathy (HCM), or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature associated with HCM),
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/or 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
disclosure also provides a use of a pharmaceutical composition
comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for
the manufacture of a medicament for the treatment of hypertrophic
cardiomyopathy (HCM), or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature associated with HCM),
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/or 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).
[0171] The compounds of formula (I) or their pharmaceutically
acceptable salts can alter the natural history of HCM and other
diseases rather than merely palliating symptoms. Form 1 polymorph
of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 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 formula (I) or their
pharmaceutically acceptable salts can specifically target the root
causes of the conditions or act upon other downstream pathways.
Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione can be
used to specifically target the root causes of the conditions or
act upon other downstream pathways. Accordingly, the compounds of
formula (I) or their pharmaceutically acceptable salts can also
confer benefit to patients suffering from heart failure with
preserved ejection fraction, ischemic heart disease, angina
pectoris, or restrictive cardiomyopathy. Accordingly, Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione can
also confer benefit to patients suffering from heart failure with
preserved ejection fraction, ischemic heart disease, angina
pectoris, or restrictive cardiomyopathy. Compounds of formula (I)
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). Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 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 pressure 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 of
formula (I) 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. Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 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 of formula (I) 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. Form 1
polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 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 of formula (I) or
their pharmaceutically acceptable salts may reduce interstitial
myocardial fibrosis and/or slow the progression, arrest, or reverse
left ventricular hypertrophy. Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione may
reduce interstitial myocardial fibrosis and/or slow the
progression, arrest, or reverse left ventricular hypertrophy.
[0172] Depending on the disease to be treated and the subject's
condition, the compounds of formula (I) or their pharmaceutically
acceptable salts provided 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 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.
[0173] Depending on the disease to be treated and the subject's
condition, Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
provided 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 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.
[0174] The compounds of formula (I) or pharmaceutically acceptable
salts thereof, or pharmaceutical compositions comprising compounds
of formula (I) or pharmaceutically acceptable salts thereof, may be
administered on a regimen of 1 to 4 times per day, preferably once
or twice per day. Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, or
pharmaceutical compositions comprising Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, may be
administered on a regimen of 1 to 4 times per day, preferably once
or twice per day.
[0175] 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 thereof, 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.
[0176] Compounds of formula (I), pharmaceutically acceptable salts
of compounds of formula (I) and/or pharmaceutical 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. Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione and/or
pharmaceutical 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 of formula (I), or pharmaceutically
acceptable salt thereof, 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.
[0177] Where a compound of the disclosure is administered in
combination with another therapeutic agent, the other therapeutic
agent can be administered simultaneously, separately or
sequentially with the compound of formula (I). The precise dosage
regimen being commensurate with the properties of the therapeutic
agent(s). Where a compound of the disclosure is administered in
combination with another therapeutic agent, the other therapeutic
agent can be administered simultaneously, separately or
sequentially with Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The
precise dosage regimen being commensurate with the properties of
the therapeutic agent(s).
EXAMPLES
[0178] Abbreviations: ACN: acetonitrile; aq: aqueous; Ar: argon;
CH.sub.2Cl.sub.2: dichloromethane; CH.sub.3CN: acetonitrile;
CH.sub.3OH: methanol; Cs.sub.2CO.sub.3: cesium carbonate; DCM:
dichloromethane; DIEA: diisopropyl ethylamine; DMF: dimethyl
formamide; DMSO: dimethyl sulfoxide; equiv.: equivalent(s);
Et.sub.2O: diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; h or
hr: hour(s); HATU:
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate,
N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-meth-
ylmethanaminium hexafluorophosphate N-oxide; HCl: hydrogen
chloride; H.sub.2O: water; IPA: isopropyl alcohol; iPr.sub.2O:
diisopropyl ether; K.sub.2CO.sub.3: potassium carbonate; LiHMDS:
lithium hexamethyldisilazane; MeOH: methanol; MgSO.sub.4: magnesium
sulfate; min: minutes; mL: milliliter; MW or .mu.W: microwave
(reaction done in microwave reactor); NaBH.sub.4: sodium
borohydride; NaBH.sub.3CN: sodium cyanoborohydride; NaCl: sodium
chloride; NaBH.sub.3CN: sodium cyanoboro hydride; NaH: sodium
hydride; NaHCO.sub.3: sodium bicarbonate; NaOH: sodium hydroxide;
NaOMe: sodium methoxide; Na.sub.2SO.sub.4: sodium sulfate; n-BuOH:
n-butanol; NH.sub.4Cl: ammonium chloride; pH: -log [H.sup.+]; RT:
room temperature; SOCl.sub.2: thionyl chloride; TFA:
trifluoroacetic acid; THF: tetrahydrofuran; THP, tetrahydropyran or
tetrahydropyranyl; and Zn: zinc powder. All of the experiments were
carried out in fume hoods with specific safety precautions and
necessary personal protective equipment.
Example 1: Synthesis
Intermediate Example 1: Preparation of
(S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)prop-
anoic acid (1-4)
##STR00017##
[0180] Step 1. Synthesis of
(S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (1-2).
To a 1000-mL round-bottom flask were added 3-fluorobenzaldehyde (50
g, 0.40 mol), (S)-2-methylpropane-2-sulfinamide (50 g, 0.41 mol),
Cs.sub.2CO.sub.3 (157 g, 0.48 mol), and dichloromethane (500 mL)
under an atmosphere of Ar. After stirring at rt for 4 h, the
reaction mixture was diluted with methyl tert-butylether (MTBE)
(1000 mL). Subsequently, the mixture was filtered, and the filtrate
was concentrated to give crude 1-2 (87 g, 95%) as an off-while
solid, which was used for the next step without further
purification. LC-MS (ES, m/z): 228 [M+H].sup.+; .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 8.55 (d, 1H), 7.63-7.48 (m, 2H),
7.41-7.48 (td, J=8.0, 5.5 Hz, 1H), 7.17-7.7.26 (m, 1H), 1.26 (d,
J=2.6 Hz, 9H).
[0181] Step 2. Synthesis of ethyl
(S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)prop-
anoate (1-3). To a suspension of Zn (38 g, 0.58 mmol) in
tetrahydrofuran (600 mL) was added a solution of 1-2 (53.5 g, 0.24
mol) and ethyl 2-bromo-2,2-difluoroacetate (120 g, 0.59 mol) in
tetrahydrofuran (250 mL) at 70.degree. C. with stirring for 40 min
under an atmosphere of Ar. After stirring at 70.degree. C. for
another 30 min, the reaction mixture was filtered, and the filtrate
was concentrated. The residue was diluted with EtOAc (1000 mL).
Next, the resulting mixture was washed with sat. aq. citric acid
(500 mL) and dried over anhydrous Na.sub.2SO.sub.4. The solvent was
removed and the residue was dried in vacuo to give 1-3 (50 g, 60%)
as a yellow oil. LC-MS (ES, m/z): 352 [M+H].sup.+.
[0182] Step 3.
(S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)prop-
anoic acid (1-4). A solution of 1-3 (80 g, 0.23 mol) in
tetrahydrofuran (1000 mL) was added 1 N aq. NaOH (350 mL) at rt
under an atmosphere of Ar. After stirring at rt for 30 min, the pH
value of the reaction mixture was adjusted to 5 with 1 N aq. citric
acid. The resulting mixture was extracted with ethyl acetate (1000
mL.times.3). Next, the combined organic extracts were washed with
brine (500 mL) and dried over anhydrous Na.sub.2SO.sub.4. The
solvent was removed and the residue was purified by Flash-Prep-HPLC
(column: C18 silica gel; mobile phase: CH.sub.3CN/H.sub.2O=10/90
(v/v) increasing to CH.sub.3CN/H.sub.2O=95/5 (v/v) over 60 min;
detector: UV 254 n) to give 1-4 (30 g, 41%) as a white solid. LC-MS
(ES, m/z): 324 [M+H].sup.+; .sup.1H-NMR (400 MHz, d.sup.6-DMSO):
.delta. 14.97 (s, 1H), 7.48-7.36 (m, 2H), 7.32 (d, J=7.8 Hz, 1H),
7.23-7.13 (m, 1H), 6.56 (d, J=10.1 Hz, 1H), 4.98 (m, 1H), 1.01 (s,
9H).
Intermediate Example 2: Preparation of
1-(tetrahydro-2H-pyran-4-yl)piperidine-2,4,6-trione (2-3)
##STR00018##
[0184] Step A-1. Synthesis of 1-(tetrahydro-2H-pyran-4-yl)urea
(2-2) (Method A). To a solution of 2-1 (24 g, 0.24 mol) in DCM
(3000 mL) was added isocyanatotrimethylsilane (30 g, 0.26 mol) at
0.degree. C. under an atmosphere of Ar. After stirring at rt
overnight, the reaction was quenched by adding MeOH (20 mL). The
solvent was removed and the residue was triturated with ether (50
mL). Subsequently, the suspension was filtered and the solid was
washed with ether (500 mL.times.3) and dried in vacuo to give 2-2
(34 g, 68%) as a white solid. H NMR (300 MHz, d.sup.6-DMSO):
.delta. 5.96 (d, J=7.8 Hz, 1H), 5.37 (s, 2H), 3.79 (m, 2H),
3.63-3.43 (m, 1H), 3.32 (m, 2H), 1.70 (m, 2H), 1.29 (m, 2H).
[0185] Step 2. Synthesis of
1-(tetrahydro-2H-pyran-4-yl)piperidine-2,4,6-trione (2-3). To a
solution of NaOMe (20 g, 0.38 mol) in MeOH (3000 mL) was added 2-2
(34 g, 0.24 mol), followed by 1,3-dimethyl propanedioate (470 g,
0.36 mol) at rt under an atmosphere of Ar. After stirring at
80.degree. C. overnight, the reaction mixture was concentrated and
the residue was dilute with water (50 mL). Subsequently, the pH
value of the resulting mixture was adjusted to 2 by adding coned.
aq. HCl at 0.degree. C. The suspension was filtered and the solid
was washed with water and dried in vacuo at 45.degree. C. for 24 h
to give 2-3 (30 g, 60%) as a white solid. .sup.1H NMR (300 MHz,
d.sub.6-DMSO): .delta. 11.25 (s, 1H), 4.69 (m, 1H), 3.91 (m, 2H),
3.60 (s, 2H), 3.33 (m, 2H), 2.43 (m, 2H), 1.59-1.40 (m, 2H).
[0186] Step B-1. Synthesis of phenyl carbamate (2-5). To a mixture
of sat. aq. ammonia (50 mL) and DCM (50 mL) was added a solution of
2-4 (30 g) in DCM (45 mL) at 0.degree. C. After stirring at
0.degree. C. for 4 h, the reaction mixture was filtered and the
solid was washed with water and dried in vacuo at 45.degree. C. for
12 h to give 2-5 (18.3 g, 70%) as a white solid. LC-MS (ES, m/z):
138 [M+H].sup.+; .sup.1H NMR (400 MHz, d.sub.6-DMSO): .delta.
7.42-7.32 (m, 2H), 7.24-7.15 (m, 1H), 7.13-7.04 (m, 2H), 6.89 (br,
2H).
[0187] Step B-2. Synthesis of 1-(tetrahydro-2H-pyran-4-yl)urea
(2-2) (Method B). A mixture of 2-5 (18.3 g, 0.13 mol), DIEA (17.3
g, 0.13 mol), and 2-1 (13.5 g, 0.13 mol) in THF (130 mL) was
stirred at 70.degree. C. for 3 h under an atmosphere of Ar.
Subsequently, the suspension was filtered and the solid was washed
with ether (100 mL) and dried in vacuo at 45.degree. C. for 12 h to
give 2-2 (18.3 g, 95%) as a white solid. .sup.1H NMR (400 MHz,
d.sub.6-DMSO): .delta. 5.96 (d, J=7.8 Hz, 1H), 5.37 (s, 2H), 3.78
(m, 2H), 3.51 (m, 1H), 3.32 (m, 2H), 1.69 (m, 2H), 1.28 (m,
2H).
Intermediate Example 3: Preparation of
(2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)prop-
anoic acid (3-3)
##STR00019##
[0189] Step 1. Synthesis of
(R,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (4-1).
A mixture of 1-1 (5.0 g, 40.3 mmol),
(R)-2-methylpropane-2-sulfinamide (5.1 g, 42.2 mmol), and
Cs.sub.2CO.sub.3 (15.7 g, 48.25 mol) in DCM (60 mL) was stirred at
rt overnight under an atmosphere of Ar. Subsequently, the reaction
mixture was diluted with ether (200 mL) and then filtered. The
filtrate was concentrated and the residue was dried in vacuo to
give crude 3-1 (10 g) as a white solid, which was used in the next
step without further purification. LC-MS (ES, m/z): 228
[M+H].sup.+; .sup.1H NMR (300 MHz, d.sub.6-DMSO): .delta. 8.58 (s,
1H), 7.88-7.73 (m, 2H), 7.60 (m, 1H), 7.45 (m, 1H), 1.19 (s,
9H).
[0190] Step 2. Synthesis of ethyl
(2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)prop-
anoate (3-2). To a solution of crude 3-1 (3.0 g, 13.2 mmol), TMEDA
(3.6 mL), and ethyl 2-fluoroacetate (2.1 g, 19.8 mol) in THF (30
mL) was added LiHMDS (1M in THF, 19.8 mL) dropwise at -78.degree.
C. over 30 min under an atmosphere of Ar. After stirring at
-78.degree. C. for 1 h, the reaction was quenched by adding 2 N aq.
HCl (45 mL) at -78.degree. C. The reaction mixture was concentrated
to remove most of THF and then extracted with EtOAc (100
mL.times.3). Subsequently, the combined organic extracts were
washed with brine and dried over anhydrous Na.sub.2SO.sub.4. The
solvent was removed and the residue was dried in vacuo to give
crude 3-2 (4.6 g) as an off-white solid, which was used for the
next step without further purification. LC-MS (ES, m/z): 334
[M+H].sup.+.
[0191] Step 3. Synthesis of
(2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)prop-
anoic acid (3-3). To a solution of crude 3-2 (6 g, 18 mmol) in THF
(60 mL) was added 1N aq. NaOH (36 mL, 36 mmol) at rt. After
stirring at rt overnight, the reaction mixture was diluted with
water (100 mL). The resulting mixture was extracted with EtOAc (100
mL.times.2). The aqueous layer was adjusted to pH 5 with sat. aq.
citric acid and the resulting mixture was extracted with EtOAc (200
mL.times.3). Next, the combined organic extracts were washed with
brine (100 mL) and dried over anhydrous Na.sub.2SO.sub.4. The
solvent was removed and the residue was purified by preparative
HPLC (column: XBridge Prep OBD C18 column, 19.times.250 mm, 5 um;
mobile phase: water (0.05% TFA (v/v)) and ACN (3.0% (v/v) up to
17.0% (v/v) in 8 min); detector: UV 220 nm) to give 3-3 (1.5 g,
27%) as a white solid. LC-MS (ES, m/z): 306 [M+H].sup.+; .sup.1H
NMR (400 MHz, d.sup.6-DMSO): .delta. 12.83 (s, 1H), 7.53-7.44 (m,
1H), 7.42-7.35 (m, 2H), 7.12 (m, 1H), 6.12 (d, J=10.7 Hz, 1H), 5.33
(m, 1H), 4.86 (m, 1H), 1.14 (s, 9H).
Comparative Example 1: Preparation of
(S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (C-1)
##STR00020##
[0193] Step 1. Synthesis of
(S)--N-((1S)-2,2-difluoro-1-(3-fluorophenyl)-3-oxo-3-(2,4,6-trioxo-1-(tet-
rahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropane-2-su-
lfinamide (C-A). To a solution of 1-4 (2.69 g, 8.32 mmol), HATU
(4.75 g, 12.49 mmol), and 2-3 (2.65 g, 12.49 mmol) in DMF (30 mL)
was added DIEA (2.15 g, 16.63 mmol) dropwise at 0.degree. C. After
stirring at rt overnight, the reaction mixture was diluted with
sat. aq. NaHCO.sub.3 (100 mL) and ice water (100 mL). The mixture
was extracted with EtOAc (100 mL.times.3) and the combined organic
extracts were washed with brine and dried over anhydrous
Na.sub.2SO.sub.4. The solvent was removed and the residue was dried
in vacuo to give crude C-A (1.23 g, 29%) as a yellow solid, which
was used for the next step without further purification. LC-MS (ES,
m/z): 518 [M+H].sup.+.
[0194] Step 2. Synthesis of
(S)--N-((1S)-2,2-difluoro-1-(3-fluorophenyl)-3-(2,4,6-trioxo-1-(tetrahydr-
o-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropane-2-sulfinam-
ide (C-B). A mixture of C-A (1 g, 1.93 mmol) and sodium
cyanoborohydride (606.8 mg, 9.66 mmol) in acetic acid (15 mL) was
stirred at rt for 1 h. Subsequently, the reaction mixture was
diluted with ice water (50 mL) and extracted with EtOAc (50
mL.times.3). The combined organic extracts were washed with brine
and dried over anhydrous Na.sub.2SO.sub.4. The solvent was removed
and the residue was dried in vacuo to give crude C-B (1.28 g) as a
white solid, which was used for the next step without further
purification. LC-MS (ES, m/z): 504 [M+H].sup.+.
[0195] Step 3. Synthesis of
5-((S)-3-amino-2,2-difluoro-3-(3-fluorophenyl)propyl)-1-(tetrahydro-2H-py-
ran-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (C-C). To a solution of
crude C-B (1.28 g) in ethanol (18 mL) was added thionyl chloride
(2.7 mL) at 0.degree. C. over 3 min. After stirring at rt for 1 h,
the reaction mixture was concentrated and dried in vacuo to give
crude C-C (800 mg) as a yellow solid, which was used for the next
step without further purification. LC-MS (ES, m/z): 400
[M+H].sup.+.
[0196] Step 4. Synthesis of
(S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (C-1). A mixture
of crude C-C (800 mg) in CH.sub.3CN (10 mL) in a sealed vial was
stirred 120.degree. C. for 20 min in a microwave reactor.
Subsequently, the mixture was diluted with water (50 mL) and the
resulting mixture was extracted with EtOAc (50 mL.times.3). The
combined organic extracts were washed with brine and dried over
anhydrous Na.sub.2SO.sub.4. The solvent was removed and the residue
was purified by preparative HPLC (column: XBridge C18 OBD Prep
Column, 19 mm.times.250 mm; mobile phase: water (0.05% (v/v)
NH.sub.3.H.sub.2O)/CH.sub.3CN=11.0% (v/v) to 30.0% (v/v) in 8 min;
detector: UV 254 nm) to give C-1 (197 mg, 27% three steps from C-A)
as a white solid. LC-MS (ES, m/z): 382 [M+H].sup.+; .sup.1H NMR
(400 MHz, d.sup.6-DMSO): .delta. 10.67 (s, 1H), 7.51-7.45 (m, 1H),
7.32-7.14 (m, 3H), 7.05 (s, 1H), 5.04-4.73 (m, 2H), 4.02-3.80 (m,
2H), 3.36-3.30 (m, 2H), 2.95-2.72 (m, 1H), 2.66-2.52 (m, 3H),
1.51-1.33 (m, 2H).
Example 1-1: Preparation of
(6S,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1)
##STR00021##
[0198] Steps 1 to 4. Synthesis of
(6S,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1). Following
the same procedure as that described for preparing
(S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (C-4) and
replacing
(S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)prop-
anoic acid (1-4) with
(2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)prop-
anoic acid (3-3), 1 was obtained as a white solid. LC-MS (ES, m/z):
364 [M+H].sup.+; .sup.1H NMR (300 MHz, d.sup.6-DMSO): .delta. 10.18
(s, 1H), 7.61-7.37 (m, 1H), 7.31-7.11 (m, 3H), 6.52 (s, 1H), 5.08
(m, 1H), 4.88 (m, 1H), 4.72 (d, J=26.8 Hz, 1H), 3.93 (m, 2H), 3.34
(m, 2H), 2.74-2.53 (m, 4H), 1.46-1.31 (m, 2H); .sup.19F NMR (376
MHz, d.sup.6-DMSO): .delta.-113.18, -192.36.
Example 1-2: Preparation of
(6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2)
##STR00022## ##STR00023##
[0200] Steps 1 to 2. Synthesis of
(2S,3S)-3-(((S)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)prop-
anoic acid (2B). Following the same procedure as that described for
preparing
(S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorop-
henyl)propanoic acid (1-4) and replacing ethyl
2-bromo-2,2-difluoroacetate with ethyl 2-bromo-2-fluoroacetate, 2B
was obtained as an off-white solid. LC-MS (ES, m/z): 306
[M+H].sup.+.
[0201] Steps 3 to 6. Synthesis of
(6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2). Following
the same procedure as that described for preparing
(S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (C-4) and
replacing
(S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)prop-
anoic acid (1-4) with
(2S,3S)-3-(((S)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)prop-
anoic acid (2B), 2 was obtained as a white solid. LC-MS (ES, m/z):
364 [M+H].sup.+; .sup.1H NMR (300 MHz, d.sup.6-DMSO): .delta. 10.66
(s, 1H), 7.51-7.37 (m, 1H), 7.21-7.08 (m, 3H), 6.76 (d, J=4.0 Hz,
1H), 5.29-5.01 (m, 1H), 4.84 (d, J=10.2 Hz, 2H), 3.97-3.86 (m, 2H),
3.30 (m, 2H), 2.58 (m, 3H), 2.12-1.88 (m, 1H), 1.46-1.34 (m, 2H);
.sup.19F NMR (376 MHz, d.sup.6-DMSO): .delta.-112.59, -175.93.
Example 1-3: Preparation of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione
(3)
##STR00024## ##STR00025##
[0203] Step 1. Synthesis of
(R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide
(3B). A mixture of 2-fluoro-5-methylbenzaldehyde (3A) (5 g, 36.2
mmol), Cs.sub.2CO.sub.3 (17.6 g, 54.0 mmol), and
(R)-2-methylpropane-2-sulfinamide (4.6 g, 38.0 mmol) in DCM (100
mL) was stirred at rt overnight under an atmosphere of Ar. The
reaction mixture was filtered and the filtrate was diluted with
ether (150 mL). Subsequently, the resulting suspension was
filtered. The filtrate was concentrated and the residue was dried
in vacuo to give 3B (8.7 g, 97%) as a yellow oil. LC-MS (ES, m/z):
242 [M+H].sup.+; .sup.1H NMR (400 MHz, d.sup.6-DMSO): .delta. 8.87
(s, 1H), 7.76 (m, 1H), 7.29 (m, 1H), 7.03 (m, 1H), 2.37 (d, J=1.0
Hz, 3H), 1.27 (s, 9H).
[0204] Step 2. Synthesis of ethyl
(2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(2-fluoro-5-methylph-
enyl)propanoate (3C). To a solution of 3B (4 g, 16.6 mmol), ethyl
2-fluoroacetate (2.6 g, 24.6 mmol), and TMEDA (4.8 mL) in anhydrous
THF (40 mL) was added LiHMDS (1 M in THF, 24.6 mL, 24.6 mmol)
dropwise at -78.degree. C. over 30 min under an atmosphere of Ar.
After stirring at -78.degree. C. for 1 h, the reaction was quenched
by adding 1 N aq. HCl (50 mL), while maintaining the inner
temperature of the mixture at <-20.degree. C. Subsequently, the
mixture was concentrated to remove most of the organic solvent and
then extracted with EtOAc (100 mL.times.3). The combined organic
extracts were washed with brine (100 mL) and dried over anhydrous
Na.sub.2SO.sub.4. The solvent was removed and the residue was dried
in vacuo to give crude 3C (6.0 g) as a yellow oil, which was used
for the next step without further purification. LC-MS (ES, m/z):
348 [M+H].sup.+.
[0205] Step 3. Synthesis of
(2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(2-fluoro-5-methylph-
enyl)propanoic acid (3D). To a solution of 3C (6.0 g, 17.3 mmol) in
THF (40 mL) was added 1N aq. NaOH (34.6 mL, 34.6 mmol) at rt. After
stirring at rt for 1 h, the reaction mixture was added ice water
(50 mL). The resulting mixture was extracted with EtOAc (100
mL.times.2). The aqueous layer was adjusted to pH 5 with sat. aq.
citric acid, followed by extraction with EtOAc (100 mL.times.3).
Subsequently, the combined organic extracts were washed with brine
(100 mL) and dried over anhydrous Na.sub.2SO.sub.4. The solvent was
removed and the residue was purified by preparative HPLC (Column:
XBridge Prep OBD C18 Column, 19.times.250 mm, 5 um; mobile phase:
water (0.05% TFA) and ACN (28.0% ACN up to 36.0% in 10 min);
detector: UV 220 n) to give 3D (2 g, 36%) as a white solid. LC-MS
(ES, m/z): 320 [M+H].sup.+; .sup.1H NMR (400 MHz, d.sup.6-DMSO):
.delta. 13.57 (br, 1H), 7.55 (dd, J=7.5, 2.2 Hz, 1H), 7.23-6.94 (m,
2H), 6.04 (d, J=10.8 Hz, 1H), 5.37-4.86 (m, 2H), 2.29 (s, 3H), 1.12
(s, 9H).
[0206] Step 4. Synthesis of
(R)--N-((1S,2R)-2-fluoro-1-(2-fluoro-5-methylphenyl)-3-oxo-3-(2,4,6-triox-
o-1-(tetrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylprop-
ane-2-sulfinamide (3E). A solution of 3D (700 mg, 2.19 mmol), 2-2
(698 mg, 3.29 mmol), and HATU (1.25 g, 3.29 mmol) in DMF (10 mL)
was added DIEA (849 mg, 6.57 mmol) at 0.degree. C. under an
atmosphere of Ar. After stirring at rt for 2 h, the reaction was
quenched by adding sat. aq. sodium bicarbonate (30 mL) and the
resulting solution was extracted with ethyl acetate (50
mL.times.3). The combined organic extracts were washed with brine
(50 mL.times.2) and dried over anhydrous Na.sub.2SO.sub.4. The
solvent was removed and the residue was dried in vacuo to give
crude 3E (1.3 g) as a white solid, which was used for the next step
without further purification. LC-MS (ES, m/z): 514 [M+H].sup.+;
.sup.1H NMR (400 MHz, d.sub.6-DMSO): .delta. 12.16 (br, 1H),
7.66-7.45 (m, 1H), 7.23-6.98 (m, 2H), 6.37 (m, 1H), 6.13 (d, J=10.7
Hz, 1H), 5.22 (m, 1H), 4.79 (m, 1H), 3.94 (m, 2H), 3.35 (t, J=11.7
Hz, 2H), 2.52-2.39 (m, 2H), 2.29 (s, 3H), 1.49 (d, J=12.2 Hz, 2H),
1.04 (s, 9H).
[0207] Step 5. Synthesis of
(R)--N-((1S,2S)-2-fluoro-1-(2-fluoro-5-methylphenyl)-3-(2,4,6-trioxo-1-(t-
etrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropane-2--
sulfinamide (3F). A solution of crude 3E (1.3 g, 2.53 mmol) in AcOH
(10 mL) was added NaBH3CN (398 mg, 6.33 mmol) at 0.degree. C. under
an atmosphere of Ar. After stirring at rt for 1 h, the reaction
mixture was added ice water (20 mL) and the resulting solution was
extracted with EtOAc (50 mL.times.3). Next, the combined organic
extracts were washed with brine (50 mL) and dried over anhydrous
Na.sub.2SO.sub.4. The solvent was removed and the residue was dried
in vacuo to give crude 3F (1.3 g) as a white solid, which was used
for the next step without further purification. LC-MS (ES, m/z):
500 [M+H].sup.+; .sup.1H NMR (400 MHz, d.sup.6-DMSO): .delta. 11.31
(d, J=28.1 Hz, 1H), 7.41 (d, J=7.4 Hz, 1H), 7.27-6.84 (m, 2H),
6.11-5.78 (m, 2H), 5.08-4.43 (m, 3H), 3.87 (m, 3H), 2.29 (s, 6H),
1.99 (s, 1H), 1.53-1.28 (m, 2H), 1.10 (d, J=2.1 Hz, 10H).
[0208] Step 6. Synthesis of
5-((2S,3S)-3-amino-2-fluoro-3-(2-fluoro-5-methylphenyl)propyl)-1-(tetrahy-
dro-2H-pyran-4-yl)pyrimidine-2,4,6 (1H,3H,5H)-trione (3G). A
solution of crude 3F (1.3 g, 2.60 mmol) in ethanol (10 mL) was
added thionyl chloride (334 mg) at 0.degree. C. After stirring at
rt for 1 h, the reaction mixture was concentrated and the residue
was dried in vacuo to give crude 3G (1.0 g) as a white solid, which
was used for the next step without further purification. LC-MS (ES,
m/z): 396 [M+H].sup.+.
[0209] Step 7. Synthesis of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4 (1H,3H)-dione (3). A
mixture of crude 3G (1.0 g, 2.53 mmol) in CH.sub.3CN (15 mL) was
put into a microwave reactor with stirring at 120.degree. C. for 30
min. Subsequently, the mixture was concentrated and the residue was
purified by preparative HPLC (column: C18 silica gel; mobile phase:
CH3CN:H2O=20:80 (v/v) increasing to CH3CN:H2O=80:20 (v/v) within 40
min; detector: UV 254 nm) to give compound 3 (302 mg, 32%), as a
white solid, which was identified as Form 1 polymorph (see Example
2). LC-MS (ES, m/z): 378 [M+H].sup.+; .sup.1H NMR (300 MHz,
d.sup.6-DMSO): .delta. 10.20 (s, 1H), 7.38-7.05 (m, 3H), 6.45 (s,
1H), 5.11-4.81 (m, 3H), 3.89 (dd, J=10.8, 3.9 Hz, 2H), 3.34-3.27
(m, 3H), 2.76-2.48 (m, 4H), 2.28 (s, 3H), 1.39-1.36 (m, 2H);
.sup.19F NMR (376 MHz, d.sup.6-DMSO): .delta.-123.51 (t, J=86.5
Hz), -191.57 (d, J=129.34 Hz).
Example 1-4: Preparation of
(6R,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4)
##STR00026## ##STR00027##
[0211] Steps 1 to 7. Synthesis of
(6R,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4).
Following the same procedure as that described for preparing
(6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2) and
replacing 3-fluorobenzaldehyde (1-1) with
2-fluoro-5-methylbenzaldehyde (3A), 4 was obtained as a white
solid. LC-MS (ES, m/z): 378 [M+H]; .sup.1H NMR (400 MHz,
d.sup.6-DMSO): .delta. 10.69 (s, 1H), 7.19-7.09 (m, 2H), 6.98 (d,
J=6.8 Hz, 1H), 6.62 (d, J=3.6 Hz, 1H), 5.08-4.84 (m, 3H), 3.91 (dd,
J=11.2, 3.6 Hz, 2H), 3.32 (m, 2H), 2.68-2.55 (m, 4H), 2.27 (s, 3H),
2.17-2.03 (m, 1H), 1.42-1.39 (m, 2H); .sup.19F NMR (376 MHz,
d.sub.6-DMSO): .delta.-124.08, -175.61.
Example 1-5: Preparation of Synthesis of
(6R,7R)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (5)
##STR00028## ##STR00029##
[0213] Steps 1 to 6. Synthesis of
(6R,7R)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (5).
Following the same procedure as that described for preparing
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3) and
replacing
(R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfin-
amide (3B) with
(S,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide
(4B), 5 was obtained as a white solid. LC-MS (ES, m/z): 378
[M+H].sup.+; .sup.1H NMR (300 MHz, d.sup.6-DMSO): .delta. 10.72 (s,
1H), 7.85-7.11 (m, 3H), 6.45 (s, 1H), 5.14-3.93 (m, 3H), 3.92 (dd,
J=10.4, 5.2 Hz, 2H), 3.52-3.29 (m, 3H), 2.82-2.66 (m, 4H), 2.31 (s,
3H), 1.39-1.36 (m, 2H); .sup.19F NMR (376 MHz, d.sup.6-DMSO):
.delta.-123.49, -191.34.
Example 1-6: Preparation of
(6S,7R)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6)
##STR00030## ##STR00031##
[0215] Steps 1 to 6.
(6S,7R)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6).
Following the same procedure as that described for preparing
(6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8--
tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2) and
replacing
(S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (1-2)
with
(R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide
(3B), 6 was obtained as a white solid. LC-MS (ES, m/z): 378
[M+H].sup.+; .sup.1H NMR (300 MHz, d.sup.6-DMSO): .delta. 10.69 (s,
1H), 7.21-7.09 (m, 2H), 6.98 (d, J=6.8 Hz, 1H), 6.66 (d, J=3.6 Hz,
1H), 5.11-4.84 (m, 3H), 3.92 (dd, J=11.1, 3.9 Hz, 2H), 3.35-3.29
(m, 2H), 2.69-2.52 (m, 4H), 2.27 (s, 3H), 2.14-2.00 (m, 1H),
1.43-1.39 (m, 2H); .sup.19F NMR (376 MHz, d.sup.6-DMSO):
.delta.-124.36, -175.43.
[0216] Additional compounds were prepared using similar approaches
to those provided above.
Characterization Data for Compounds
TABLE-US-00001 [0217] TABLE 1A Observed bcMF MS Synthetic pCa_6
IC50 STRUCTURE [M + H].sup.+ Proton NMR method(s) MEAN ##STR00032##
388 .sup.1H NMR (400 MHz, d.sup.6- DMSO in ppm): .delta. 7.68 -
7.51 (m, 2H), 7.33 - 7.29 (m, 1H), 5.14 - 4.83 (m, 3H), 4.20 (s,
1H), 3.91 - 3.88 (m, 2H), 3.39 - 3.28 (m, 2H), 2.77 - 2.58 (m, 4H),
1.39 - 1.31 (m, 2H) Scheme 3 0.54 ##STR00033## 364 .sup.1H NMR (400
MHz, d.sup.6- DMSO in ppm): .delta. 10.73 (s, 1H), 7.43 - 7.36 (m,
1H), 7.27 - 7.18 (m, 3H), 6.65 (d, J = 4.0 Hz, 1H), 5.13 - 4.97 (m,
2H), 4.86 (tt, J = 12.1 and 4.2 Hz, 1H), 3.91 (dd, J = 11.4 and 4.5
Hz, 2 H), 3.36 - 3.29 (m, 2H), 2.69 - 2.55 (m, 3H), 2.05 (ddd, J =
40.8, 7.0 and 3.3 Hz, 1H), 1.45 - .37 (m, 2H) Scheme 2 1.46
##STR00034## 364 .sup.1H NMR (400 MHz, d.sup.6- DMSO in ppm):
.delta. 10.24 (s, 1H), 7.45 - 7.38 (m, 1H), 7.30 - 7.21 (m, 3H),
6.44 (s, 1H), 5.08 (dm, J = 47.4 Hz, 1H), 4.98 (d, J = 25.0 Hz,
1H), 4.87 (tt, J = 12.1 and 4.2 Hz, 1H), 3.92 (dd, J = 11.2 and 4.4
Hz, 2H), 3.37 - 3.29 (m, 2H), 2.78 - 2.52 (m, 4H), 1.44 - 1.36 (m,
2H) Scheme 1 5.59 ##STR00035## 394 .sup.1H NMR (400 MHz, d.sup.6-
DMSO in ppm): .delta. 10.26 (s, 1H), 7.20 (dd, J = 10.1 and 9.0 Hz,
1H), 6.97 (ddd, J = 9.0, 4.0 and 2.5 Hz, 1H), 6.91 (dd, J = 6.1 and
2.5 Hz, 1H), 6.47(s, 1H), 5.14 - 4.81 (m, 3H), 3.91 (dd, J = 11.4
and 4.6 Hz, 2H), 3.74 (s, 3H), 3.36 - 3.28 (m, 2H), 2.75 2.53 (m,
4H), 1.43 - 1.35 (m, 2H) Scheme 3 1.02 ##STR00036## 394 .sup.1H NMR
(400 MHz, d.sup.6- DMSO in ppm): .delta. 10.75 (s,1H), 7.19 (dd, J
= 10.0 and 9.1 Hz, 1H), 6.94 (dt, J = 9.1 and 3.5 Hz, 1H), 6.72 (s,
1H), 6.65 (dd, J = 6.1 and 3.5 Hz, 1H), 5.12 - 4.94 (m, 2H), 4.86
(tt, J = 12.1 and 4.0 Hz, 1H), 3.90 (dd, J = 11.4 and 4.2 Hz, 2H),
3.71 (s, 3H), 3.37 - 3.28 (m, 2H), 2.69 - 2.53 (m, 3H), 2.09 (ddd,
J = 39.6, 16.8 and 3.4 Hz, 1H), 1.44 - 1.37 (m, 2H) Scheme 4 0.49
##STR00037## 378 .sup.1H NMR (300 MHz, d.sup.6- DMSO in ppm):
.delta. 10.69 (s, 1H), 7.21 - 7.09 (m, 2H), 6.98 (d, J = 6.8 Hz,
1H), 6.66 (d, J = 3.6 Hz, 1H), 5.11 - 4.84 (m, 3H), 3.92 (dd, J =
11.1, 3.9 Hz, 2H), 3.35 - 3.29 (m, 2H), 2.69 - 2.52 (m, 4H), 2.27
(s, 3H), 2.14 - 2.00 (m, 1H), 1.43 - 1.39 (m, 2H) Scheme 6 26.4
##STR00038## 378 .sup.1H NMR (300 MHz, d.sup.6- DMSO in ppm):
.delta. 10.72 (s, 1H), 7.85 - 7.11 (m, 3H), 6.45 (s, 1H), 5.14 -
3.93 (m, 3H), 3.92 (dd, J = 10.4, 5.2 Hz, 2H), 3.52 - 3.29 (m, 3H),
2.82 - 2.66 (m, 4H), 2.31 (s, 3H), 1.39 - 1.36 (m, 2H) Scheme 5
20.84 ##STR00039## 378 .sup.1H NMR (400 MHz, d.sup.6- DMSO in ppm):
.delta. 10.69 (s, 1H), 7.19 - 7.09 (m, 2H), 6.98 (d, J = 6.8 Hz,
1H), 6.62 (d, J = 3.6 Hz, 1H), 5.08 - 4.84 (m, 3H), 3.91 (dd, J =
11.2, 3.6 Hz, 2H), 3.32 (m, 2H), 2.68 - 2.55 (m, 4H), 2.27 (s, 3H),
2.17 - 2.03 (m, 1H), 1.42 - 1.39 (m, 2H) Scheme 4 0.37 ##STR00040##
378 .sup.1H NMR (300 MHz, d.sup.6- DMSO in ppm): .delta. 10.20 (s,
1H), 7.38 - 7.05 (m, 3H), 6.45 (s, 1H), 5.11 - 4.81 (m, 3H), 3.89
(dd, J = 10.8, 3.9 Hz, 2H), 3.34 - 3.27 (m, 3H), 2.76 - 2.48 (m,
4H), 2.28 (s, 3H), 1.39 - 1.36 (m, 2H) Scheme 3 1.11 ##STR00041##
364 .sup.1H NMR (300 MHz, d.sup.6- DMSO in ppm): .delta. 10.18 (s,
1H), 7.61 - 7.37 (m, 1H), 7.31 - 7.11 (m, 3H), 6.52 (s, 1H), 5.08
(m, 1H), 4.88 (m, 1H), 4.72 (d, J = 26.8 Hz, 1H), 3.93 (m, 2H),
3.34 (m, 2H), 2.74 - 2.53 (m, 4H), 1.46 - 1.31 (m, 2H) Scheme 1
3.0325 ##STR00042## 364 .sup.1H NMR (300 MHz, d.sup.6- DMSO in
ppm): .delta. 10.13 (s, 1H), 7.57 - 7.37 (m, 1H), 7.18 (m, 3H),
6.47 (s, 1H), 5.03 (d, J = 47.8 Hz, 1H), 4.90 - 4.76 (m, 1H), 4.67
(d, J = 26.6 Hz, 1H), 3.88 (m, 2H), 3.33 (m, 1H), 3.25 (m, 1H),
2.76 - 2.48 (m, 4H), 1.37 (m, 2H) Scheme 5 23.17 ##STR00043## 364
.sup.1H NMR (300 MHz, d.sup.6- DMSO in ppm): .delta. 10.66 (s, 1H),
7.51 - 7.37 (m, 1H), 7.21 - 7.08 (m, 3H), 6.76 (d, J = 4.0 Hz, 1H),
5.29 - 5.01 (m, 1H), 4.84 (d, J = 10.2 Hz, 2H), 3.97 - 3.86 (m,
2H), 3.30 (m, 2H), 2.58 (m, 3H), 2.12 - 1.88 (m, 1H), 1.46 - 1.34
(m, 2H) Scheme 2 2.134 ##STR00044## 394 .sup.1H NMR (400 MHz, DMSO-
d.sup.6): .delta. 10.24 (s, 1H), 7.40 (d, J = 7.1 Hz, 1H), 7.33 (s,
1H), 7.25 - 7.16 (m, 1H), 6.45 (s, 1H), 5.30 (t, J = 5.6 Hz, 1H),
5.16 - 4.86 (m, 3H), 4.49 (d, J = 5.1 Hz, 2H), 3.92 (dd, J = 11.4,
4.4 Hz, 2H), 3.36 (s, 2H), 2.63 (s, 4H), 1.40 (d, J = 12.2 Hz, 2H)
Scheme 3 0.78
Example 2
Single Crystal X-Ray Analysis--Form 1
[0218] SXRD analysis was conducted on an Agilent Technologies (Dual
Source) SuperNova diffractometer using monochromated Cu K.alpha.
(.lamda. 1.54178 .ANG.) radiation generated by sealed tube. The
diffractometer was fitted with an Oxford Cryosystems low
temperature device to enable data collection to be performed at
120(1) K and the crystal encased in a protective layer of Paratone
oil. The data collected were corrected for absorption effects based
on Gaussian integration over a multifaceted crystal model,
implemented as a part of the CrysAlisPro software package (Agilent
Technologies, 2014).
[0219] The structure was solved by direct methods (SHELXS97).sup.1
and developed by full least squares refinement on F.sup.2
(SHELXL97).sup.1 interfaced via the OLEX2 software package (see
FIG. 4). Images produced were done so via OLEX2..sup.2 Data was
collected, solved and refined in the orthorhombic space-group
P2.sub.12.sub.12.sub.1 and a search for higher metric symmetry
using the ADDSYMM.sup.3 routine of PLATON.sup.4 but failed to
uncover any higher order symmetry. All non-hydrogen atoms were
located in the Fourier map and their positions refined prior to
describing their thermal movement of all non-hydrogen atoms
anisotropically. Within the structure, one, complete molecule of 3
(also referred to as a compound of Example 3) was located in the
asymmetric unit only. Due to the weak diffraction data obtained,
the Flack parameter could be calculated to -0.0657 with esd of
0.7497 (calculated from 1477 Bijovet pairs with 97.6%
completeness). Attempts to refine the structure using TWIN and BASF
commands did not yield further improvements. All hydrogen atoms
were placed in calculated positions using a riding model with fixed
Uiso at 1.2 times for all CH, CH.sub.2 and NH groups, and 1.5 times
for all CH.sub.3 groups. The highest residual Fourier peak was
found to be 1.34 e.ANG..sup.-3 approx 0.68 .ANG. from C(16) and the
deepest Fourier hole was found to be -0.89 e.ANG..sup.-3 approx
0.58 .ANG. from O(2).
Crystal Data--Form 1
[0220] C.sub.19H.sub.21F.sub.2N.sub.3O.sub.3 (M=377.39 g/mol):
orthorhombic, space group P2.sub.12.sub.12.sub.1 (no. 19),
a=28.153(2) .ANG., b=6.6890(3) .ANG., c=9.1390(6) .ANG.,
V=1721.04(19) .ANG..sup.3, Z=4, T=120(1) K, .mu.(CuK.alpha.)=0.964
mm.sup.-1, Dcalc=1.456 g/cm.sup.3, 30202 reflections measured
(10.18.degree..ltoreq.2.THETA..ltoreq.153.36.degree.), 3570 unique
(R.sub.int=0.1117, R.sub.sigma=0.0636) which were used in all
calculations. The final R1 was 0.1591 (>2sigma(I)) and wR.sub.2
was 0.3889 (all data).
[0221] X-ray Powder Diffraction (XRPD), Dynamic Scanning
Calorimetry (DSC) and Thermo Gravimeric Analysis (TGA) data for
Form 1 of the compound of Example 1-3 are shown in FIGS. 1A-1C, 2
and 3, respectively.
Biological Examples
[0222] Compounds were profiled by assessing their physicochemical
properties, biochemical activities, cell-based activities,
selectivity profiles, pharmacokinetic (PK) profiles,
pharmacodynamic (PD) profiles, and safety profiles in various in
vitro and in vivo assays, including but not limited to myosin
ATPase assays (bovine cardiac myobril system (bcMF) with/without
serum and rabbit skeletal myobril system (rbskMF), cardiomyocyte
contractility and reactive metabolite identification.
[0223] Compounds with a reduced half-life were selected to enable a
potentially more rapid dose adjustment, since a shorter half-life
allows a faster time to get to steady-state exposures. Removal, or
minimization, of dependence on polymorphic cytochrome P450 (CYP)
enzymes, such as CYP2C19, for the metabolic clearance of the drug
candidates provided a potential advantage for reduced human PK
variability that may occur for instance between poor and rapid drug
metabolizers. Removal, or minimization, of potent CYP enzyme
induction properties of a new drug candidates provided an advantage
to avoid potential for drug-drug interactions. Increased
selectivity of the drug candidate for cardiac myosin over skeletal
myosin had a benefit for desired human pharmacokinetics related to
myosin modulator drug distribution. Myosin modulator candidate
drugs with decreased potency toward skeletal myosin were predicted
to distribute less into skeletal muscle tissue, due to lower drug
binding to skeletal myosin, leading to decreased volume of
distribution and therefore decreased half-life in human.
Preclinical pharmacokinetic/pharmacodynamics studies were performed
to optimize the selection compounds with that may allow oral dosing
with reduced risk of drug-induced liver toxicity. Lammert et al.
(2008) Relationship Between Daily Dose of Oral Medications and
Idiosyncratic Drug-induced Liver Injury: Search for Signals.
Hepatology, 47: 2003-2009.
KS Solubility Assay
[0224] Small molecule agents were assessed for their kinetic
solubility in PBS at pH7.4 at rt using Reserpine (kinetic
solubility <15 .mu.M in PBS at 7.4) as a negative control and
Verapamil (kinetic solubility >200 .mu.M in PBS at 7.4) as a
positive control. 2 .mu.L of the 20 mM DMSO stock solution of a
compound was added into a well in a 96-well plate, followed by
adding 198 .mu.L of PBS at rt. After shaking at room temperature
for 1.5 h, the mixture was filtered under vacuum through a 96-well
filter plate, which was pre-washed with 100 .mu.L of 70% ethanol
per well. Subsequently, 70 .mu.L of the filtrate was added into a
well in a 96-well reading plate, which was pre-loaded with 70 .mu.L
of DMSO per well. The concentration of the sample in a well was
determined on the basis of the interagration on LC with UV
detection as compared to the standard curve of each compound
established in DMSO.
Myosin Inhibition Assay (bcMF pCa 6 IC.sub.50 (.mu.M))
[0225] 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 a 50%
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, 2 mM BME, 0.5 mM
NADH, and 1.5 mM PEP at the desired free calcium concentration
required to achieve 50% activation of the myofibrils.
[0226] A dilution series of compound was created in DMSO such that
the final desired concentration of compound would be achieved in a
volume of 30 .mu.L with a fixed DMSO concentration of 3.3% (v/v).
Typically 1 .mu.L of the dilution series were added to 384 well
plate to achieve a 10 point dose response. Following the addition
of 14 .mu.L of a solution containing bovine cardiac myofibrils,
PK/LDH and a solution of calcium (that achieved 50% activation),
the enzymatic reaction was started with the addition of 15 .mu.L of
a solution containing ATP, PEP and NADH. The reaction progress was
followed in a PerkinElmer Envision plate reader at ambient
temperature using clear bottom 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
EXCEL XLfit. The IC.sub.50 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 IC.sub.50 greater than the highest
concentration tested (ie. IC.sub.50>50 .mu.M).
Myosin Inhibition Assay (bcMF Serum pCa 6 IC.sub.50 (.mu.M))
[0227] Inhibition of the enzymatic activity of bovine cardiac
myosin associated with the release of ADP (adenosine diphosphate)
at the calcium concentrate that achieves a 50% activation of the
bovine cardiac myofibril system in the presence of 10% human serum.
The procedure was the same as that bovin cardiac myosin inhibition
assay (bcMF pCa 6 IC.sub.50 (.mu.M)) but with the addition of 10%
human serum.
Myosin Inhibition Assay (rbskMF pCa 6 IC.sub.50 (.mu.M))
[0228] Inhibition of the enzymatic activity of rabbit skeletal
myosin associated with the release of ADP (adenosine diphosphate)
at the calcium concentrate that achieves a 50% activation of the
rabbit skeletal myofibril system. The procedure was the same as
that of bovin cardiac myosin inhibition assay (bcMF pCa 6 IC.sub.50
(.mu.M)) by replacing bovine cardiac myofibril with rabbit skeletal
myofibril.
Pharmacokinetic/Pharmacodynamics (PK/PD) Relationship
[0229] The ability of small molecules to dose-dependently modulate
systolic cardiac performance was assessed non-invasively using
echocardiography in isoflurane-anesthetized SD rats. First, cardiac
function/geometry were studied serially both before and during
(.about. every 3 min) a continuous 30-60 min intravenous infusions
(2.0 mg/kg/hr IV, n=4). Subsequently, a set of conscious rats were
also treated with either vehicle control (0 mg/kg PO, n=3) or three
dose-levels of compound 3 via oral gavage: LOW (2 mg/kg PO, n=4),
MID (5 mg/kg PO, n=4), or HIGH (10 mg/kg PO, n=5). In these
animals, cardiac function/geometry were recorded at two separate
time-points/days under isoflurane anesthesia: once prior to dosing
(i.e., at baseline, day -2) and at 2 hrs post-dosing (day 0), a
time when exposures are known to approach steady-state and peak
responses are expected. In these experiments, left-ventricular
fractional shortening (FS), an index of systolic performance, as
well as LV dimensions/volumes and heart rates were measured using a
high-frequency transducer and parasternal long-axis transthoracic
views (Vevo2100, VisualSonic). FS was defined as the end-diastole
normalized change in internal dimensions/diameter of the left
ventricle between end-systole (LVESd) and end-diastole (LVEDd)
(i.e., FS=100.times.[LVEDd-LVESd]/LVEDd). LV volumes were derived
assuming a Teichholz model
(LVV=7.times.[2.4+LVid].sup.-1.times.LVid.sup.3). In all cases,
blood samples were taken (via tail-vein micro-sampling) at the time
of each echocardiographic examination in order to establish
pharmacokinetic/pharmacodynamics (PK/PD) relationships.
Cardiomyocyte Contractility Assay
[0230] 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 10V. 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 (at 0.3 .mu.M concentration), myocytes are first perfused
for 60 seconds with Tyrodes buffer followed by 5 min 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. The % inhibition measurement is calculated by
subtracting the FS value from 100%.
Reactive Metabolite Identification
[0231] In vitro determination of reactive metabolite formation for
small molecules by detection of glutathione adducts formed in vitro
in incubations with human liver microsomes fortified with NADPH and
glutathione.
[0232] Methods: The metabolism of small molecules (30 .mu.M) for
glutathione adduct formation was assessed in incubations (200 .mu.L
volume, n=3 incubations per treatment, 60 min incubation time) with
liver microsomes from human (1 mg/mL protein) conducted in
potassium phosphate buffer (0.1 M, pH 7.4) for 1 h at 37.degree. C.
in a 96-well plate (2 mL well volume) and were performed in the
absence of NADPH (used as a negative control) and in the presence
of NADPH (1 mM) and glutathione (GSH, 10 mM). Incubations with
liver microsomes were performed in a shaking water bath incubator
with slow horizontal shaking (30 rpm). To obtain 30 .mu.M
incubation concentration of a compound, a 3 mM substrate stock
solution in DMSO was used. Final incubation mixtures contained 148
.mu.L of potassium phosphate buffer, 10 .mu.L of liver microsome
solution (20 mg protein/mL), 2 .mu.L of the 3 mM substrate solution
and where incubations were initiated by the addition of 40 .mu.L of
NADPH solution (5 mM dissolved in potassium phosphate buffer).
Non-NADPH containing incubations were supplemented with 40 .mu.L of
potassium phosphate buffer. Post-incubation, reactions were
terminated by adding an equal volume of acetonitrile containing 20
nM carbamazepine internal standard and 3% formic acid. Quenched
samples then were centrifuged (4,600 rpm, 4.degree. C., 10-min)
after which the supernatants were transferred to a 96-well LC-MS
sample analysis plate and diluted with one volume equivalent of
HPLC-grade water, and then heat sealed with aluminum foil prior to
analysis by liquid chromatography/mass spectrometry (LC-MS/MS).
[0233] Analyte identification: The LC-MS/MS detection (with in-line
UV detection at 280 nm) of test compounds and potential GSH-adducts
was focused on extracting selected ion chromatographic profiles
using the protonated molecular ion MH.sup.+ m/z for parent to 4
decimal places, and corresponding protonated molecular ions of
predicted GSH-adduct metabolites (m/z MH.sup.+ parent+305.0681 amu)
using Xcalibur software (version 2.1.0, Thermo Fisher Scientific,
Waltham, Mass.). Relative GSH-adduct abundance in vitro in liver
microsome extracts was assessed using the LC/UV absorbance at 280
nm peak area ratio obtained by using Xcalibur software (version
2.1.0) between the detected GSH-adducts from NADPH- and
GSH-fortified incubation extracts and the corresponding LC/UV peak
area of the parent compound from minus NADPH containing incubation
extracts. The extent of GSH-adduct formation was determined by
LC-MS/MS analysis with in-line LC-UV detection at 280 nm by
dividing the glutathione-adduct LC/UV peak area by the LC/UV peak
area of the corresponding parent HCM-1 NG analog determined from
analysis of control (-NAPDH, -GSH) incubations extracts.
[0234] Materials: Pooled male human (HLM, 50 donors) liver
microsomes were obtained from Bioreclamation IVT (Baltimore, Md.).
Glutathione (GSH) and NADPH were purchased from Sigma Chemical Co.
(St. Louis, Mo.). All solvents used for liquid
chromatography-tandem mass spectrometry (LC-MS/MS) analyses were of
chromatographic grade.
[0235] LC-MS Conditions: Extracts from incubations with liver
microsomes and hepatocytes were characterized by LC-MS and LC-MS/MS
on a Thermo Electron LTQ Orbitrap XL mass spectrometer coupled with
a Dionex UltiMate 3000 UHPLC containing in-line diode array
detection and an OAS-3300TXRS Autosampler (40 .mu.L injection
volume). Electrospray ionization (ESI) was employed in the positive
ion mode with the needle potential held at 5.01 kV, a sheath flow
rate of 35.02, aux flow rate of 9.99, a current of 2.6 uA, a
capillary temperature of 325.degree. C., and a capillary voltage of
15.99. Vacuum conditions used were an ion gauge pressure used was
2.33.times.10.sup.-5 Torr and a convection gauge pressure of 0.90
Torr. Positive ion mode full scan (m/z 100 to m/z 1000) LC-MS
analysis was conducted with a scan time of 0.73-sec and source
collision energy of 10 V. The tandem MS/MS conditions used were 2
mTorr helium collision gas and a collision potential of 35 eV.
Xcalibur software (version 2.1.0, Thermo Fisher Scientific,
Waltham, Mass.) was used to acquire all data.
Capillary temperature (.degree. C.): 325 Source heater temperature
(.degree. C.): 345 Sheath gas flow (mL/min): 50 Auxiliary gas flow
(mL/min): 12 Sweep gas flow (mL/min): 5 Source voltage (kV): 5.01
Source current (.mu.A): 2.6 S-lens RF level: 50
[0236] Data dependent scans were utilized that collected MS/MS
spectra of the most abundant masses in the Orbitrap (15,000
resolving power) full scan mass spectrum.
[0237] HPLC conditions: Incubation extracts were chromatographed on
a Phenomenex Kinetex.RTM., 2.6 .mu.m, C18, 100 .ANG., 100.times.2.1
mm reverse phase column with a column oven temperature of
30.degree. C. for the chromatographic resolution of HCM-1 NG
compounds and corresponding glutathione adducts. Chromatographic
resolution was achieved by reverse phase gradient elution at a flow
rate of 0.3 mL/min into the ESI source over 30 min, and where the
gradient aqueous mobile phase solvent-A consisted of water with
0.1% formic acid (v/v) and the organic mobile phase (solvent-B)
contained acetonitrile with 0.1% formic acid (v/v). Elution was
achieved by an initial aqueous solvent-A mobile phase at 95% with a
linear decrease to 50% solvent-A over 20 min, followed by linear
decrease to 0% solvent-A over 3.5 min, and held constant at 0%
solvent-A for 1 min. Finally, a linear increase of the gradient to
95% solvent-A over 0.5 min, followed by 5 min of equilibration at
95% solvent-A prior to further analyses.
Column: Phenomenex Kinetex.RTM., 2.6 .mu.m, C18, 100 .ANG.,
100.times.2.1 mm reverse phase column Column oven temperature:
30.degree. C. Flow rate: 0.3 mL/min Mobile phase solvent-A: water
with 0.1% formic acid (v/v) Mobile phase solvent-B: acetonitrile
with 0.1% formic acid (v/v)
Elution Gradient:
0 min 95% A
[0238] 0 to 20 min 50% A; linear 20 to 23.5 min 0% A; linear
23.5 to 24.5 min 0% A
[0239] 24.5 to 25.0 min 95% A; linear
25.0 to 30.0 min 95% A
Biological Evaluation Tables
TABLE-US-00002 [0240] TABLE 5 bcMF Cardiac bcMF serum selectivity
%GSH-adduct pCa 6 pCa 6 ratio vs % inhibition (+NADPH, +GSH)
IC.sub.50 IC.sub.50 rbskMF pCa of FS relative to parent Structure
(.mu.M) (.mu.M) 6 IC.sub.50 at 0.3 .mu.M (-NADPH, -GSH)
##STR00045## 1.57 3.49 5.48 ++ (Early after depolarization or EAD)
Not Detected ##STR00046## 2.13 3.11 10.71 ##STR00047## 3.03 3.7
7.38 Not Detected ##STR00048## 1.11 1.56 4.51 +++ Not Detected
In Table 1B, in the column headed "% inhibition of FS at 0.3
.mu.M", + represents inhibition of fractional shortening less than
33%, ++ represents inhibition of fractional shortening from 33% to
66%, +++ represents inhibition of fractional shortening greater
than 66% (i.e., the greatest inhibition at +++).
TABLE-US-00003 TABLE 6 Glutathione Adduct Standard Detection in
Human Liver Average Deviation (SD) Microsome Incubations (triple
(triple Compound (single measurement) measurements) measurements)
##STR00049## 0.3% 0.4 0.1 ##STR00050## Not Detected Not Detected --
##STR00051## Not Detected Not Detected -- ##STR00052## Not Detected
Not Detected -- ##STR00053## Not Detected Not Detected --
##STR00054## Not Detected Not Detected -- ##STR00055## Not Detected
Not Detected -- ##STR00056## Not Detected Not Detected --
##STR00057## Not Detected Not Detected -- ##STR00058## Not Detected
Not Detected -- ##STR00059## Not Detected Not Detected --
##STR00060## Not Detected Not Detected -- Table 1C represents the
data from a single experiment.
[0241] As demonstrated above, these compounds showed minimal or no
development of reactive metabolites.
X-ray Powder Diffraction (XRPD)
[0242] XRPD analysis was carried out on a PANalytical X'pert pro,
scanning the samples between 3 and 35.degree. 2.theta.. The
material was gently ground to release any agglomerates and loaded
onto a multi-well plate with Kapton or Mylar polymer film to
support the sample. The multi-well plate was then placed into the
diffractometer and analyzed using Cu K radiation (.alpha..sub.1
.lamda.=1.54060 .ANG.; .alpha..sub.2=1.54443 .ANG.; .beta.=1.39225
.ANG.; .alpha..sub.1:.alpha..sub.2 ratio=0.5) running in
transmission mode (step size 0.0130.degree. 2.theta.) using 40
kV/40 mA generator settings.
Thermogravimetric Analysis (TGA)
[0243] Approximately, 5 mg of material was weighed into an open
aluminum pan and loaded into a simultaneous
thermogravimetric/differential thermal analyzer (TG/DTA) and held
at room temperature. The sample was then heated at a rate of
10.degree. C./min from 20.degree. C. to 400.degree. C. during which
time the change in sample weight was recorded along with any
differential thermal events (DTA). Nitrogen was used as the purge
gas, at a flow rate of 300 cm.sup.3/min.
Differential Scanning Calorimetry (DSC)
[0244] Approximately, 5 mg of material was weighed into an aluminum
DSC pan and sealed non-hermetically with a pierced aluminum lid.
The sample pan was then loaded into a Seiko DSC6200 (equipped with
a cooler) cooled and held at 20.degree. C. Once a stable heat-flow
response was obtained, the sample and reference were heated to max
330.degree. C. at scan rate of 10.degree. C./min and the resulting
heat flow response monitored. Nitrogen was used as the purge gas,
at a flow rate of 50 cm.sup.3/min. Modulated DSC was carried with
amplitude=0.32.degree. C. and frequency=0.017 Hz.
[0245] The disclosure also comprises the following clauses: [0246]
1. A compound having the formula:
[0246] ##STR00061## [0247] or a pharmaceutically acceptable salt
thereof, wherein [0248] the subscript n is 1 or 2; [0249] each
R.sup.1 is a member selected from the group consisting of fluoro,
chloro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, and
C.sub.2-C.sub.4 alkynyl; wherein at least one R.sup.1 is fluoro;
and [0250] one of R.sup.2a and R.sup.2b is fluoro and the other of
R.sup.2a and R.sup.2b is H; or optionally, [0251] wherein the
subscript n is 1 or 2; [0252] each R.sup.1 is a member selected
from the group consisting of fluoro, chloro, optionally substituted
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-C.sub.4
haloalkyl, optionally substituted C.sub.1-C.sub.4 alkoxy,
optionally substituted C.sub.1-C.sub.4 haloalkoxy, and optionally
substituted C.sub.2-C.sub.4 alkynyl; wherein at least one R.sup.1
is fluoro; and [0253] one of R.sup.2a and R.sup.2b is fluoro and
the other of R.sup.2a and R.sup.2b is H. [0254] 2. The compound of
clause 1, or a pharmaceutically acceptable salt thereof wherein
R.sup.2a is fluoro. [0255] 3. The compound of clause 1, or a
pharmaceutically acceptable salt thereof wherein R.sup.2b is
fluoro. [0256] 4. The compound of clause 1, or a pharmaceutically
acceptable salt thereof wherein R.sup.2a is fluoro, and n is 1.
[0257] 5. The compound of clause 1, or a pharmaceutically
acceptable salt thereof wherein R.sup.2a is fluoro, and n is 2.
[0258] 6. The compound of clause 1, or a pharmaceutically
acceptable salt thereof wherein R.sup.2b is fluoro, and n is 1.
[0259] 7. The compound of clause 1, or a pharmaceutically
acceptable salt thereof wherein R.sup.2b is fluoro, and n is 2.
[0260] 8. The compound of any one of clauses 1 to 3, or a
pharmaceutically acceptable salt thereof wherein n is 1. [0261] 9.
The compound of clause 1, having the formula:
##STR00062##
[0261] or pharmaceutically acceptable salt thereof, wherein the
subscript n is 1; and [0262] R.sup.1 is a member independently
selected from the group consisting of fluoro, chloro,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C1-C.sub.4
alkoxy, C.sub.1-C.sub.4 haloalkoxy, and C.sub.2-C.sub.4 alkynyl;
and [0263] one of R.sup.2a and R.sup.2b is fluoro and the other of
R.sup.2a and R.sup.2b is H; or optionally, wherein n is 1; and
[0264] R.sup.1 is a member independently selected from the group
consisting of fluoro, chloro, optionally substituted
C.sub.1-C.sub.4 alkyl, optionally substituted C.sub.1-C.sub.4
haloalkyl, optionally substituted C.sub.1-C.sub.4 alkoxy,
optionally substituted C.sub.1-C.sub.4 haloalkoxy, and optionally
substituted C.sub.2-C.sub.4 alkynyl; and [0265] one of R.sup.2a and
R.sup.2b is fluoro and the other of R.sup.2a and R.sup.2b is H.
[0266] 10. The compound of clause 8, having the formula:
[0266] ##STR00063## [0267] or a pharmaceutically acceptable salt
thereof. [0268] 11. The compound of clause 1, or a pharmaceutically
acceptable salt thereof where n is 2; optionally one R.sup.1 is
fluoro and the other is selected from the group consisting of
fluoro, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkoxy and
C.sub.2-C.sub.4 alkynyl; optionally one R.sup.1 is fluoro and the
other is selected from the group consisting of fluoro, methyl,
methoxy and ethynyl; or optionally, [0269] wherein n is 2;
optionally one R.sup.1 is fluoro and the other is selected from the
group consisting of fluoro, optionally substituted C.sub.1-C.sub.4
alkyl, optionally substituted C.sub.2-C.sub.4 alkoxy and optionally
substituted C.sub.2-C.sub.4 alkynyl; optionally one R.sup.1 is
fluoro and the other is selected from the group consisting of
fluoro, hydroxymethyl, methyl, methoxy and ethynyl. [0270] 12. The
compound of any one of clauses 1 to 3, or a pharmaceutically
acceptable salt thereof wherein n is 2, optionally having the
formula:
[0270] ##STR00064## [0271] or a pharmaceutically acceptable salt
thereof. [0272] 13. The compound of clause 12, or a
pharmaceutically acceptable salt thereof wherein one R.sup.1 is
fluoro and the other is selected from the group consisting of
fluoro, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, and
C.sub.2-C.sub.4 alkynyl; optionally fluoro, methyl, methoxy and
ethynyl (--C.ident.CH), optionally methyl, methoxy and ethynyl
(--C.ident.CH); or optionally, [0273] wherein one R.sup.1 is fluoro
and the other is selected from the group consisting of fluoro,
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 alkoxy, and optionally substituted
C.sub.2-C.sub.4 alkynyl; optionally fluoro, hydroxymethyl, methoxy
and ethynyl (--C.ident.CH), optionally methyl, methoxy and ethynyl
(--C.ident.CH). [0274] 14. The compound of any one of clauses 1 to
3, having the formula:
[0274] ##STR00065## [0275] or a pharmaceutically acceptable salt
thereof. [0276] 15. The compound of clause 14, or a
pharmaceutically acceptable salt thereof wherein R.sup.1 is
selected from the group consisting of fluoro, C1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, and C.sub.2-C.sub.4 alkynyl; optionally
fluoro, methyl, methoxy and ethynyl (--C.ident.CH), optionally
methyl, methoxy and ethynyl (--C.ident.CH); or optionally, [0277]
wherein R.sup.1 is selected from the group consisting of fluoro,
optionally substituted C.sub.1-C.sub.4 alkyl, optionally
substituted C.sub.1-C.sub.4 alkoxy, and optionally substituted
C.sub.2-C.sub.4 alkynyl; optionally fluoro, methyl, methoxy and
ethynyl (--C.ident.CH), optionally methyl, hydroxymethyl, methoxy
and ethynyl (--C.ident.CH). [0278] 16. The compound of clause 1,
having the formula:
##STR00066##
[0278] or a pharmaceutically acceptable salt thereof. [0279] 17.
The compound of clause 1, wherein the compound is:
[0279] ##STR00067## [0280] or pharmaceutically acceptable salt of
any of the foregoing. [0281] 18. The compound of clause 1, wherein
the compound is:
[0281] ##STR00068## [0282] or a pharmaceutically acceptable salt of
any of the foregoing. [0283] 19. The compound of clause 1, having
the formula:
[0283] ##STR00069## [0284] or a pharmaceutically acceptable salt
thereof. [0285] 20. The compound of clause 1, having the
formula:
[0285] ##STR00070## [0286] or a pharmaceutically acceptable salt
thereof. [0287] 21. The compound of clause 1, having the
formula:
[0287] ##STR00071## [0288] or a pharmaceutically acceptable salt
thereof. [0289] 22. The compound of clause 1, having the
formula:
[0289] ##STR00072## [0290] or a pharmaceutically acceptable salt
thereof. [0291] 23. The compound of clause 1, having the
formula:
[0291] ##STR00073## [0292] or a pharmaceutically acceptable salt
thereof. [0293] 24. The compound of clause 1, having the
formula:
[0293] ##STR00074## [0294] or a pharmaceutically acceptable salt
thereof. [0295] 25. A pharmaceutical composition comprising a
compound according to any one of clauses 1 to [0296] 24, or
pharmaceutically acceptable salt thereof, optionally further
comprising a pharmaceutically acceptable excipient. [0297] 26. The
pharmaceutical composition according to clause 25, wherein the
composition is substantially free of other isomers at the carbon
atom bearing the phenyl ring. [0298] 27. The pharmaceutical
composition according to clause 25 or 26, wherein the composition
is substantially free of other isomers at the carbon atom bearing
fluoro adjacent the carbon atom bearing the phenyl ring. [0299] 28.
A method of treatment, comprising administering to a subject in
need thereof an effective amount of a compound according to any one
of clauses 1 to 24, or a pharmaceutically acceptable salt thereof,
or a pharmaceutical composition according to any one of clauses 25
to 27. [0300] 29. A method of treating hypertrophic cardiomyopathy
(HCM) or a cardiac disorder (for example a cardiac disorder having
a pathophysiological feature of HCM), comprising administering to a
subject in need thereof an effective amount of a compound according
to any one of clauses 1 to 24, or a pharmaceutically acceptable
salt thereof, or a pharmaceutical composition according to any one
of clauses 25 to 27. [0301] 30. A method of treating a disease or
disorder selected from the group consisting of diastolic heart
failure (for example a 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 according to any one of
clauses 1 to 24, or a pharmaceutically acceptable salt thereof, or
a pharmaceutical composition according to any one of clauses 25 to
27. [0302] 31. A method of treating a disease or disorder
characterized by left ventricular hypertrophy (for example 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 one of clauses 1 to 24, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition according to any one of clauses 25 to 27. [0303] 32. A
method of treating hypertrophic cardiomyopathy (HCM), or a cardiac
disorder (for example a cardiac disorder having a
pathophysiological feature associated with HCM), comprising
administering to a subject in need thereof an effective amount of a
compound according to any one of clauses 1 to 24, or a
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition according to any one of clauses 25 to 27, 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/or 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). [0304] 33. A compound according
to any one of clauses 1 to 24, or pharmaceutically acceptable salt
thereof, or a pharmaceutical composition according to any one of
clauses 25 to 27, for use as a medicament. [0305] 34. A compound
according to any one of clauses 1 to 24, or pharmaceutically
acceptable salt thereof, or a pharmaceutical composition according
to any one of clauses 25 to 27, for use in the treatment of
hypertrophic cardiomyopathy, or a cardiac disorder (for example a
cardiac disorder having a pathophysiological feature of HCM).
[0306] 35. A compound according to any one of clauses 1 to 24, or
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition according to any one of clauses 25 to 27, for use in
the treatment of a disease or disorder selected from the group
consisting of diastolic heart failure (for example of heart failure
with preserved ejection fraction), ischemic heart disease, angina
pectoris, and restrictive cardiomyopathy. [0307] 36. A compound
according to any one of clauses 1 to 24, or pharmaceutically
acceptable salt thereof, or a pharmaceutical composition according
to any one of clauses 25 to 27, for use in the treatment of a
disease or disorder characterized by left ventricular hypertrophy
(for example 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. [0308] 37. A compound according
to any one of clauses 1 to 24, or pharmaceutically acceptable salt
thereof, or a pharmaceutical composition according to any one of
clauses 25 to 27, for use in the treatment of hypertrophic
cardiomyopathy (HCM), or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature associated with HCM),
wherein the compound is for use in combination 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/or 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). [0309] 38. A compound according to any one of
clauses 1 to 24, or pharmaceutically acceptable salt thereof, or a
pharmaceutical composition according to any one of clauses 25 to
27, for the manufacture of a medicament. [0310] 39. Use of compound
according to any one of clauses 1 to 24 or pharmaceutically
acceptable salt thereof, or a pharmaceutical composition according
to any one of clauses 25 to 27, for the manufacture of a medicament
for the treatment of hypertrophic cardiomyopathy, or a cardiac
disorder (for example a cardiac disorder having a
pathophysiological feature of HCM). [0311] 40. Use of compound
according to any one of clauses 1 to 24 or pharmaceutically
acceptable salt thereof, or a pharmaceutical composition according
to any one of clauses 25 to 27, for the manufacture of a medicament
for the treatment of a disease or disorder selected from the group
consisting of diastolic heart failure (for example heart failure
with preserved ejection fraction), ischemic heart disease, angina
pectoris, and restrictive cardiomyopathy. [0312] 41. Use of
compound according to any one of clauses 1 to 24 or
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition according to any one of clauses 25 to 27, for the
manufacture of a medicament for the treatment of a disease or
disorder characterized by left ventricular hypertrophy (for example
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. [0313]
42. Use of compound according to any one of clauses 1 to 24 or
pharmaceutically acceptable salt thereof, or a pharmaceutical
composition according to any one of clauses 25 to 27, for the
manufacture of a medicament for the treatment of hypertrophic
cardiomyopathy (HCM), or a cardiac disorder (for example a cardiac
disorder having a pathophysiological feature associated with HCM),
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/or 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). [0314] 43.
Form 1 polymorph of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
characterized by at least one of: [0315] a. a powder X-ray
diffraction pattern having two or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees; [0316] b. a DSC thermogram
showing endotherms at about 226.05.degree. C., at about
302.47.degree. C., and at about 310.13.degree. C.; or [0317] c. an
X-ray crystal structure substantially the same as in FIG. 4. [0318]
44. The polymorph of clause 43, characterized by a powder X-ray
diffraction pattern having three or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees. [0319] 45. The polymorph of
clause 43, characterized by a powder X-ray diffraction pattern
having four or more peaks expressed in degrees
2-theta.+-.0.2.degree. and selected from 11.3, 12.4, 13.3, 16.5,
17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5,
32.9, 34.3, 35.5, and 38.8 degrees. [0320] 46. The polymorph of
clause 43, characterized by a powder X-ray diffraction having peaks
expressed in degrees 2-theta.+-.0.2.degree. at each of 11.3, 12.4,
and 13.3 degrees. [0321] 47. The polymorph of clause 43,
characterized by a powder X-ray diffraction having peaks expressed
in degrees 2-theta.+-.0.2.degree. at each of 11.3, 12.4, 13.3,
16.5, 17.3, 19.3, 20.4, and 29.5 degrees. [0322] 48. The polymorph
of clause 43, characterized by melt onsets of about 221.51.degree.
C., about 299.53.degree. C., and about 308.81.degree. C. [0323] 49.
The polymorph of clause 43, wherein the polymorph has a powder
X-ray diffraction pattern substantially the same as in FIG. 1A.
[0324] 50. The polymorph of any one of clauses 43-49, wherein the
Form 1 polymorph is substantially free of other forms of
(6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-
-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. [0325]
51. A pharmaceutical composition comprising a polymorph of any one
of clauses 43-50, and a pharmaceutically acceptable excipient.
[0326] 52. The composition of clause 51, wherein the ratio of the
amount of the Form 1 polymorph to the sum of the amounts of other
forms is equal to or greater than 80:20. [0327] 53. The composition
of clause 51, wherein the ratio of the amount of the Form 1
polymorph to the sum of the amounts of other forms is equal to or
greater than 90:10. [0328] 54. The composition of clause 51,
wherein the ratio of the amount of the Form 1 polymorph to the sum
of the amounts of other forms is equal to or greater than 95:5.
[0329] 55. The composition of clause 51, wherein the ratio of the
amount of the Form 1 polymorph to the sum of the amounts of other
forms is equal to or greater than 97:3. [0330] 56. The composition
of clause 51, wherein the ratio of the amount of the Form 1
polymorph to the sum of the amounts of other forms is equal to or
greater than 98:2. [0331] 57. The composition of clause 51, wherein
the ratio of the amount of the Form 1 polymorph to the sum of the
amounts of other forms is equal to or greater than 99:1. [0332] 58.
A method of treating hypertrophic cardiomyopathy (HCM), or a
cardiac disorder having a pathophysiological feature of HCM,
comprising administering to a subject in need thereof an effective
amount of a polymorph of any one of clauses 43-50, or a
pharmaceutical composition of any one of clauses 51-57. [0333] 59.
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 polymorph of any one of clauses 43-50, or a
pharmaceutical composition of any one of clauses 51-57. [0334] 60.
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 polymorph of any one clauses 43-50, or a
pharmaceutical composition of any one of clauses 51-57, 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/or 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).
[0335] The recitation of a listing of chemical groups in any
definition of a variable herein includes definitions of that
variable as any single group or combination of listed groups.
[0336] Although the foregoing disclosure 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.
* * * * *