Tetrahydropyran (THP)-substituted bicyclic-pyrimidinedione compound

Abstract

To provide 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.SOLUTION: 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, characterized by a powder X-ray diffraction pattern having two or more peaks expressed in degrees 2θ±0.2° 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.SELECTED DRAWING: None

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 752,278, filed on October 29, 2018, under the name of "Tetrahydropyran (THP) - Substituted Bicyclic - Pyrimidine Dione Compounds", the entire content of which is incorporated herein by reference.

Background Art

[0002] Genetic (hereditary) hypertrophic cardiomyopathy (HCM) includes a highly penetrant group of monogenic autosomal - dominant cardiomyopathies. HCM is caused by one or more of over 1,000 known point mutations in any one of the structural protein genes that make up the sarcomere, which is the functional unit of the myocardium. In about 1 in 500 of the general population, left ventricular hypertrophy is recognized that cannot be explained by other known etiologies (e.g., hypertension or valvular disease), and many of these are shown to be HCM when other genetic causes (e.g., lysosomal storage diseases) and metabolic or infiltrative causes are excluded.

[0003] Mutations in sarcomere genes that cause HCM have a high penetrance but show significant variability in clinical severity and clinical course. Some genotypes are associated with a progressive course, but there is considerable variation even among and within families with the same mutation. Sexual dimorphism has also been noted, and generally, male patients are more severely affected than female patients. Many patients with HCM rarely or never complain of symptoms over a long period, but HCM is a progressive disease with significant cumulative distress related to the disease state. The main symptoms are exercise intolerance, which may be exacerbated by exercise and other activities that increase heart rate and / or decrease preload. As with many other disorders, symptoms tend to worsen with age. The most common clinical burden for patients with HCM is exertional dyspnea, which can limit daily activities and lead to debilitation.

[0004] Patients with HCM often present symptoms in the absence of confirmed hemodynamic abnormalities such as left ventricular outflow tract obstruction (with or without mitral regurgitation). The symptoms of exertional dyspnea in patients can rapidly deteriorate with the emergence of common complications of HCM that can induce acute pulmonary edema, which increases the risk of systemic arterial thromboembolic diseases including atrial fibrillation and stroke. Other adverse events associated with HCM include intolerance to hypovolemia or hypervolemia and syncope. Associated coronary artery disease confers a higher risk of acute coronary syndrome than in patients without HCM. Sudden cardiac death (SCD) in patients with HCM is rare and difficult to predict, but it is a major cause of non-traumatic death in young adults. For survivors of SCD, ICD replacement is a standard technique, and while risk profiling in other HCM patients is not clear, it is used to identify those who should be treated carefully with ICD replacement for primary prevention.

[0005] Medical therapies for HCM are limited to treating symptoms and do not address the underlying root cause of the disease - the breakdown of normal sarcomere function. The treatments available today are not always consistently effective in reducing symptoms and typically show a decline in effectiveness over the course of the disease. Patients are therefore treated empirically with beta blockers, non-dihydropyridine calcium channel blockers and / or disopyramide. None of these drugs have indications for treating HCM, and there is essentially no rigorous clinical trial evidence available to justify their use. This unfortunate situation is due to the fact that new medical therapies for HCM have not been identified for many years. For patients with hemodynamically significant outflow tract obstruction (resting gradient > 30 mmHg), appropriately selected patients may require surgical myectomy or alcohol septal ablation, usually to relieve the hemodynamic obstruction. What the present application provides are new therapeutic agents and methods that alleviate the long-standing unmet need for improved treatments for HCM and related cardiac disorders.

DETAILED DESCRIPTION OF THE INVENTION

[0006] Summary of the Invention In one aspect, formula (I):

Chemical formula

[0007] In one aspect, formula (I):

Chemical formula

[0008] In another aspect, a polymorph of form 1 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 provided (the "polymorph of form 1"). In another aspect, the polymorph of form 1 is characterized by at least one of the following: a. A powder X-ray diffraction pattern represented at an angle 2θ ± 0.2° and having two or more peaks 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°; b. A DSC thermogram showing endotherms at about 226.05°C, about 302.47°C, and about 310.13°C; or c. An X-ray crystal structure substantially the same as FIG. 4.

[0009] In another aspect, the present specification provides a pharmaceutical composition comprising a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

[0010] In one aspect, the present specification provides a method of treating a heart disease or disorder in a subject in need thereof, the method 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 heart disease or disorder. For example, the heart disease or disorder can be cardiomyopathy (e.g., hypertrophic cardiomyopathy), heart failure (e.g., heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction), valvular disease (e.g., valvular aortic stenosis), congenital heart disease (e.g., tetralogy of Fallot), left ventricular hypertrophy, angina (e.g., refractory angina), or Chagas disease.

[0011] In one aspect, the present specification provides a method for treating a heart disease or disorder, comprising administering to a subject in need of treatment an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical composition described herein, or a polymorph described herein, wherein the heart 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, endocardial 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 heart disease or disorder is selected from the group consisting of nHCM, oHCM, HFpEF, HFmREF, aortic stenosis, Loeffler endocarditis, endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, tetralogy of Fallot, angina pectoris, refractory angina pectoris, and Chagas disease.

[0012] In one aspect, the present specification provides a method for treating a heart disease or disorder, comprising administering to a subject in need of treatment an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical composition described herein, or a polymorph described herein, wherein the compound or a pharmaceutically acceptable salt thereof, polymorph, or pharmaceutical composition is administered as monotherapy.

[0013] In one aspect, the present specification provides a method for treating a heart disease or disorder, which comprises administering to a subject in need of treatment an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, a pharmaceutical composition described herein, or a polymorph described herein, wherein the compound or a pharmaceutically acceptable salt thereof, polymorph, or pharmaceutical composition is administered as a combination therapy, and an additional therapeutic agent is administered in the combination therapy. In certain aspects, the additional therapeutic agent is selected from the group consisting of a β - adrenergic blocker (β - blocker), a renin - angiotensin - aldosterone system (RAAS) inhibitor (e.g., an angiotensin receptor antagonist such as an angiotensin - converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist), an angiotensin receptor neprilysin inhibitor (ARNI) (e.g., sacubitril / valsartan), a mineralocorticoid receptor antagonist (MRA) (e.g., an aldosterone inhibitor; e.g., a potassium - sparing diuretic such as eplerenone, spironolactone or canrenone), a cholesterol - lowering agent (e.g., a statin), a neutral endopeptidase inhibitor (NEPi), a positive inotropic agent (e.g., digoxin, pimobendan, a β - adrenergic receptor agonist; e.g., a phosphodiesterase (PDE) - 3 inhibitor such as dobutamine, milrinone or a calcium sensitizer such as levosimendan), potassium, magnesium, a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor, a vasodilator (e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor or a smooth muscle myosin modulator), a diuretic (e.g., furosemide), an anti - arrhythmic agent, an anticoagulant (e.g., warfarin), an antithrombotic agent, an anti - platelet agent, a sodium - glucose cotransporter 2 inhibitor (SGLT2) (e.g., empagliflozin, dapagliflozin, sotagliflozin) or a combination thereof.In some embodiments, the additional therapeutic agent is an angiotensin II receptor antagonist (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, elsartan 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, isotelin, 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, supprasartan, saralasin, salmesin, 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 embodiments, the additional therapeutic agent is an ARNI selected from the group consisting of sacubitril, valsartan, or a combination of sacubitril and valsartan (sacubitril / valsartan). In some embodiments, the additional therapeutic agent is an SGLT2 selected from the group consisting of empagliflozin, dapagliflozin, and sotagliflozin. In some embodiments, the additional therapeutic agent improves the cardiovascular condition of the subject. In certain embodiments, the additional therapeutic agent is selected from the group consisting of beta blockers, diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers, angiotensin II receptor antagonists, mineralocorticoid receptor antagonists, ARNIs, RAAS inhibitors, antiarrhythmic agents, and SGLT2 inhibitors.

[0014] In another aspect, the present specification provides a method for preventing or treating a disease or disorder in which diastolic dysfunction is present or is a significant feature (e.g., but not limited to, hypertrophic cardiomyopathy (HCM) or a heart disease having the pathophysiological features or symptoms of HCM). The method includes administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need 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) (e.g., 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.

[0015] In another aspect, the present specification provides a method for 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, the method comprising administering to a subject in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0016] In another aspect, the present specification provides a method for preventing or treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload, which comprises administering to a subject in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a therapy aimed at correcting or alleviating the main cause of volume or pressure overload, such as valve repair / replacement or effective antihypertensive therapy, wherein the disease or disorder is selected from the group consisting of chronic mitral valve regurgitation, chronic aortic valve stenosis, and chronic systemic hypertension.

[0017] In another aspect, the present specification provides a method for preventing or treating a heart disease having pathophysiological features associated with hypertrophic cardiomyopathy (HCM) or symptoms thereof, which comprises administering to a subject in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a therapeutic agent that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist, or a neprilysin inhibitor); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor); and a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload of the heart (e.g., any class of vasodilators such as a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin regulator). HCM may be obstructive HCM (oHCM) or non-obstructive HCM (nHCM).

[0018] In another aspect, there is provided a pharmaceutical composition comprising a polymorph of Form 1 and a pharmaceutically acceptable excipient.

[0019] In another aspect, there is provided a method for treating hypertrophic cardiomyopathy (HCM) or a heart disease having pathophysiological characteristics of HCM, the method comprising administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of the polymorph of Form 1 or the polymorph of Form 1.

[0020] In another aspect, there is provided a method for treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload, wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension, and in combination with a treatment aimed at modifying or alleviating the main cause of volume or pressure overload, such as valve repair / replacement or effective antihypertensive therapy, administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of the polymorph of Form 1 or the polymorph of Form 1.

[0021] In another aspect, there is provided a method for treating hypertrophic cardiomyopathy (HCM) or a heart disease having pathophysiological characteristics associated with HCM, the method comprising a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist, or a neprilysin inhibitor) that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation; a therapeutic agent (e.g., a positive inotrope such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload (e.g., any class of vasodilators such as a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin regulator), and administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of the polymorph of Form 1 or the polymorph of Form 1. The present invention contemplates including analogs that are fully labeled with isotopes of the compound of formula (I). Isotopes include atoms having the same atomic number but different masses. For example, isotopes of hydrogen include 2H(D) and 3 H(T) are included, and the carbon isotopes include 13 C and 14 C. The compounds of formula (I) labeled with isotopes can be prepared according to methods generally known in the art. Such compounds have various uses, but are not limited thereto, as standards or reagents in determining biological / pharmacological activities. For the stable isotope-labeled compounds of formula (I), the biological, pharmacological or pharmacokinetic properties can also be suitably adjusted.

Brief Description of the Drawings

[0022]

Figure 1

Figure 2

Figure 3

Figure 4

[0023] A series of tetrahydropyran (THP)-substituted bicyclic pyrimidine dione compounds have been found to suppress excessive contractility in a hypercontractile state and / or promote cardiac relaxation in a failing heart. Without being bound by theory, these compounds are thought to stabilize the conformation of β-myosin after ATP hydrolysis and before strongly binding to actin filaments and releasing phosphate, thereby reducing the proportion of myosin molecules that can participate in the "power stroke" part of the muscle contraction cycle. Thus, the present compounds can improve cardiac elasticity, reduce dynamic and / or static left ventricular outflow tract obstruction, improve diastolic left ventricular relaxation, reduce left ventricular diastolic (filling) pressure, reduce functional mitral regurgitation, and / or reduce left atrial and pulmonary capillary wedge pressure in HCM patients, and help resolve the debilitating exertional dyspnea and / or symptoms associated with left ventricular outflow obstruction (pre-syncopal dizziness or syncope) often associated with these diseases. The preferred compounds of the present application are optimally designed to have a relatively short half-life in humans. For example, certain compounds of the present invention are planned 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 are designed to produce few reactive metabolites during testing, have low dependence on polymorphic CYP enzymes (e.g., CYP 2C19), and / or have no or reduced risk of CYP induction (e.g., CYP3A4 induction). Some other advantages of the compounds of the present application relate to the inhibitory selectivity for myosin in the heart compared to skeletal myosin and / or the desirable time course of efficacy in response to drug dose administration. Furthermore, the compounds of the present application have beneficial solubility. For example, the micromolar solubility at pH 7.4 is 50 or more, e.g., 70 or more. In some cases, the compounds of the present application have a micromolar solubility of 80 or more, e.g., 90 or more. The compounds of the present application can also be used in the treatment of other heart diseases.

[0024] As used herein, the term "about" is used to describe a range (e.g., temperature, mass, weight), indicates the ordinary meaning in the relevant technical field, and generally refers to the error associated with the equipment for collecting measured or read values. Generally, when referring to temperature, the term "about" indicates an error of ±0 to 2 °C.

[0025] As used herein, the term "alkyl" means a straight-chain or branched saturated aliphatic group having the indicated number of carbon atoms. Alkyl can contain any number of carbons, such as C 1-2 、C 1-3 、C 1-4 、C 2-3 、C 2-4 and C 3-4 etc. For example, C 1-4 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In some examples, the alkyl group may be optionally substituted. In some embodiments, the alkyl group is unsubstituted. In some embodiments, the alkyl group is substituted. The substituents of the alkyl group include, but are not limited to, any of the substituents described herein that form a stable group. In certain embodiments, the substituent may be one or more hydroxy groups. In 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 described above, wherein at least one hydrogen atom of the hydrocarbon moiety is substituted with a hydroxy group (-OH). Thus, "hydroxyalkyl" refers to, for example, hydroxymethyl, 2-hydroxyethyl, and 2-hydroxypropyl.

[0026] As used herein, the term "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight-chain or branched aliphatic group. One or more carbon-carbon triple bonds may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. The alkynyl group may be substituted or unsubstituted.

[0027] As used herein, the term "cycloalkyl" means a saturated or partially unsaturated monocyclic ring containing 3 to 4 ring atoms or a predetermined number of atoms. Examples of saturated monocyclic cycloalkyl rings include, for example, cyclopropyl or cyclobutyl. The cycloalkyl group may be partially unsaturated having one or more double bonds within the ring. A representative cycloalkyl group that is partially unsaturated is cyclobutene. Unless otherwise indicated, the cycloalkyl group is unsubstituted.

[0028] As used herein, the term "alkoxy" means an alkyl group having an oxygen atom linking the alkyl group to the point of attachment: that is, alkyl-O-. For the alkyl portion, the alkoxy group can have any suitable number of carbon atoms such as C 1-2 or C 1-4 and the like. Examples of alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. The alkoxy group may be optionally substituted (unsubstituted or substituted).

[0029] As used herein, the terms "halo" and "halogen" refer to fluorine, chlorine, bromine, and iodine.

[0030] As used herein, the terms "haloalkyl" and "haloalkoxy" refer to alkyl and alkoxy groups as shown above, in which at least one hydrogen atom of the hydrocarbon moiety is replaced by a halogen atom. Further, this term can also refer to perhalogenated forms of alkyl and alkoxy. Thus, "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.

[0031] When a numerical range is recited, each value and sub-range within that range is intended to be encompassed. For example, "C" 1-6 alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.

[0032] It will be understood that the above-described groups and / or compounds described herein may optionally be substituted with any number of substituents or functional groups. That is, any of the above groups may optionally be substituted. As used herein, the term "optionally substituted" is intended to include unsubstituted and / or substituted variants (i.e., "optionally substituted" may be used interchangeably with "substituted or unsubstituted"). As used herein, the term "substituted" is intended to include all acceptable substituents of organic compounds, and "acceptable" means within the scope of the chemical rules of valence known to those skilled in the art. Generally, the term "substituted" means replacing a hydrogen group in a given structure with a group of a particular substituent, regardless of whether the term "optionally" precedes it, and the substituents included in the formulas herein. If one or more positions of any given structure may be substituted with one or more substituents selected from a particular group, the substituents may be the same or different at all positions. Also, "substituted" is understood to include that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo conversions such as rearrangement, cyclization, elimination, etc. In some cases, "substituted" may generally indicate replacing hydrogen with the substituents described herein. However, as used herein, "substituted" does not include substitution and / or modification of important functional groups for identifying molecules such that a "substituted" functional group becomes a different functional group upon substitution. For example, a "substituted phenyl group" must still be composed of a phenyl moiety, and in this definition, it cannot be changed to, for example, a pyridine ring by substitution. In a broad aspect, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Examples of substituents include, for example, those described herein. Acceptable substituents may be one or more and may be the same or different for a suitable organic compound.For the purposes of this specification, heteroatoms such as nitrogen may have any permissible substituents of the organic compounds described herein that satisfy the valences of the hydrogen substituents and / or heteroatoms. Further, this specification is not intended to be limited in any way by the permissible substituents of the organic compounds. The term "stable" as used herein preferably refers to a compound that has sufficient stability to allow for manufacture and maintains the integrity of the compound for a period sufficient to be detected, preferably for a period sufficient to be useful for the purposes detailed herein.

[0033] Examples of substituents include halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic group, -CF3, -CN, aryl, aryloxy, perhaloalkoxy, aralkoxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkoxy, azide, amino, halide, alkylthio, nitrile, acylalkyl, carboxyester, -carboxamide, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, -carboxamidealkylaryl, -carboxamidearyl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxamidealkyl-, cyano, alkoxyalkyl, perhaloalkyl, arylalkyloxyalkyl, and the like.

[0034] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, have no excessive toxicity, irritation, allergic response or other problems or complications, and are suitable for use in contact with human and animal tissues, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable substances may be compatible not only with the compounds of formula (I) but also with other ingredients in which the compounds are formulated.

[0035] As used herein, the term "salt" refers to an acid salt or a basic salt of a compound of formula (I). Pharmaceutically acceptable salts can be obtained, for example, from inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid, etc.) and quaternary ammonium ions. Pharmaceutically acceptable salts are understood to be non-toxic.

[0036] Certain embodiments of the compounds of the invention may contain one or more basic functional groups and can thus form 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 the compounds of the present application. These salts can be prepared in situ in the dosage vehicle or manufacturing process, or by reacting the purified compounds of the invention in their free base form separately with a suitable organic or inorganic acid and then isolating the salts thus formed during purification. Non-limiting examples of salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate (see, for example, Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19).

[0037] Pharmaceutically acceptable salts of the compounds described herein include, for example, non-toxic salts or quaternary ammonium salts of compounds obtained from non-toxic organic or inorganic acids. For example, such non-toxic salts include salts obtained from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, etc.; and organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothionic acid, etc.

[0038] In some cases, the compounds of the present application may contain one or more acidic functional groups, and thus can form 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 the compounds of the present application. These salts can likewise be produced in situ in the dosage vehicle or in the manufacturing process, or the purified compound in free acid form can be reacted separately with a suitable base (e.g., a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation), ammonia or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Non-limiting examples of alkali or alkaline earth salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and aluminum salts, etc. Non-limiting examples of organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc.

[0039] Additional information regarding 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.

[0040] The neutral form of a compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in conventional ways. The form of the parent compound may differ from the various salt forms in certain physical properties (e.g., solubility in polar solvents).

[0041] The specific compounds of the present application have asymmetric carbon atoms (chiral centers) or double bonds, and racemates, diastereomers, geometric isomers, positional isomers and individual isomers (e.g., separate enantiomers) are all intended to be included within the scope of this specification. When a stereochemical depiction is shown, it means a compound in which one of the isomers is present and the other isomers are substantially absent. "Substantially free of" other isomers means that based on the molar amount of all isomers of the present application isomers present, at least about 80% of the isomers should be present, more preferably at least about 90%, for example about 95% or more. The depicted isomer may be present in an amount of at least about 99%. For example, when the isomers disclosed herein are provided in a pharmaceutical composition, the composition may contain at least about 99% of the disclosed isomers in the pharmaceutical composition based on the total molar amount of all isomers of the disclosed compound present in the pharmaceutical composition (e.g., the disclosed isomers and all other isomers).

[0042] As used herein, the term "pharmaceutical composition" refers to a product comprising a compound of formula (I) and a mixture with one or more other chemical components. A pharmaceutical composition can include any product directly or indirectly resulting from a combination of excipients and / or a predetermined amount of other optional components and a predetermined amount of a specified component as defined herein.

[0043] As used herein, the term "excipient" refers to a substance that aids in the administration of an effective agent to a subject. Useful pharmaceutical excipients herein include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorants, and colorants. Those skilled in the art will understand that other excipients may be useful in the present invention.

[0044] As used herein, the terms "treat", "treating", and "treatment" refer to any indicator related to success in the treatment or alleviation of a pathology, injury, symptom, or sign associated with a disease or disorder (e.g., a heart disease having the pathophysiological characteristics of HCM), which includes, for example, alleviation of symptoms, remission, reduction; making the pathology, injury, symptom, or sign such that the patient is more tolerable; or reducing the frequency or duration of the pathology, injury, symptom, or sign, and includes any objective or subjective parameters such as these. Treatment or alleviation can be based on any objective or subjective parameter, including, for example, the results of a physical examination.

[0045] As used herein, the terms "prevent", "preventing", or "prevention" refer to prophylactic treatment of a subject that does not have and has never had a pathology, injury, symptom, or sign associated with a disease or disorder (e.g., a heart disease having the pathophysiological characteristics of HCM), but is at risk of developing such pathology, injury, symptom, or sign, or a subject that has presented or has not presented a condition, injury, symptom, or sign but is at risk of recurrence of such condition, injury, symptom, or sign. In certain embodiments, the subject has a higher risk of developing a condition, injury, symptom, or sign or a higher risk of recurrence of a condition, injury, symptom, or sign compared to an average healthy member of the population. In certain embodiments, prevention refers to preventing the development of a condition, injury, symptom, or sign.

[0046] "Effective amount" or "pharmaceutically effective amount" means an amount sufficient to achieve the stated purpose (e.g., achieve the administered effect, treat a disease, reduce enzyme activity, reduce one or more signs of a disease or condition, reduce intracellular viral replication, etc.). Examples of "effective amount" are amounts sufficient to contribute to the treatment of a disease and the alleviation of symptoms, also referred to as "therapeutically effective amount". "Alleviation" of a symptom means a decrease in the severity or frequency of the symptom or the disappearance of the symptom.

[0047] The "subject" to which administration is intended 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 elderly adult)) or a non-human animal. "Patient" refers to a human subject in need of treatment for a disease.

[0048] Hypertrophic cardiomyopathy (HCM) is clinically identified as left ventricular (LV) hypertrophy of unknown origin in the absence of known causes such as pressure overload, systemic disease, or infiltrative processes. One phenotype of HCM is enhanced myocardial contractility associated with reduced LV compliance, which clinically manifests as reduced ventricular volume, frequent ejection fraction excess, increased wall thickness, and diastolic dysfunction. Symptoms or signs in HCM patients include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), syncope (especially during or immediately after exercise), rapid heartbeat, palpitations or a feeling of a pounding heart, and heart murmurs.

[0049] Obstructive HCM (oHCM), also known as hypertrophic obstructive cardiomyopathy (HOCM), refers to HCM in which there is left ventricular outflow tract obstruction (LVOT).

[0050] Non-obstructive HCM (nHCM) refers to HCM without outflow tract obstruction at rest or on provocation.

[0051] Heart failure is a clinical syndrome in which a patient's heart is unable to supply sufficient blood to the body. Some people with heart failure have difficulty pumping enough blood to maintain other organs in the body. Others have a hardened and stiffened myocardium that blocks or reduces blood flow to the heart. Heart failure can occur on the right side, left side, or both sides of the heart simultaneously. Heart failure can be either acute (short-term) or chronic (continuous). Symptoms of heart failure include, but are not limited to, excessive fatigue, sudden weight gain, loss of appetite, persistent cough, arrhythmia, palpitations, abdominal swelling, shortness of breath, swelling in the legs or ankles, bulging neck veins, and edema.

[0052] Heart failure with preserved ejection fraction (HFpEF), also called diastolic heart failure or diastolic dysfunction, refers to heart failure when the heart's ejection fraction is normal (e.g., 50% or more). In many cases, the myocardium contracts normally, but the ventricles do not relax as they should during ventricular filling, resulting in a reduced stroke volume.

[0053] Stable dilated cardiomyopathy refers to patients with dilated cardiomyopathy without accompanying acute symptom exacerbation. These patients have reduced diastolic function and can have their symptoms controlled or stabilized using available treatment methods.

[0054] Diastolic dysfunction refers to an abnormality in diastolic function. Abnormalities in diastolic function include left ventricular relaxation impairment, filling, diastolic distensibility or stiffness impairment. These characteristics can be measured using echocardiography. Additional determinants for diagnosing diastolic dysfunction using echocardiogram are described in J Am Soc Echocardiogr. 29(4):277-314 (2016), the content of which is incorporated by reference. Left ventricular stiffness can be measured by cardiac magnetic resonance. Cardiac magnetic resonance is used to measure peak filling velocity, time to peak filling, and peak diastolic strain rate. Diastolic dysfunction may also be associated with elevated levels of blood biomarkers. 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.

[0055] Diastolic dysfunction includes a range of diseases, such as hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF) - both impairment related to active relaxation and impairment related to ventricular stiffness (e.g., diabetic HFpEF); ischemic cardiomyopathy, cardiac transplant vasculopathy, restrictive cardiomyopathy (e.g., gene mutations in one or more sarcomere proteins), inflammatory cardiomyopathy (e.g., Reiter's syndrome and EMF), infiltrative cardiomyopathy (e.g., amyloid, sarcoid, and XRT), storage diseases (e.g., hemochromatosis, Fabry, and glycogen storage diseases, etc.), congenital heart diseases (e.g., pressure overload RV, tetralogy of Fallot (e.g., preoperative and early postoperative diastolic dysfunction), valvular heart disease (e.g., aortic stenosis), etc., but is not limited to these.

[0056] Class IHCM refers to HCM that is Class I according to the New York Heart Association (NYHA).

[0057] Class II-III nHCM refers to nHCM that is Class II or Class III according to NYHA.

[0058] Class II-III oHCM refers to oHCM that is Class II or Class III according to NYHA.

[0059] NYHA Class I refers to the classification where the patient or subject has no restriction on physical activity and does not experience excessive fatigue, palpitations, or dyspnea (shortness of breath) during daily physical activities.

[0060] NYHA Class II refers to the classification where the patient or subject has a slight restriction in physical activity, has no pain at rest, and experiences fatigue, palpitations, or dyspnea (shortness of breath) during daily physical activities.

[0061] NYHA Class III refers to the classification where the patient or subject has a significant restriction in physical activity, has no pain at rest, and experiences fatigue, palpitations, or dyspnea during activities less than daily physical activities.

[0062] NYHA Class IV refers to the classification where the patient or subject cannot perform any physical activity without experiencing pain associated with heart failure symptoms at rest, and the pain increases with any physical activity.

[0063] As used herein, "Valsalva gradient" refers to the pressure gradient across the entire LVOT when an individual is performing the Valsalva maneuver.

[0064] III. Compounds In one aspect, herein, Formula (I):

Chemical formula

[0065] In one aspect, herein, formula (I):

Chemical formula

[0066] Also provided is a pharmaceutically acceptable salt of the compound of formula (I).

[0067] In certain embodiments, the compound of formula (I) has the formula:

Chemical formula

[0068] In certain embodiments, the compound of formula (I) has the formula:

Chemical formula

[0069] In some examples, n in the compound of formula (I) is 1. The compound of formula (I) can have the formula:

Chemical Formula

[0070] Also provided are pharmaceutically acceptable salts of the compounds of formula (Ib).

[0071] In some examples, n in the compound of formula (I) is 2. In some examples, when n is 2, one R 1 is fluoro and the other may be selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and C2-C4 alkynyl; optionally fluoro, methyl, methoxy and ethynyl (-C≡CH), optionally methyl, methoxy and ethynyl (-C≡CH).

[0072] In some examples, n in the compound of formula (I) is 2. In some examples, when n is 2, one R 1is fluoro and the other is fluoro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy and optionally substituted C2-C4 alkynyl; optionally fluoro, methyl, methoxy and ethynyl (-C≡CH), optionally methyl, methoxy and ethynyl (-C≡CH) which may be selected from the group consisting of.

[0073] The compound of formula (I) is of the formula:

Chemical formula

[0074] The compound of formula (I) is of the formula:

Chemical formula

[0075] In some examples, for formula (I), one R 1is fluoro, and the other is selected from the group consisting of fluoro, C1-C4 alkyl, C1-C4 alkoxy and C2-C4 alkynyl; optionally fluoro, methyl, methoxy and ethynyl (-C≡CH); optionally methyl, methoxy and ethynyl (-C≡CH).

[0076] In some examples, for formula (I), one R 1 is fluoro, and the other is selected from the group consisting of fluoro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy and optionally substituted C2-C4 alkynyl. In some examples, for formula (I), one R 1 is fluoro, and the other is optionally selected from the group consisting of fluoro, methyl, methoxy and ethynyl (-C≡CH), optionally methyl, methoxy and ethynyl (-C≡CH). In some examples, for formula (I), one R 1 is fluoro, and the other is hydroxy-substituted alkyl. In some examples, for formula (I), one R 1 is fluoro, and the other is hydroxymethyl.

[0077] Pharmaceutically acceptable salts of the compounds of formula (Ic) are also provided.

[0078] The compounds of formula (I) are of the formula:

Chemical formula

[0079] The compound of formula (I) has the formula:

Chem.

[0080] Pharmaceutically acceptable salts of the said compounds of formula (Id) are also provided.

[0081] The compound of formula (I) has the formula:

Chem.

[0082] Pharmaceutically acceptable salts of the said compounds of formula (Ie) are also provided.

[0083] The compound of formula (I) has the formula:

Chem.

[0084] The compound of formula (I) can be a compound of the formula:

Chem.

[0085] The compound is

Chem.

[0086] The compound is

Chem.

[0087] The above-described compound or a pharmaceutically acceptable salt thereof can be provided (e.g., in a pharmaceutical composition) in a state substantially free of other isomers at the carbon atom having a phenyl ring (i.e., having an absolute configuration different from those disclosed and depicted herein). The compound or a pharmaceutically acceptable salt thereof may alternatively or additionally be provided such that it is substantially free of other isomers at the carbon atom bearing fluorine adjacent to the carbon atom carrying the phenyl ring. For example, when provided as a pharmaceutical composition, the composition may be substantially free of other isomers at the carbon atom having a phenyl ring. Similarly, the composition may alternatively or additionally be substantially free of other isomers at the carbon atom bearing fluorine adjacent to the carbon atom having a phenyl ring. In some embodiments, being substantially free means that the enantiomeric excess (ee) at the carbon atom having a phenyl ring is 95% or more, 98% or more, 99% or more, or 100%. In some embodiments, being substantially free means that at the carbon atom bearing fluorine adjacent to the carbon atom having a phenyl ring, it means an ee of 95% or more, 98% or more, 99% or more, or 100%. In some embodiments, being substantially free means a diastereomeric excess (de) of 95% or more, 98% or more, 99% or more, or 100%.

[0088] In another aspect, provided herein is a polymorph of Form 1 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 polymorph of Form 1 has at least one of: a. a powder X-ray diffraction pattern represented at an angle 2θ ± 0.2° and having two or more peaks 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°; b. a DSC thermogram showing endotherms at about 226.05 °C, about 302.47 °C, and about 310.13 °C; or c. An X-ray crystal structure substantially the same as that of FIG. 4 characterized thereby. In another aspect, the polymorph of Form 1 is represented by 2θ ± 0.2° and is characterized by a powder X-ray diffraction pattern having 3 or more peaks 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°. In one aspect, the polymorph of Form 1 is represented by 2θ ± 0.2° and is characterized by a powder X-ray diffraction pattern having 4 or more peaks 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°. In one aspect, the polymorph of Form 1 is characterized by a powder X-ray diffraction pattern represented by the angles 2θ ± 0.2° of 11.3, 12.4 and 13.3° respectively. In another aspect, the polymorph of Form 1 is characterized by a powder X-ray diffraction pattern having peaks represented by the angles 2θ ± 0.2° of 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4 and 29.5° respectively. In another aspect, the polymorph of Form 1 is characterized by melting onset temperatures of about 221.51 °C, about 299.53 °C and about 308.81 °C. In one aspect, the polymorph of Form 1 has a powder X-ray diffraction pattern substantially the same as that of FIG. 1A. In one aspect, the polymorph of Form 1 substantially does not contain another form 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.

[0089] The compound of formula (I) can be prepared by any suitable method. The compound can be prepared, for example, by the reaction pathways outlined in the following examples. One skilled in the art will understand that the compound of formula (I) can be prepared using other synthetic methods including transformations such as those described in Larock, Comprehensive Organic Transformations, A Guide to Functional Group Preparations, Wiley, 1999.

[0090] In another aspect, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may include a pharmaceutically acceptable excipient. The composition is useful for treating conditions such as hypertrophic cardiomyopathy in humans and other subjects. In certain aspects, the pharmaceutical composition further comprises an additional therapeutic agent. Examples of non-limiting additional therapeutic agents include agents that attempt to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists or neprilysin inhibitors); inotropic agents that improve cardiac function by stimulating cardiac contractility (e.g., the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or agents that reduce cardiac preload (diuretics such as furosemide) or afterload (vasodilators of any class, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators). In certain aspects, the additional therapeutic agent in the pharmaceutical composition is a cardiovascular therapeutic agent.In a further aspect, examples of additional therapeutic agents include beta-adrenergic blockers (beta-blockers), renin-angiotensin-aldosterone system (RAAS) inhibitors (e.g., angiotensin receptor antagonists such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists), angiotensin receptor neprilysin inhibitors (ARNI) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (MRA) [e.g., aldosterone inhibitors such as potassium-wasting diuretics (e.g., eplerenone, spironolactone or canrenone)], cholesterol-lowering agents (e.g., statins), neutral endopeptidase inhibitors (NEPi), positive inotropes [e.g., digoxin, pimobendan, beta-adrenergic receptor agonists (e.g., dobutamine), phosphodiesterase (PDE)-3 inhibitors (e.g., milrinone) or calcium sensitizers (e.g., levosimendan)], potassium or magnesium, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors, vasodilators (e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin modulators), diuretics (e.g., furosemide), antiarrhythmic agents, anticoagulants (e.g., warfarin), antithrombotic agents, antiplatelet agents or combinations thereof.Suitable angiotensin II receptor antagonists (ARBs) include, for example, 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, E-4177, elsartan, 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, surasartan, saralasin, salmesin, 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 valsartan.In certain embodiments, the additional therapeutic agent may be an ARNI, such as sacubitril / valsartan (Entresto®), or a sodium-glucose co-transporter 2 inhibitor (SGLT2), such as empagliflozin (Jardiance®), dapagliflozin (Farxiga®), sotagliflozin. In some embodiments, the subject is administered an additional therapeutic agent to improve the subject's cardiovascular condition. The additional therapeutic agent may be, for example, a beta blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor antagonist, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, or an antiarrhythmic agent. In certain embodiments, the additional therapeutic agent is an ANRI, such as sacubitril / valsartan or an SGLT2 inhibitor.

[0091] In another embodiment, provided herein is a pharmaceutical composition comprising the polymorph of Form 1. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In one embodiment, provided herein is a pharmaceutical composition, wherein the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 80:20. In another embodiment, the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 90:10. In one embodiment, the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 95:5. In one embodiment, the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 97:3. In certain cases, the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 98:2. In certain cases, the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 99:1.

[0092] In certain embodiments, pharmaceutical compositions containing polymorphs of Form 1 further comprise an additional therapeutic agent. Non-limiting examples of additional therapeutic agents include agents that attempt to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists or neprilysin inhibitors); agents that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropic agents such as the β-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, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin modulators). In certain embodiments, the additional therapeutic agent in the pharmaceutical composition is a cardiovascular therapeutic agent.In a further aspect, examples of additional therapeutic agents include beta - adrenergic blockers (beta - blockers), renin - angiotensin - aldosterone system (RAAS) inhibitors (e.g., angiotensin receptor antagonists such as angiotensin - converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists), angiotensin receptor neprilysin inhibitors (ARNI) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (MRA) (e.g., aldosterone inhibitors such as potassium - wasting diuretics like eplerenone, spironolactone or canrenone), cholesterol - lowering agents (e.g., statins), neutral endopeptidase inhibitors (NEPi), positive inotropes [e.g., digoxin, pimobendan, beta - adrenergic receptor agonists (e.g., dobutamine), phosphodiesterase (PDE) - 3 inhibitors (e.g., milrinone) or calcium sensitizers (e.g., levosimendan)], potassium or magnesium, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors, vasodilators (e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin modulators etc.), diuretics (e.g., furosemide), anti - arrhythmic agents, anticoagulants (e.g., warfarin), antithrombotic agents, anti - platelet agents or combinations thereof.Suitable angiotensin II receptor antagonists (ARBs) include, for example, the following: 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, elsartan, 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, isotelin, 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, suralsartan, saralasin, salmesin, 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 may be mentioned.In certain embodiments, the additional therapeutic agent may be an ARNI, such as sacubitril / valsartan (Entresto®), or a sodium-glucose cotransporter 2 inhibitor (SGLT2), such as empagliflozin (Jardiance®), dapagliflozin (Farxiga®), or sotagliflozin. In some embodiments, the subject is administered an additional therapeutic agent to improve the subject's cardiovascular condition. The additional therapeutic agent may be, for example, a beta blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor antagonist, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, or an antiarrhythmic agent. In certain embodiments, the additional therapeutic agent is an ANRI, such as sacubitril / valsartan or an SGLT2 inhibitor.

[0093] A pharmaceutical composition for administering a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof shown herein is preferably in unit dosage form and can be manufactured by any of the methods known in the fields of pharmacy and drug delivery technology. All methods include the step of combining a compound of formula (I) or a pharmaceutically acceptable salt thereof with a carrier containing one or more additional components. Generally, the pharmaceutical composition is manufactured by uniformly and intimately admixing a compound of formula (I) or a pharmaceutically acceptable salt thereof with a liquid carrier or a finely divided solid carrier or both, and shaping it into the desired formulation as needed. In the pharmaceutical composition of the present invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof is generally included in an amount sufficient to achieve the desired effect on myocardial contractility (e.g., often reducing supra-normal contractility in HCM) and / or improving left ventricular relaxation during diastole. Such improvement in relaxation can relieve symptoms in hypertrophic cardiomyopathy and / or other etiologies of diastolic dysfunction. The pharmaceutical composition of the present invention can alternatively or additionally alleviate the effects of diastolic dysfunction that cause coronary blood flow disorders, thereby improving angina pectoris and / or ischemic heart disease as an adjuvant to the latter. The pharmaceutical composition of the present invention can alternatively or additionally provide benefits for beneficial left ventricular remodeling in HCM and / or another etiology of left ventricular hypertrophy resulting from chronic volume or pressure overload, for example, due to valvular heart disease and / or systemic hypertension.

[0094] A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof may be in a form suitable for oral use, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders and effervescent tablets. Compositions for use in the mouth can be prepared according to any method for manufacturing pharmaceutical compositions known in the art, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants and preservatives in order to provide a pharmaceutically elegant and palatable formulation. Tablets contain the compound of formula (I) or a pharmaceutically acceptable salt thereof admixed with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, sodium phosphate; granulating and disintegrating agents such as corn starch, alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid, talc. Tablets may or may not be coated, but may be enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, sustained release substances such as glyceryl monostearate or glyceryl distearate may be used. It is also possible to coat the tablets for osmotic therapy for controlling release.

[0095] An oral pharmaceutical composition can be provided as a hard gelatin capsule in which a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin as a gelatin capsule, or as a soft gelatin capsule in which a compound of formula (I) or a pharmaceutically acceptable salt thereof is mixed with an oil medium such as water or, for example, peanut oil, liquid paraffin or olive oil. Further, an emulsion can be produced using a water-immiscible component such as oil and stabilized using a surfactant such as monoglyceride, PEG ester, etc.

[0096] An aqueous suspension contains a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof admixed with an excipient suitable for the manufacture of an aqueous suspension. Such excipients include, for example, suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents are natural phosphates (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate, etc.), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxy cetanol, etc.), partial esters obtained from ethylene oxide, fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate, etc.) or condensation products of partial esters obtained from ethylene oxide, fatty acids and hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate, etc.). The aqueous suspension may also contain one or more preservatives, such as 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.

[0097] The oily suspension can be formulated by suspending the compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof in a vegetable oil such as peanut oil, olive oil, sesame oil, coconut oil or a mineral oil such as liquid paraffin. The oily suspension may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweeteners and flavoring agents as described above can be added to provide an orally palatable formulation. These compositions can be preserved by adding an antioxidant such as ascorbic acid.

[0098] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water are provided by admixing the compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing agents, wetting agents, suspending agents are exemplified by those described above. Additional excipients such as sweeteners, flavoring agents, coloring agents etc. may also be present.

[0099] The pharmaceutical compositions provided herein may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or peanut oil or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifying agents may be natural gums such as acacia gum or tragacanth gum, natural phosphatides such as soy lecithin and esters or partial esters obtained from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Also, the emulsion may contain sweetening and flavoring.

[0100] Syrups and elixirs may be formulated with a sweetening agent such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may contain an antifoaming agent, a preservative, a flavoring agent and a coloring agent. Oral solutions can be prepared by combining, for example, cyclodextrin, PEG, surfactants etc.

[0101] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using the appropriate dispersing or wetting agents and suspending agents described above. Also, the sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (for example, in a 1,3-butanediol solution, etc.). It is possible to use acceptable vehicles and solvents, including water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, a sterile fixed oil has conventionally been used as a solvent or suspension medium. For this purpose, any brand of fixed oil containing synthetic monoglycerides or diglycerides can be used. Additionally, fatty acids such as oleic acid are used in the manufacture of injectables.

[0102] The compounds of formula (I) or their pharmaceutically acceptable salts or polymorphs provided herein can also be administered in the form of suppositories for rectal administration of the drug. Since these compositions are solid at room temperature but liquid at rectal temperature, they can be manufactured by mixing the drug with a suitable non-irritating excipient that melts in the rectum to release the drug. Such materials include cocoa butter or polyethylene glycol. Furthermore, the compounds can be administered ophthalmically by solution or ointment. Additionally, transdermal delivery of the compound of interest can be achieved by means such as iontophoresis. For topical use, creams, ointments, jellies, solutions, or suspensions containing the compounds provided herein or their pharmaceutically acceptable salts can be used. As used herein, topical application also means including the use of mouthwashes and gargles.

[0103] The compounds of formula (I) provided herein, or pharmaceutically acceptable salts or polymorphs thereof, can also be conjugated to a carrier that is a polymer suitable as a targetable drug carrier. Such polymers can include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Further, the compounds of formula (I) provided herein, or pharmaceutically acceptable salts thereof, can be conjugated to a carrier that is a biodegradable polymer useful for achieving sustained release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. The polymers and semipermeable membrane polymer matrices may be formed into shaped articles such as valves, stents, tubes, prostheses, and the like.

[0104] Mutations that cause HCM result in significant changes in the structure of myosin. These mutations act via different mechanisms depending on their position within the myosin gene. The well-studied HCM mutations R403Q and R453C are located in different parts of the motor domain and cause disruption of various mechanisms that result in a common outcome of increased force generation. Without wishing to be bound by a particular theory, it is believed that the compounds of formula (I) provided herein, or pharmaceutically acceptable salts thereof, can bind directly to the mutant sarcomeric proteins and correct the dysfunction, either in cis (affecting the same specific function) or in trans (altering a complementary function). Thus, they can provide a therapeutic benefit to HCM patients by resolving the contractile hyperactivity and / or relaxation impairment associated with this disease.

[0105] Accordingly, this specification provides a method of treating hypertrophic cardiomyopathy (HCM) or a heart disease having one or more pathophysiological features associated with HCM. The method of the present application includes administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of a compound provided herein, or a compound of formula (I) or a pharmaceutically acceptable salt thereof. The method of the present application includes administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of a compound provided herein or a polymorph of form 1 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.

[0106] This specification also provides a method of treating hypertrophic cardiomyopathy (HCM) or a heart disease. The method includes administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of a compound provided herein, or a compound of formula (I) or a pharmaceutically acceptable salt thereof. The method of the present application includes administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of a polymorph of form 1 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 a polymorph of form 1 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.

[0107] Diastolic dysfunction refers to a series of diseases, including but not limited to hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF) - for example, both impaired active relaxation and impaired ventricular stiffness (e.g., diabetic HFpEF), ischemic cardiomyopathy, cardiac transplant vasculopathy, restrictive cardiomyopathy (e.g., gene mutations of one or more sarcomere proteins), inflammatory cardiomyopathy (e.g., Reiter syndrome, EMF), infiltrative cardiomyopathy (e.g., amyloid, sarcoid, and XRT), storage diseases (e.g., hemochromatosis, Fabry disease, and glycogen storage disease), congenital heart diseases (e.g., pressure-overloaded RV, tetralogy of Fallot (e.g., preoperative and early postoperative diastolic dysfunction), and valvular heart disease (e.g., aortic stenosis)), or is an important feature.

[0108] A method for treating a heart disease or disorder in a subject in need of treatment, the method comprising administering to the subject an effective amount of a compound or a salt thereof as described herein, or a polymorph of form 1 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 some embodiments, diastolic dysfunction is a feature of, and / or is associated with, the heart disease or disorder. For example, the heart disease or disorder can be cardiomyopathy (e.g., hypertrophic cardiomyopathy), heart failure (e.g., heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction), valvular disease (e.g., valvular aortic stenosis), congenital heart disease (e.g., tetralogy of Fallot), left ventricular hypertrophy, angina (e.g., refractory angina), or Chagas disease. In one embodiment, a normal or preserved ejection fraction (e.g., an ejection fraction of about 50% or greater) is a feature of the heart disease or disorder. In some such cases, features of the heart disease or disorder include a normal or preserved ejection fraction and diastolic dysfunction. For example, a subject in need of treatment for a heart disease or disorder (e.g., HCM, HFpEF, valvular aortic stenosis) may have diastolic impairment and an ejection fraction of about 50% or greater. In one embodiment, a mid-range ejection fraction (e.g., an ejection fraction of about 40% to about 50%) is a feature of the heart disease or disorder. In some such cases, a subject in need of treatment for the heart disease or disorder may have a mid-range ejection fraction and diastolic impairment. For example, a subject in need of treatment for a heart disease or disorder (e.g., heart failure with a mid-range ejection fraction) may have diastolic impairment and an ejection fraction of about 40% to about 50%.

[0109] In one aspect, a method for treating diastolic dysfunction in a subject in need of treatment is provided. In one aspect, the method comprises administering to the subject an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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 some instances, the diastolic dysfunction is left ventricular diastolic dysfunction, right ventricular diastolic dysfunction, or both. The diastolic dysfunction can be chronic, stable, or acute. In some aspects, the subject in need of treatment for diastolic dysfunction has 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., amyloidosis, sarcoidosis and / or due to radiotherapy), inflammatory cardiomyopathy (e.g., Löffler 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 (e.g., refractory angina). In one aspect, the subject in need of treatment for diastolic dysfunction has 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 one aspect, the subject in need of treatment for diastolic dysfunction may have undergone one or more surgical procedures. For example, 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 embodiments, a subject in need of treatment for diastolic dysfunction may use an artificial heart valve (e.g., an artificial aortic valve). In some embodiments, a subject in need of treatment for diastolic dysfunction has postoperative diastolic dysfunction. For example, the subject may have postoperative diastolic dysfunction (e.g., right ventricular diastolic dysfunction) after corrective surgery for a congenital disorder (e.g., tetralogy of Fallot). In some examples, a subject in need of treatment for diastolic dysfunction has a normal ejection fraction or a preserved ejection fraction. In another example, a subject in need of treatment for diastolic dysfunction has a moderate ejection fraction.

[0110] In certain aspects, methods are provided for treating cardiomyopathy (e.g., hypertrophic) in a subject in need of treatment. In certain aspects, the method comprises administering to the subject an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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. Non-limiting examples of cardiomyopathies that can be treated using the compounds described herein include hypertrophic cardiomyopathy (e.g., obstructive cardiomyopathy, non-obstructive cardiomyopathy), restrictive cardiomyopathy, infiltrative cardiomyopathy (e.g., associated with diastolic dysfunction) and inflammatory cardiomyopathy (e.g., associated with diastolic dysfunction). In certain aspects, the cardiomyopathy is hypertrophic cardiomyopathy. In certain aspects, the hypertrophic cardiomyopathy is nHCM. The method may comprise administering to a subject in need of treatment for nHCM an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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. A subject in need of treatment for nHCM may have NYHA class II, III or IV heart failure. In other examples, the hypertrophic cardiomyopathy is oHCM. The method may comprise administering to a subject in need of treatment for oHCM an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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. A subject in need of treatment for oHCM may have NYHA class II, III or IV heart failure.

[0111] In one aspect, the cardiomyopathy is restrictive cardiomyopathy. The method may comprise administering to a subject in need of treatment for restrictive cardiomyopathy an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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 one aspect, the restrictive cardiomyopathy may be caused by, for example, one or more mutations (e.g., genetic mutations) in sarcomere proteins. In one aspect, the cardiomyopathy is infiltrative cardiomyopathy. Infiltrative cardiomyopathy may be caused by amyloidosis, sarcoidosis, and / or radiotherapy. In some examples, the infiltrative cardiomyopathy may be characterized by diastolic dysfunction. A method of treating infiltrative cardiomyopathy may comprise administering to a subject in need of treatment an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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 one aspect, the cardiomyopathy is inflammatory cardiomyopathy. Non-limiting examples of inflammatory cardiomyopathy include Loeffler endocarditis and endomyocardial fibrosis. In some examples, the inflammatory cardiomyopathy may be characterized by diastolic dysfunction. A method of treating inflammatory cardiomyopathy may comprise administering to a subject in need of treatment an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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.

[0112] In one aspect, a method of treating heart failure (e.g., HFpEF, HFmrEF) in a subject in need of treatment is provided. The method may comprise administering an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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 heart failure is left heart failure, right heart failure, or both. The heart failure can 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 can be treated with the compounds described herein include HFpEF, diabetic HFpEF, and HFmrEF. In one aspect, the heart failure is HFpEF. In one aspect, a subject in need of treatment for HFpEF may have normal or high contractility (e.g., as measured by echocardiogram). In some cases, a subject in need of treatment for HFpEF may have abnormal longitudinal global strain (e.g., less than -15%). In one aspect, a subject in need of treatment for HFpEF may be afflicted with diabetes (type I, type II) and / or valvular disease (e.g., aortic stenosis). In some examples, a subject in need of treatment for HFpEF may have an artificial valve (e.g., aortic valve) due to valvular disease (e.g., aortic valve stenosis). A method of treating HFpEF (e.g., diabetic HFpEF) in a subject in need of treatment may comprise administering an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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 one aspect, the heart failure is HFmrEF.This method may involve administering to a subject in need of treatment for HFmrEF an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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 in need of treatment for HFmrEF may have NYHA class II, III or IV heart failure.

[0113] In certain embodiments, a method of treating left ventricular hypertrophy in a subject in need of treatment is provided. This method involves administering to the subject an effective amount of a compound of formula (I) or a salt thereof, or a polymorph of form 1 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 some embodiments, the subject in need of treatment for left ventricular hypertrophy has an abnormal left ventricular wall thickness. The left ventricular wall thickness of the subject may be thicker than normal but below the diagnostic criteria for hypertrophic cardiomyopathy. For example, the subject in need of treatment for left ventricular hypertrophy may have a left ventricular wall thickness 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 certain embodiments, the subject in need of treatment for left ventricular hypertrophy has left ventricular hypertrophy in the absence of hypertrophic cardiomyopathy. In certain embodiments, the subject in need of treatment for left ventricular hypertrophy may be suffering from hypertension (e.g., chronic and / or systemic). In certain embodiments, left ventricular hypertrophy may be caused, for example, by chronic mitral regurgitation, chronic aortic regurgitation, chronic aortic stenosis and / or chronic systemic hypertension.

[0114] Additional determinants for diagnosing diastolic dysfunction using echocardiograms are described in J Am Soc Echocardiogr. 29(4):277-314 (2016), the contents of which are incorporated herein by reference for all purposes.

[0115] Subjects in need of treatment for diastolic dysfunction include subjects in 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 in whom left ventricular stiffness measured by echocardiogram or left ventricular stiffness measured by cardiac magnetic resonance is indicated.

[0116] In one aspect, the subject in need of treatment is selected from a patient population having HFpEF.

[0117] The present specification also provides a method for treating a disease or disorder selected from the group consisting of diastolic heart failure (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, the method comprising administering to a subject in need of treatment an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0118] The compound of formula (I) can be administered as monotherapy or in combination therapy. In combination therapy, the compound of formula (I) is used in combination with another treatment regimen, for example, standard of care (SOC) for the subject's cardiac symptoms or another therapy useful for the treatment of related diseases or disorders. The additional therapeutic agent may be administered by a route and in an amount generally used for said agent, or in a reduced amount, and may be administered simultaneously with, sequentially or concurrently with the compound of formula (I).

[0119] In certain embodiments, the compound of formula (I) is administered in addition to the SOC for the symptoms of diastolic dysfunction such as diastolic heart failure. In further embodiments, in addition to the compound of formula (I), an additional therapeutic agent is administered to the subject, such as a β-blocker, an RAAS inhibitor (e.g., an angiotensin receptor antagonist such as an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist), an angiotensin receptor neprilysin inhibitor (ARNI) (e.g., sacubitril / valsartan), a mineralocorticoid receptor antagonist (e.g., an aldosterone inhibitor; e.g., a potassium-wasting diuretic such as eplerenone, spironolactone or canrenone), a cholesterol-lowering agent (e.g., a statin), a neutral endopeptidase inhibitor (NEPi), a cardiotonic agent (e.g., a β-adrenergic receptor agonist such as digoxin, pimobendan, dobutamine, a phosphodiesterase (PDE)-3 inhibitor such as milrinone or a calcium sensitizer such as levosimendan), potassium or magnesium, a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor, a vasodilator (e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor or a smooth muscle myosin regulator, etc.), a diuretic (e.g., furosemide), an antiarrhythmic agent, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent or a combination thereof.

[0120] Suitable ARBs include, for example, the following: 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, elsartan, 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, isotelin, 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, suralsartan, saralasin, salmesin, 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 valsartan.In certain embodiments, the additional therapeutic agent may be an ARNI, such as sacubitril / valsartan (Entresto®), or a sodium-glucose cotransporter 2 inhibitor (SGLT2), such as empagliflozin (e.g., Jardiance®), dapagliflozin (e.g., Farxiga®), or sotagliflozin. In some embodiments, the subject is administered an additional therapeutic agent to improve the subject's cardiovascular condition. The additional therapeutic agent may be, for example, a beta blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor antagonist, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, or an antiarrhythmic agent. In certain embodiments, the additional therapeutic agent is an ANRI, such as sacubitril / valsartan or an SGLT2 inhibitor. In yet another embodiment, a subject being treated for heart failure with a compound of formula (I) is also treated with an ARNI, a beta blocker, and an MRA.

[0121] This specification also provides a method of treating a disease or disorder selected from the group consisting of dilated cardiomyopathy (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina, and restrictive cardiomyopathy, the method comprising administering to a subject in need of treatment an effective amount of the 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 form 1. This specification also provides a method of treating a disease or disorder selected from the group consisting of dilated cardiomyopathy (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina, and restrictive cardiomyopathy, the method comprising administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of the 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 form 1.

[0122] The polymorph of form 1 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 administered as monotherapy or in combination therapy. In combination therapy, the polymorph of form 1 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 another treatment regimen, for example, standard of care (SOC) for the subject's heart disease or another therapy useful for the treatment of related diseases and disorders. The additional therapeutic agent may be administered by the routes and amounts generally used for such agents or in reduced amounts and may be administered simultaneously, sequentially, or concurrently with the polymorph of form 1 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 embodiments, the polymorph of form 1 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 in addition to SOC for the symptoms of dilated dysfunction such as dilated cardiomyopathy.In a further aspect, the subject is administered, in addition to the polymorph of form 1 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 β-blocker, an RAAS inhibitor (e.g., an angiotensin receptor agonist such as an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, etc.), an angiotensin receptor neprilysin inhibitor (ARNI) (e.g., sacubitril / valsartan), a mineralocorticoid receptor antagonist (e.g., an aldosterone inhibitor; e.g., a potassium-wasting diuretic such as eplerenone, spironolactone, canrenone, etc.), a cholesterol-lowering agent (e.g., a statin), a neutral endopeptidase inhibitor (NEPi), a positive inotropic agent (e.g., a β-adrenergic receptor agonist such as digoxin, pimobendan, dobutamine, etc., a phosphodiesterase (PDE)-3 inhibitor such as milrinone, or a calcium sensitizer such as levosimendan), potassium or magnesium, a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor, a vasodilator (e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin regulator), a diuretic (e.g., furosemide), an antiarrhythmic agent, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent, or a combination thereof. Suitable ARBs are provided herein (supra). In certain embodiments, the additional therapeutic agent may be an ARNI such as sacubitril / valsartan (Entresto®) or a sodium-glucose cotransporter 2 inhibitor (SGLT2) such as empagliflozin (Jardiance®), dapagliflozin (Farxiga®). In one aspect, the polymorph of form 1 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 and an additional therapeutic agent for improving the cardiovascular condition is administered to the subject.The additional therapeutic agent may be, for example, a beta blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor antagonist, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor or an antiarrhythmic agent. In certain embodiments, the additional therapeutic agent is an ANRI such as sacubitril / valsartan or an SGLT2 inhibitor. In yet another embodiment, a subject being treated for heart failure with the polymorph of form 1 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.

[0123] This specification also provides a method of treating a disease or disorder characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a therapy (e.g., including valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main cause of the volume or pressure overload, for the disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis and chronic systemic hypertension. This specification also provides a method of treating a disease or disorder characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), 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, in combination with a therapy (e.g., including valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main cause of the volume or pressure overload, for the disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis and chronic systemic hypertension.

[0124] This specification also provides a method for treating a disease or disorder characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), comprising treating the disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension, in combination with a therapy (e.g., including valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main cause of volume or pressure overload, by administering to a subject in need of treatment an effective amount of the polymorph of form 1 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. This specification also provides a method for treating a disease or disorder characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), comprising treating the disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension, in combination with a therapy (e.g., including valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main cause of volume or pressure overload, by administering to a subject in need of treatment a pharmaceutical composition comprising an effective amount of the polymorph of form 1 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.

[0125] This specification also provides a method for treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological features associated with HCM), the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with (1) a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist, a neprilysin inhibitor, etc.) that attempts to prevent cardiac remodeling by delaying the progression of heart failure by downregulating cardiac neurohormonal stimulation; (2) a therapeutic method (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or (3) a therapeutic method that reduces the preload (e.g., a diuretic such as furosemide) or afterload (vasodilators of any class, e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators, etc.) of the heart.

[0126] This specification also provides a method for treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological characteristics associated with HCM), the method comprising administering to a subject in need thereof a pharmaceutical composition comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with: (1) a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist, or a neprilysin inhibitor, etc.) that attempts to prevent cardiac remodeling by delaying the progression of heart failure by down-regulating cardiac neurohormonal stimulation; (2) a therapeutic method (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or (3) a therapeutic method that reduces the preload (e.g., a diuretic such as furosemide) or afterload (vasodilators of any class, e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, smooth muscle myosin modulators, etc., but not limited thereto) of the heart.

[0127] This specification also relates to a method of treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological characteristics associated with HCM), comprising administering to a subject in need thereof an effective amount of the polymorph of form 1 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 combination with (1) a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist, a neprilysin inhibitor, etc.) that attempts to prevent cardiac remodeling by delaying the progression of heart failure by downregulating cardiac neurohormonal stimulation; (2) a treatment method (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or (3) a cardiac preload (e.g., a diuretic such as furosemide) or afterload (any class of vasodilators, e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator, etc., but not limited thereto).

[0128] This specification also relates to a method of treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological characteristics associated with HCM), comprising administering to a subject in need of treatment a pharmaceutical composition comprising a polymorph of form 1 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 combination with (1) a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neprilysin inhibitor, etc.) that attempts to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation to slow the progression of heart failure; (2) a therapeutic method (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or (3) the cardiac preload (e.g., a diuretic such as furosemide) or afterload (any class of vasodilators, e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor or a smooth muscle myosin modulator, etc., but not limited thereto).

[0129] This specification also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. This specification also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. This specification also provides a polymorph of form 1 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. This specification also provides a pharmaceutical composition comprising a polymorph of form 1 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.

[0130] This specification also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of hypertrophic cardiomyopathy or a heart disease (e.g., a heart disease having pathophysiological characteristics associated with HCM). This specification also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of hypertrophic cardiomyopathy or a heart disease (e.g., a heart disease having pathophysiological characteristics associated with HCM). This specification also provides a polymorph of form 1 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 heart disease (e.g., a heart disease having pathophysiological characteristics associated with HCM). This specification also provides a pharmaceutical composition comprising a polymorph of form 1 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 heart disease (e.g., a heart disease having pathophysiological characteristics associated with HCM).

[0131] This specification also provides 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 dilated cardiomyopathy (such as heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. This specification also provides 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 dilated cardiomyopathy (such as heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. This specification also provides a polymorph of form 1 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 dilated cardiomyopathy (such as heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. This specification also provides a pharmaceutical composition comprising a polymorph of form 1 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 dilated cardiomyopathy (such as heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy.

[0132] This specification also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; wherein the compounds of the present application are used in combination with a treatment method (e.g., including valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main causes of volume or pressure overload. This specification also provides 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 characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; wherein the compounds of the present application are used in combination with a treatment method (e.g., including valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main causes of volume or pressure overload. This specification also provides a polymorph of form 1 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 characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; wherein the compound is used in combination with a therapy (e.g., including valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main causes of volume or pressure overload.This specification also provides a pharmaceutical composition comprising a polymorph of form 1 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 characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; wherein the compound is used in combination with a treatment (e.g., including valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main cause of volume or pressure overload.

[0133] This specification also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having the pathophysiological characteristics of HCM), wherein the compound is (1) a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neuropeptidase inhibitor, etc.) that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation; (2) a therapeutic method (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or (3) a therapeutic agent (e.g., a diuretic such as furosemide) that reduces the preload of the heart or a therapeutic agent (including but not limited to vasodilators of all classifications, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators) that reduces the afterload of the heart, for use in combination therewith. This specification 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 heart disease (e.g., a heart disease having the pathophysiological characteristics of HCM), wherein the compound is (1) a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neuropeptidase inhibitor, etc.) that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation; (2) a therapeutic method (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or (3) a therapeutic agent (e.g., a diuretic such as furosemide) that reduces the preload of the heart or a therapeutic agent (including but not limited to vasodilators of all classifications, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators) that reduces the afterload of the heart, for use in combination therewith.

[0134] This specification also provides a polymorph of Form 1 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 heart disease (e.g., a heart disease having the pathophysiological characteristics of HCM), wherein said compound delays the progression of heart failure by downregulating the neurohormonal stimulation of the heart and attempts to prevent cardiac remodeling, and is a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neprilysin inhibitor, etc.); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor); and / or a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload of the heart (including, but not limited to, vasodilators of any class, e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators) for use in combination therewith.This specification also provides a pharmaceutical composition comprising a polymorph of Form 1 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 heart disease (e.g., a heart disease having the pathophysiological characteristics of HCM), wherein said compound is a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neprilysin inhibitor, etc.) that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation; a therapeutic agent (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or a therapeutic agent (e.g., a diuretic such as furosemide) that reduces the preload of the heart or a therapeutic agent (including, but not limited to, vasodilators of any classification, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators) that reduces the afterload of the heart for use in combination therewith.

[0135] This specification also provides for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. This specification also provides for the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. This specification also provides for the use of polymorph form 1 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. This specification also provides for the use of a pharmaceutical composition comprising polymorph form 1 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.

[0136] This specification also provides the use of 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 heart disease (e.g., a heart disease having the pathophysiological characteristics of HCM). This specification also provides the 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 heart disease (e.g., a heart disease having the pathophysiological characteristics of HCM). This specification also provides the use of polymorph form 1 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 heart disease (e.g., a heart disease having the pathophysiological characteristics of HCM). This specification also provides the use of a pharmaceutical composition comprising polymorph form 1 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 heart disease (e.g., a heart disease having the pathophysiological characteristics of HCM).

[0137] The present specification also provides the use of 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 dilated cardiomyopathy (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. The present specification also provides the 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 dilated cardiomyopathy (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. The present specification also provides the use of polymorph form 1 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 dilated cardiomyopathy (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. The present specification also provides the use of a pharmaceutical composition comprising polymorph form 1 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 dilated cardiomyopathy (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy.

[0138] The present specification also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating left ventricular hypertrophy (e.g., due to volume or pressure overload), said disease or disorder (selected from the group consisting of chronic mitral valve regurgitation, chronic aortic valve stenosis and chronic systemic hypertension), in combination with a therapy aimed at correcting or alleviating the main cause of volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy). The present specification also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating left ventricular hypertrophy (e.g., due to volume or pressure overload), said disease or disorder (selected from the group consisting of chronic mitral valve regurgitation, chronic aortic valve stenosis and chronic systemic hypertension), in combination with a therapy aimed at correcting or alleviating the main cause of volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy). The present specification also provides the use of a polymorph of form 1 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 treating left ventricular hypertrophy (e.g., due to volume or pressure overload), said disease or disorder (selected from the group consisting of chronic mitral valve regurgitation, chronic aortic valve stenosis and chronic systemic hypertension), in combination with a therapy aimed at correcting or alleviating the main cause of volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy).This specification also provides for the use of a pharmaceutical composition comprising the polymorph of form 1 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 (e.g., due to volume or pressure overload), the disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis and chronic systemic hypertension, in combination with a therapy (e.g., valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main cause of volume or pressure overload.

[0139] This specification also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological features associated with HCM) in combination with a therapeutic agent that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating the neurohormonal stimulation of the heart (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neprilysin inhibitor, etc.); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a positive inotropic agent such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload of the heart (including, but not limited to, vasodilators of any class, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators). This specification also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological features associated with HCM) in combination with a therapeutic agent that attempts to slow the progression of heart failure and prevent cardiac remodeling by downregulating the neurohormonal stimulation of the heart (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neprilysin inhibitor, etc.); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a positive inotropic agent such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload of the heart (including, but not limited to, vasodilators of any class, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators).

[0140] This specification also provides for the use of the polymorph of form 1 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 the manufacture of a medicament for treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological features associated with HCM) in combination with a therapeutic agent that down-regulates the neurohormonal stimulation of the heart to retard the progression of heart failure and prevent cardiac remodeling (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist, or a neprilysin inhibitor, etc.); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor); and / or a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload of the heart (including, but not limited to, vasodilators of all classes, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators).This specification also relates to a use of a pharmaceutical composition comprising a polymorph of form 1 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 combination with a therapeutic agent that downregulates cardiac neurohormonal stimulation to slow the progression of heart failure and prevent cardiac remodeling (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neprilysin inhibitor, etc.); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor); and / or a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload of the heart (including, but not limited to, vasodilators of all classes, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators), for manufacturing a pharmaceutical for treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological features associated with HCM).

[0141] The compound of formula (I) or a pharmaceutically acceptable salt thereof can not only relieve symptoms but also change the natural course of diseases such as HCM. The polymorph of form 1 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 not only relieve symptoms but also change the natural course of HCM and other diseases. The mechanism that brings clinical benefits to HCM patients may extend to patients with other forms of heart diseases with similar pathophysiology regardless of the presence of genetic effects. For example, an effective treatment for HCM by improving ventricular relaxation in diastole is considered to be effective in a wider population characterized by diastolic dysfunction. The compound of formula (I) or a pharmaceutically acceptable salt thereof can specifically target the root cause of symptoms or act on another downstream pathway. The polymorph of form 1 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 cause of symptoms or act on another downstream pathway. Therefore, the compound of formula (I) or a pharmaceutically acceptable salt thereof can also benefit patients suffering from heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris or restrictive cardiomyopathy. Thus, the polymorph of form 1 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 benefit patients suffering from heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris or restrictive cardiomyopathy.Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with a treatment aimed at modifying or alleviating the main causes of volume or pressure overload (valve repair / replacement, effective antihypertensive therapy), can favorably promote ventricular remodeling in left ventricular hypertrophy due to volume or pressure overload; for example, in mitral valve regurgitation, aortic valve stenosis or chronic systemic hypertension. The polymorph of form 1 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, in combination with a treatment aimed at modifying or alleviating the main causes of volume or pressure overload (valve repair / replacement, effective antihypertensive therapy), favorably promote ventricular remodeling in left ventricular hypertrophy due to volume or pressure overload; for example, in mitral valve regurgitation, aortic valve stenosis or chronic systemic hypertension. By reducing left ventricular filling pressure, the risk of pulmonary edema and respiratory failure can be reduced. By reducing or eliminating functional mitral valve regurgitation and lowering left atrial pressure, the risk of paroxysmal or persistent atrial fibrillation can be reduced, and concomitantly, the risk of complications such as arterial thromboembolism (including but not limited to cerebral artery embolism) can be decreased. By reducing or eliminating dynamic and / or static left ventricular outflow tract obstruction, the need for surgical or percutaneous septal reduction therapy with the risk of short-term and long-term complications can be decreased. The compound of formula (I) or a pharmaceutically acceptable salt thereof can reduce the severity of the chronic ischemic state associated with HCM, thereby reducing the risk of sudden cardiac death (SCD) or a comparable risk (frequent and / or recurrent ICD discharges) and / or the need for potentially toxic antiarrhythmic drugs in patients with an implantable defibrillator.(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 polymorph of Form 1 reduces the severity of chronic ischemic conditions associated with HCM, thereby reducing the risk of sudden cardiac death (SCD) or its equivalent (frequent and / or recurrent ICD discharges) and / or the need for potentially toxic antiarrhythmic drugs in patients with an implanted defibrillator. The compound of formula (I) or a pharmaceutically acceptable salt thereof is considered valuable in reducing or eliminating the need for concomitant medications with potential toxicity, drug-drug interactions and / or side effects. (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 polymorph of Form 1 is considered valuable in reducing or eliminating the need for concomitant medications with potential toxicity, drug-drug interactions and / or side effects. The compound of formula (I) or a pharmaceutically acceptable salt thereof can result in a reduction in and / or a delay in the progression of interstitial myocardial fibrosis, and suppression or reversal of left ventricular hypertrophy. (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 polymorph of Form 1 can result in a reduction in and / or a delay in the progression of interstitial myocardial fibrosis, and suppression or reversal of left ventricular hypertrophy.

[0142] Depending on the disease to be treated and the symptoms of the subject, the compounds of formula (I) provided herein or their pharmaceutically acceptable salts may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intrathoracically by injection or infusion, subcutaneously or by implantation), by implant (e.g., when the compound is conjugated to a stent device, etc.), by inhalation spray, intranasally, intravaginally, rectally, sublingually or by topical administration routes, and may be formulated alone or together into appropriate dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each administration route.

[0143] Depending on the disease to be treated and the symptoms of the subject, the polymorph of form 1 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 orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intrathoracically by injection or infusion, subcutaneously or by implantation), by implant (e.g., when the compound is conjugated to a stent device, etc.), by inhalation spray, intranasally, intravaginally, rectally, sublingually or by topical administration routes, and may be formulated alone or together into appropriate dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each administration route.

[0144] The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof, may be administered in a regimen of 1 to 4 times a day, preferably 1 or 2 times a day. A pharmaceutical composition comprising (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 polymorph of form 1 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 in a regimen of 1 to 4 times a day, preferably 1 or 2 times a day.

[0145] However, the specific dosage range and frequency of administration for a particular patient will vary and will depend on various factors, including the activity of the specific compound or pharmaceutically acceptable salt used, the metabolic stability and duration of action of that compound or pharmaceutically acceptable salt, the age, weight, genetic characteristics, general health, sex and diet of the subject, as well as the mode and time of administration, the rate of excretion, drug combinations, and the severity of the specific symptoms of the subject being treated.

[0146] The compounds of formula (I), pharmaceutically acceptable salts and / or pharmaceutical compositions thereof provided herein can be used in combination with additional therapeutic agents used in the treatment, prevention, suppression or alleviation of diseases or conditions for which the compounds and compositions provided herein are effective. The polymorph of form 1 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 the pharmaceutical compositions provided herein can be used in combination with another drug used in the treatment, prevention, suppression or alleviation of diseases or conditions for which the compounds and compositions provided herein are useful. Such additional therapeutic agents may be administered simultaneously or sequentially with the compounds or compositions provided herein, by the routes and in the amounts generally used for that purpose. When the compounds or compositions provided herein are used simultaneously with one or more other drugs, pharmaceutical compositions containing not only the compounds or compositions provided herein but also such other drugs are preferred. Accordingly, the pharmaceutical compositions provided herein include those containing, in addition to the compounds or compositions provided herein, one or more other active ingredients or therapeutic agents. Suitable additional active agents include, for example, therapeutic agents that slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists or neprilysin inhibitors); inotropic agents that improve cardiac function by stimulating myocardial contraction (e.g., dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor); and therapeutic agents that reduce the preload of the heart (e.g., diuretics such as furosemide) or therapeutic agents that reduce the afterload of the heart (vasodilators of any class, e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin modulators, etc.).The weight ratio of the compound of formula (I) or a pharmaceutically acceptable salt thereof provided herein to a second active ingredient may be varied and depends on the effective amounts of each ingredient. Generally, the effective amounts of each are used.

[0147] When the compounds herein are administered in combination with another therapeutic agent, the other therapeutic agent can be administered simultaneously with, separately from, or sequentially to the compound of formula (I). The exact dosing regimen is one that conforms to the properties of the therapeutic agent. When the compounds herein are administered in combination with another therapeutic agent, the other therapeutic agent can be administered simultaneously with, separately from, or in sequence with polymorph form 1 of (6S,7S)-6-fluoro-7-(2-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The exact dosing regimen is an amount that conforms to the properties of the therapeutic agent.

Examples

[0148] Abbreviations: ACN: acetonitrile; aq: aqueous solution; Ar: argon; CH2Cl2: dichloromethane; CH3CN: acetonitrile; CH3OH: methanol; Cs2CO3: cesium carbonate; DCM: dichloromethane; DIEA: diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; equiv.: equivalent; Et2O: diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; h or hr: hour; HATU: 1-[(bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HCl: hydrogen chloride; H2O: water; IPA: isopropyl alcohol; iPr2O: diisopropyl ether; K2CO3: potassium carbonate; LiHMDS: lithium hexamethyldisilazane; MeOH: methanol; MgSO4: magnesium sulfate; min: minute; mL: milliliter; MW or μW: microwave (reaction conducted in a microwave reactor); NaBH4: sodium borohydride; NaBH3CN: sodium cyanoborohydride; NaCl: sodium chloride; NaBH3CN: sodium cyanoborohydride; NaH: sodium hydride; NaHCO3: sodium bicarbonate; NaOH: sodium hydroxide; NaOMe: sodium methoxide; Na2SO4: sodium sulfate; n-BuOH: n-butanol; NH4Cl: ammonium chloride; pH: -log[H + ; RT: room temperature; SOCl2: thionyl chloride; TFA: trifluoroacetic acid; THF: tetrahydrofuran; THP: tetrahydropyran or tetrahydropyranyl; and Zn: zinc powder. All experiments were conducted in a draft chamber equipped with specific safety precautions and required personal protective equipment.

[0149] Example 1: Synthesis Intermediate Example 1: Production of (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) Scheme I-1

Chem.

[0150] Step 1. Synthesis of (S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (1-2) To a 1000 mL round-bottom flask, under an Ar atmosphere, 3-fluorobenzaldehyde (50 g, 0.40 mol), (S)-2-methylpropane-2-sulfinamide (50 g, 0.41 mol), Cs2CO3 (157 g, 0.48 mol) and dichloromethane (500 mL) were added. After stirring at room temperature for 4 hours, the reaction mixture was diluted with methyl tert-butyl ether (MTBE) (1000 mL). Next, the mixture was filtered and the filtrate was concentrated to obtain crude product 1-2 (87 g, 95%) as an off-white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 228 [M+H] + ; 1 1H NMR (300 MHz, CDCl3): δ 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).

[0151] Step 2. Synthesis of ethyl (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoate (1-3) 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) was added to a suspension of Zn (38 g, 0.58 mmol) / tetrahydrofuran (600 mL) with stirring at 70 °C for 40 minutes under an Ar atmosphere. After stirring at 70 °C for an additional 30 minutes, the reaction mixture was filtered and the filtrate was concentrated. The residue was diluted with EtOAc (1000 mL). Then, the resulting mixture was washed with a saturated aqueous citric acid solution (500 mL) and dried over anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to obtain 1-3 (50 g, 60%) as a yellow oil. LC-MS (ES, m / z): 352 [M+H] + .

[0152] Step 3. (S)-3-(((S)-tert-Butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) A solution of 1-3 (80 g, 0.23 mol) / tetrahydrofuran (1000 mL) was added to 1N aqueous NaOH solution (350 mL) at room temperature under an Ar atmosphere. After stirring at room temperature for 30 minutes, the pH value of the reaction mixture was adjusted to 5 using 1N aqueous citric acid solution. The resulting mixture was extracted with ethyl acetate (1000 mL x 3). Then, the combined organic extracts were washed with brine (500 mL) and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by Flash-Prep-HPLC (column: C18 silica gel; mobile phase: increasing from CH3CN / H2O = 10 / 90 (v / v) to CH3CN / H2O = 95 / 5 (v / v) over 60 minutes; detector: UV254 nm) to obtain 1-4 (30 g, 41%) as a white solid. LC-MS (ES, m / z): 324 [M+H] + ; 1 H-NMR (400 MHz, d 6-DMSO): δ 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).

[0153] Intermediate Example 2: Preparation of 1-(tetrahydro-2H-pyran-4-yl)piperidine-2,4,6-trione (2-3) Scheme I-2

Chemical Structure

[0154] 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), isocyanatotrimethylsilane (30 g, 0.26 mol) was added at 0 °C under an Ar atmosphere. After stirring overnight at room temperature, the reaction was quenched by adding MeOH (20 mL). The solvent was removed and the residue was triturated with ether (50 mL). Next, the suspension was filtered and the solid was washed with ether (500 mL x 3) and dried in vacuo to obtain 2-2 (34 g, 68%) as a white solid. 1 H NMR (300 MHz, d 6 -DMSO): δ 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).

[0155] 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), 2-2 (34 g, 0.24 mol) was added at room temperature under an Ar atmosphere, and then 1,3-dimethylpropanedioate (470 g, 0.36 mol) was added. After stirring overnight at 80 °C, the reaction mixture was concentrated, and the residue was diluted with water (50 mL). Next, the pH value of the resulting mixture was adjusted to 2 by adding concentrated aqueous HCl at 0 °C. The suspension was filtered, the solid was washed with water, and dried in vacuo at 45 °C for 24 h to obtain 2-3 (30 g, 60%) as a white solid. 1 H NMR (300 MHz, d 6 -DMSO): δ 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).

[0156] Step B-1. Synthesis of phenyl carbamate (2-5) To a mixed solution of saturated aqueous ammonia (50 mL) and DCM (50 mL), a solution of 2-4 (30 g) in DCM (45 mL) was added at 0 °C. After stirring at 0 °C for 4 h, the reaction mixture was filtered, the solid was washed with water, and dried in vacuo at 45 °C for 12 h to obtain 2-5 (18.3 g, 70%) as a white solid. LC-MS (ES, m / z): 138 [M+H] + ; 1 H NMR (400 MHz, d 6 -DMSO): δ 7.42 - 7.32 (m, 2H), 7.24 - 7.15 (m, 1H), 7.13 - 7.04 (m, 2H), 6.89 (br, 2H).

[0157] 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 °C for 3 h under an Ar atmosphere. The suspension was then filtered, the solid was washed with ether (100 mL) and dried in vacuo at 45 °C for 12 h to give 2-2 (18.3 g, 95%) as a white solid. 1 H NMR (400 MHz, d 6 -DMSO): δ 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).

[0158] Intermediate Example 3: Preparation of (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (3-3) Scheme I-3

Chemical Structure

[0159] 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 Cs2CO3 (15.7 g, 48.25 mol) in DCM (60 mL) was stirred at room temperature overnight under an Ar atmosphere. The reaction mixture was then diluted with ether (200 mL) and then filtered. The filtrate was concentrated and the residue was dried in vacuo to give the crude product 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] + ; 1 H NMR (300 MHz, d 6-DMSO): δ 8.58 (s, 1H), 7.88 - 7.73 (m, 2H), 7.60 (m, 1H), 7.45 (m, 1H), 1.19 (s, 9H).

[0160] Step 2. Synthesis of ethyl (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoate (3-2) To a solution of crude product 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 (1 M in THF, 19.8 mL) dropwise over 30 minutes at -78 °C under an Ar atmosphere. After stirring at -78 °C for 1 hour, the reaction was quenched by adding 2N aqueous HCl solution (45 mL) at -78 °C. The reaction mixture was concentrated to remove most of the THF and then extracted with EtOAc (100 mL x 3). Next, the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to obtain crude product 3-2 (4.6 g) as an off-white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 334 [M+H] + .

[0161] Step 3. Synthesis of (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (3-3) To a solution of the crude product 3-2 (6 g, 18 mmol) in THF (60 mL), 1N aqueous NaOH solution (36 mL, 36 mmol) was added at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL x 2). The aqueous layer was adjusted to pH 5 using saturated aqueous citric acid, and the resulting mixture was extracted with EtOAc (200 mL x 3). Then, the combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by preparative HPLC (column: XBrIdge Prep OBD C18 column, 19 x 250 mm, 5um; mobile phase: water (0.05% TFA (v / v)) and ACN (from 3.0% (v / v) to 17.0% (v / v) over 8 minutes); detector: UV220 nm) to obtain 3-3 (1.5 g, 27%) as a white solid. LC-MS (ES, m / z): 306 [M+H] + ; 1 H NMR (400 MHz, d 6 -DMSO): δ 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).

[0162] 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) Scheme C-1

Chemical formula

[0163] Synthesis of Engineering 1. (S)-N-((1S)-2,2-difluoro-1-(3-fluorophenyl)-3-oxo-3-(2,4,6-trioxo-1-(tetrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropan-2-sulfinamide (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 °C. After stirring overnight at room temperature, the reaction mixture was diluted with saturated aqueous NaHCO3 (100 mL) and ice water (100 mL) overnight. The mixture was extracted with EtOAc (100 mL x 3), and the combined organic extracts were washed with brine and dried over anhydrous Na2SO4. 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 in the next step without further purification. LC-MS (ES, m / z): 518 [M+H] + .

[0164] Synthesis of Engineering 2. (S)-N-((1S)-2,2-difluoro-1-(3-fluorophenyl)-3-(2,4,6-trioxo-1-(tetrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropan-2-sulfinamide (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 room temperature for 1 h. Next, the reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine and dried over anhydrous Na2SO4. 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 in the next step without further purification. LC-MS (ES, m / z): 504 [M+H] + .

[0165] Synthesis of Engineering 3.5-((S)-3-amino-2,2-difluoro-3-(3-fluorophenyl)propyl)-1-(tetrahydro-2H-pyran-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), thionyl chloride (2.7 mL) was added at 0 °C over 3 minutes. After stirring at room temperature for 1 hour, the reaction mixture was concentrated and dried in vacuo to obtain crude C-C (800 mg) as a yellow solid, which was used in the next step without further purification. LC-MS (ES, m / z): 400 [M+H] + .

[0166] Engineering 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 CH3CN (10 mL) in a sealed vial was stirred in a microwave reactor at 120 °C for 20 minutes. Next, the mixture was diluted with water (50 mL), and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine and dried over anhydrous Na2SO4. The solvent was removed, and the residue was purified by preparative HPLC (column: XBridge C18 OBD Prep Column, 19 mm x 250 mm; mobile phase: within 8 minutes, water (0.05% (v / v) NH3·H2O) / CH3CN = 11.0% (v / v) - 30.0% (v / v); detector: UV254 nm) to obtain C-1 (197 mg, 27% in 3 steps from C-A) as a white solid. LC-MS (ES, m / z): 382 [M+H] + ; 1 1H NMR (400 MHz, d 6-DMSO): δ 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).

[0167] 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) Scheme 1

Chemical formula

[0168] Steps 1-4. 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) (S)-3-(((S)-tert-Butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) was replaced with (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (3-3) according to the same method described for the 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-4), and 1 was obtained as a white solid. LC-MS (ES, m / z): 364 [M+H] + ; 1 H NMR (300 MHz, d 6-DMSO): δ 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); 19 F NMR (376 MHz, d 6 -DMSO): δ -113.18, -192.36.

[0169] 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) Scheme 2 [Chemical Structure]

[0170] Steps 1-2: Synthesis of (2S,3S)-3-(((S)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (2B) (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) was prepared by the same method described for the preparation of (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4), except that ethyl 2-bromo-2,2-difluoroacetate was replaced with ethyl 2-bromo-2-fluoroacetate. 2B was obtained as an off-white solid. LC-MS (ES, m / z): 306 [M+H] + .

[0171] Steps 3-6: 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) In the same manner as described for the production 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-4), (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) was replaced with (2S,3S)-3-(((S)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (2B) to obtain 2 as a white solid. LC-MS (ES, m / z): 364 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ 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); 19 F NMR (376 MHz, d 6 -DMSO): δ -112.59, -175.93.

[0172] Examples 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) Scheme 3

Chemical Structure

[0173] Step 2. Synthesis of ethyl (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(2-fluoro-5-methylphenyl)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), LiHMDS (1 M in THF, 24.6 mL, 24.6 mmol) was added dropwise at -78 °C over 30 minutes under an Ar atmosphere. After stirring at -78 °C for 1 hour, the reaction was quenched by adding 1 N aqueous HCl solution (50 mL) while maintaining the internal temperature of the mixture at < -20 °C. Next, the mixture was concentrated to remove most of the organic solvent and then extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was removed and the residue was dried under vacuum to give crude 3C (6.0 g) as a yellow oil, which was used in the next step without further purification. LC-MS (ES, m / z): 348 [M+H] + .

[0174] Step 3. Synthesis of (3D) (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(2-fluoro-5-methylphenyl)propanoic acid To a solution of 3C (6.0 g, 17.3 mmol) in THF (40 mL) was added 1N aqueous NaOH solution (34.6 mL, 34.6 mmol) at room temperature. After stirring at room temperature for 1 hour, ice water (50 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (100 mL x 2). The aqueous layer was adjusted to pH 5 using saturated aqueous citric acid and then extracted with EtOAc (100 mL x 3). Next, the combined organic extracts were washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was removed and the residue was purified by preparative HPLC (column: XBridge Prep OBD C18 Column, 19 x 250 mm, 5um; mobile phase: water (0.05% TFA) and ACN (from 28.0% ACN to 36.0% in 10 minutes); detector: UV220 nm) to obtain 3D (2 g, 36%) as a white solid. LC-MS (ES, m / z): 320 [M+H] + ; 1 H NMR (400 MHz, d 6 -DMSO): δ 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).

[0175] Step 4. Synthesis of (3E) (R)-N-((1S,2R)-2-fluoro-1-(2-fluoro-5-methylphenyl)-3-oxo-3-(2,4,6-trioxo-1-(tetrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropan-2-sulfinamide 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 with DIEA (849 mg, 6.57 mmol) at 0 °C under an Ar atmosphere. After stirring at room temperature for 2 h, the reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL), and the resulting solution was extracted with ethyl acetate (50 mL x 3). The combined organic extracts were washed with brine (50 mL x 2) and dried over anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give the crude product 3E (1.3 g) as a white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 514 [M+H] + ; 1 H NMR (400 MHz, d 6 -DMSO): δ 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).

[0176] Step 5. Synthesis of (R)-N-((1S,2S)-2-fluoro-1-(2-fluorophenyl)-3-(2,4,6-trioxo-1-(tetrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropan-2-sulfinamide (3F) A solution of crude product 3E (1.3 g, 2.53 mmol) in AcOH (10 mL) was added to NaBH3CN (398 mg, 6.33 mmol) at 0 °C under an Ar atmosphere. After stirring at room temperature for 1 h, the reaction mixture was added to ice water (20 mL), and the resulting solution was extracted with EtOAc (50 mL x 3). The combined organic extracts were then washed with brine (50 mL) and dried over anhydrous Na2SO4. 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 in the next step without further purification. LC-MS (ES, m / z): 500 [M+H] + ; 1 H NMR (400 MHz, d 6 -DMSO): δ 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).

[0177] Step 6. Synthesis of 5-((2S,3S)-3-amino-2-fluoro-3-(2-fluoro-5-methylphenyl)propyl)-1-(tetrahydro-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 to thionyl chloride (334 mg) at 0 °C. After stirring at room temperature 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 in the next step without further purification. LC-MS (ES,m / z): 396 [M+H] + .

[0178] 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 CH3CN (15 mL) was placed in a microwave reactor and stirred at 120 °C for 30 minutes. The mixture was then concentrated and the residue was purified by preparative HPLC (column: C18 silica gel; mobile phase: increasing from CH3CN:H2O = 20:80 (v / v) to CH3CN:H2O = 80:20 (v / v) within 40 minutes; detector: UV 254 nm) to give compound 3 (302 mg, 32%) as a white solid, which was identified as the polymorph of Form 1 (see Example 2). LC-MS (ES, m / z): 378 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ 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); 19 F NMR (376 MHz, d 6 -DMSO): δ -123.51 (t, J = 86.5 Hz), -191.57 (d, J = 129.34 Hz).

[0179] Examples 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) Scheme 4

Chemical Structure

[0180] Production of Engineering 1-7. (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) (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) was prepared in the same manner as described for the production 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), replacing 3-fluorobenzaldehyde (1-1) with 2-fluoro-5-methylbenzaldehyde (3A) to obtain 4 as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 1 H NMR (400 MHz, d 6 -DMSO): δ 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); 19 F NMR (376 MHz, d 6 -DMSO): δ -124.08, -175.61.

[0181] Example 1-5: Production related to the 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) Scheme 5

Chemical Structure

[0182] Synthesis of Engineering 1-6. (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 method as described for the 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), (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide (3B) was replaced with (S,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide (4B) to obtain 5 as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ 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); 19 F NMR (376 MHz, d 6 -DMSO): δ -123.49, -191.34.

[0183] 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) Scheme 6

Chemical formula

[0184] Process 1-6. (6S,7R)-6-Fluoro-7-(2-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6) (S,E)-N-(3-Fluorobenzylidene)-2-methylpropane-2-sulfinamide (1-2) was replaced with (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide (3B) according to the same method described for the 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), and 6 was obtained as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ 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); 19 F NMR (376 MHz, d 6 -DMSO): δ -124.36, -175.43.

[0185] Additional compounds were prepared using a method similar to the method described above.

Table 1

Table 2

[0186] Example 2 Single crystal X-ray analysis - Form 1 SXRD analysis was performed on a SuperNova diffractometer from Agilent Technologies (Dual Source) using monochromatic Cu Kα (λ 1.54178 Å) radiation generated from a sealed tube. The diffractometer was equipped with a cryogenic device from Oxford Cryosystems that enables data collection at 120(1) K, and the crystal was protected with Paratone oil. The collected data was corrected for absorption effects based on Gaussian integration for a multi-faceted crystal model implemented as part of the CrysAlisPro software package (Agilent Technologies, 2014).

[0187] The structure was solved by the direct method (SHELXS97) 1 and expanded by full least-squares refinement (SHELXL97) on F via the interface of the OLEX2 software package (see Figure 4). The obtained images were processed according to OLEX2 2 Full least-squares refinement on F 1 (see Figure 4). The obtained images were processed according to OLEX2 2 as follows. The data was collected, analyzed, refined to the orthorhombic space group P212121, and the ADDSYMM of PLATON 4 of PLATON 3Higher-order metric symmetries were explored using routines, but no higher-order symmetries could be revealed. All non-hydrogen atoms were placed in the Fourier map, their positions refined, and then the thermal motions of all non-hydrogen atoms were described anisotropically. Within this structure, only one complete molecule of 3 (also referred to as the compound of Example 3) was located in the asymmetric unit. Since the obtained diffraction data were weak, the Flack parameter was calculated to be -0.0657 and the esd was 0.7497 (calculated from 1477 Bijovet pairs, showing 97.6% completeness). Attempts were made to refine the structure using the TWIN command and the BASF command, but no further improvement was seen. All hydrogen atoms were placed at the calculated positions fixed by a riding model using fixed Uiso, 1.2 times for all CH, CH2, NH groups and 1.5 times for all CH3 groups. The highest residual Fourier peak was 1.34 e. Å from C(16) -3 at about 0.68 Å, and the deepest Fourier hole was -0.89 e. Å from O(2) -3 and was found to be about 0.58 Å.

[0188] Crystal data - Form 1 C 19 H 21 F2N3O3 (M = 377.39 g / mol): Orthorhombic space group P212121 (no. 19), a = 28.153(2) Å, b = 6.6890(3) Å, c = 9.1390(6) Å, V = 1721.04(19) Å 3 , Z = 4, T = 120(1) K, μ(CuKα) = 0.964 mm -1 , Dcalc = 1.456 g / cm 3 , 30202 reflection measurements (10.18° < 2θ < 153.36°), 3570 unique (R int = 0.1117, R sigma = 0.0636) (all of these were used for all calculations). The final R 1 was 0.1591 (>2Sigma(I)) and wR2 was 0.3889 (all data).

[0189] The X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA) data for Form 1 of the compounds of Examples 1-3 are shown in Figures 1A-1C, 2, and 3, respectively.

[0190] Biological Examples Compounds were profiled by evaluating their physicochemical properties, biochemical activity, intracellular activity, selectivity profile, pharmacokinetic (PK) profile, pharmacodynamic (PD) profile, and safety profile in various in vitro and in vivo assays, such as, but not limited to, myosin ATPase assays (with / without bovine cardiac myofibril system (bcMF) serum, rabbit skeletal myofibril system (rbskMF), cardiomyocyte contractility, and identification of reactive metabolites, etc.).

[0191] If the half-life is short, the time to reach the exposure steady state is shortened. Therefore, compounds with a short half-life were selected to enable more rapid dose adjustment. In addition, regarding the metabolic clearance of drug candidates, by eliminating or minimizing the dependence on polymorphic cytochrome P450 (CYP) enzymes such as CYP2C19, there is a possibility of reducing human PK variability that can occur between subjects with slow and fast drug metabolism. By eliminating or minimizing strong CYP enzyme induction properties regarding new drug candidates, there is an advantage that the possibility of drug-drug interactions can be avoided. Drug candidates with higher selectivity for cardiac myosin than skeletal myosin showed advantages for the intended human pharmacokinetics related to the drug distribution of myosin modulator candidate drugs. Myosin modulator candidate drugs with low efficacy against skeletal muscle myosin were predicted to have reduced distribution to skeletal muscle tissue due to decreased binding to skeletal muscle myosin, resulting in decreased distribution volume and decreased half-life in humans. In preclinical trials, pharmacokinetic / pharmacodynamic studies were conducted to optimally select compounds that can enable oral administration while reducing the risk of drug-induced hepatotoxicity. Lammert et al. (2008) Relationship Between Daily Dose of Oral Medications and idiosyncratic Drug-induced Liver injury; Search for Signals. Hepatology, 47: 2003-2009.

[0192] KS solubility assay Reserpine (solubility < 15 μM in PBS at 7.4 °C) was used as a negative control and verapamil (solubility > 200 μM in PBS at 7.4 °C) was used as a positive control to evaluate the solubility of small molecule drugs in PBS (pH 7.4) at room temperature. 2 μL of a 20 mM DMSO stock solution of the compound was added to each well of a 96-well plate, and then 198 μL of PBS was added at room temperature. After shaking for 1.5 hours at room temperature, the mixture was vacuum filtered through a 96-well filter plate and pre-washed with 100 μL of 70% ethanol per well. Then, 70 μL of the filtrate was added to a 96-well reading plate well that had been pre-filled with 70 μL of DMSO per well. The concentration of the sample in the well was determined based on LC integration by UV detection, compared to the standard curve of each compound established in DMSO.

[0193] Myosin inhibition assay (bcMF pCa6 IC 50 (μM)) The ability of small molecule drugs to inhibit the enzymatic activity of bovine cardiac myosin was evaluated using a biochemical assay in which the release of ADP (adenosine diphosphate) from cardiac myosin was coupled to an enzyme binding system consisting of pyruvate kinase and lactate dehydrogenase (PK / LDH), and the decrease in absorbance of NADH (340 nm) was monitored as a function of time. PK converts ADP to ATP by converting PEP (phosphoenolpyruvate) to pyruvate. Pyruvate is then converted to lactate by LDH converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide). Cardiac myosin is obtained from demembranated myofibrillar form of bovine heart. Prior to testing small molecule drugs, the calcium responsiveness of bovine myofibrils was evaluated and the calcium concentration achieving 50% activation of the myofibril line was selected as the final condition for evaluating the inhibitory activity of small molecule drugs. All enzymatic activities were measured in a buffer (PM12 buffer) at pH 6.8 containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)) and 2 mM magnesium chloride. The final assay conditions were 1 mg / mL bovine cardiac myofibrils, 0.4 mM PK / LDH, 50 μM ATP, 0.1 mg / mL BSA (bovine serum albumin), 10 ppm antifoaming agent, 2 mM BME, 0.5 mM NADH, and 1.5 mM PEP, the desired free calcium concentration required for 50% activation of myofibrils.

[0194] Under the condition of fixing the DMSO concentration at 3.3% (v / v), a dilution system of the compound in DMSO was prepared so that a compound with a predetermined concentration could finally be obtained in a volume of 30 μL. Usually, 1 μL of the dilution system was added to a 384-well plate to obtain a 10-point dose-response. After adding a solution (14 μL) containing bovine cardiac myofibrils, PK / LDH, and calcium solution (achieving 50% activation), a solution (15 μL) containing ATP, PEP, and NADH was added to initiate the enzyme reaction. The progress of the reaction was monitored at room temperature using a transparent-bottom plate with a PerkinElmer Envision plate reader. The plate reader was set to read the absorbance at 340 nm in the reaction rate mode for 15 minutes. The data was recorded as the slope of the absorbance reaction with respect to time. The slope of the absorbance response with respect to time was normalized by the slope of the plate containing DMSO. Next, this normalized rate was plotted as a function of the low molecular concentration, and the data was subjected to 4-parameter fitting using EXCEL XLfit. IC 50 is the concentration at which 50% of the total reaction is inhibited. Drugs that did not achieve 50% inhibition at the highest concentration tested were reported as having an IC 50 higher than the highest concentration tested (i.e., IC 50 > 50 μM).

[0195] Myosin inhibition assay (bcMF serum pCa 6 IC 50 (μM)) In the presence of 10% human serum, enzyme activity inhibition of bovine cardiac myosin related to ADP (adenosine diphosphate) release at the calcium concentration that achieves 50% activation of the bovine cardiac myofibril system was performed. This method is the same as the bovine cardiac myosin inhibition assay (bcMF pCa 6 IC 50 (μM)) except that 10% human serum was added.

[0196] Myosin inhibition assay (rbskMF pCa 6 IC 50 (μM)) Inhibited the enzymatic activity of rabbit skeletal myosin related to ADP (adenosine diphosphate) release at the calcium concentration that achieved 50% activation of the cardiomyofibrillar system of rabbit skeleton. The method was to replace bovine cardiomyofibrils with rabbit skeletal cardiomyofibrils and perform the same method as the bovine cardiac myosin inhibition assay (bcMF pCa 6 IC 50 (μM)).

[0197] Pharmacokinetic / pharmacodynamic (PK / PD) relationship The ability of small molecule compounds to dose-dependently regulate systolic cardiac function was non-invasively evaluated using echocardiography of isoflurane-anesthetized SD rats. First, cardiac function and heart rate were continuously measured before and during continuous intravenous administration at 2.0 mg / kg / hr for 30 - 60 minutes (~ every 3 minutes). Then, conscious rats were orally administered vehicle control (0 mg / kg PO, n = 3) or three dose levels of Compound 3: 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 / heart shape at two different time points / day under isoflurane anesthesia was recorded: once before administration (i.e., baseline, Day 2) and 2 hours after administration (Day 0), i.e., the time when it is known to approach a steady state due to exposure and the peak of the response is expected. In these experiments, left ventricular fractional shortening (FS), an index of contractility, and LV size / volume and heart rate were measured using a high-frequency transducer and parasternal long-axis transthoracic images (Vevo2100, Visual Sonic Inc.). FS was defined as the change in size / diameter within the left ventricle between end-systole (LVESd) and end-diastole (LVEDd) normalized to end-diastole (i.e., FS = 100x[LVEDd - LVESd] / LVEDd). The volume of the LV was calculated considering the Teichholz model (LVV = 7x[2.4 + LVid] -1 xLVid 3 ). In all cases, blood samples were collected (by tail vein microsampling) at each time point of echocardiography to establish the pharmacokinetic / pharmacodynamic (PK / PD) relationship.

[0198] Contractility assay of cardiomyocytes The contractility of adult rat ventricular cardiomyocytes was determined by edge detection using an IonOptix contractility system. An aliquot of cardiomyocytes in Tyrode buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl2, 1.5 mM CaCl2, 4 mM HEPES, 11 mM glucose) was placed in a perfusion chamber (Series 20 RC-27NE; Warner instruments), attached to a coverslip, and then perfused at 37 °C with Tyrode buffer. The cardiomyocytes were stimulated and recorded at 1 Hz and 10 V. Only cardiomyocytes with a cell length of 120 - 180 microns, a basal shortening rate corresponding to 3 - 8% of the cell length, and a clear striation in the resting state before pacing with a contraction velocity greater than 100 microns per second were used for the contraction experiment. To measure the response to the compound (0.3 μM concentration), first the cardiomyocytes were perfused with Tyrode buffer for 60 seconds, then the compound was administered for 5 minutes, and then washed with Tyrode buffer for 140 seconds. Data were continuously recorded using IonOptix software. Contractility data were analyzed using Ionwizard software (IonOptix). For each cell, 10 - 20 contractility transients were averaged to compare the baseline (without compound) and compound-treated conditions. The activity of the compound was measured by its effect on the fractional shortening (FS), where the fractional shortening is the ratio of the peak length of the cell during contraction divided by the reference cell length normalized to 100% for untreated cells. The inhibition rate was calculated by subtracting the FS value from 100%.

[0199] Identification of reactive metabolites The formation of low-molecular-weight reactive metabolites was determined in vitro by detecting glutathione adducts formed during incubation with human liver microsomes activated with NADPH and glutathione.

[0200] Method: The metabolism of small molecules (30 μM) for glutathione adduct formation was evaluated in potassium phosphate buffer (0.1 M, pH 7.4) at 37 °C for 1 hour using a 96-well plate (well volume 2 mL) in the absence of NADPH (used as a negative control) and in the presence of NADPH (1 mM) and glutathione (GSH, 10 mM) by incubation (200 μL volume, n = 3 incubations / treatment, 60-minute incubation time) with human-derived liver microsomes (1 mg / mL protein). Incubation with liver microsomes was carried out in a shaking water bath incubator shaken gently horizontally (30 rpm). A 3 mM substrate stock solution dissolved in DMSO was used to make the incubation concentration of the compound 30 μM. The final incubation mixture contained 148 μL of potassium phosphate buffer, 10 μL of liver microsome solution (20 mg protein / mL), 3 mM substrate solution (2 μL), and the incubation was started by adding 40 μL of NADPH solution (5 mM dissolved in potassium phosphate buffer). For incubations without NADPH, 40 μL of potassium phosphate buffer was added. After incubation, an equal volume of acetonitrile containing 20 nM carbamazepine internal standard and 3% formic acid was added to terminate the reaction. The reacted samples were centrifuged (4,600 rpm, 4 °C, 10 minutes), and the supernatant was transferred to a 96-well LC-MS sample analysis plate, diluted with 1 volume equivalent of HPLC-grade water, and then sealed with aluminum foil before analysis by liquid chromatography / mass spectrometry (LC-MS / MS).

[0201] Identification of Analytes: LC-MS / MS detection of test compounds and potential GSH-adducts (by in-line UV detection at 280 nm) was focused on extracting the ion chromatographic profiles using Xcalibur software (version 2.1.0, Thermo Fisher Scientific, Waltham, MA) with the m / z of the parent protonated molecular ion MH+ to four decimal places and the corresponding protonated molecular ion of the predicted GSH-adduct metabolite (m / z MH+parent + 305.0681 amu). The relative amount of GSH adducts in vitro in the liver microsome extract was evaluated using the ratio of the LC / UV absorbance at 280 nm obtained between the GSH adduct detected from the incubation extract supplemented with NADPH and GSH and the corresponding LC / UV peak area of the parent compound from the incubation extract containing -NADPH, using Xcalibur software (version 2.1.0). The degree of GSH adduct formation was determined by LC-MS / MS analysis using in-line LC-UV detection at 280 nm by dividing the LC / UV peak area of the glutathione adduct by the corresponding LC / UV peak area of the parent HCM-1NG analog determined from the analysis of the control (-NAPDH, -GSH) incubation extract.

[0202] Materials: Human liver microsomes (HLM, 50 donors) 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) were of chromatography grade.

[0203] LC-MS conditions: Extracts incubated with liver microsomes and hepatocytes were characterized by LC-MS and LC-MS / MS using a Thermo Electron LTQ Orbitrap XL mass spectrometer integrated with a Dionex UltiMate 3000 UHPLC containing an in-line diode array detector and an OAS-3300TXRS autosampler (40 μL injection volume). Electrospray ionization (ESI) was carried out in positive ion mode with the following settings: 5.01 kV, sheath liquid flow rate 35.02, aux flow rate 9.99, current 2.6 μA, capillary temperature 325 °C, and capillary voltage 15.99. Vacuum conditions were used, and the ion gauge pressure used was 2.33x10 -5 Torr, and the reflux gauge pressure was 0.90 Torr. LC-MS analysis in positive ion mode full scan (m / z 100 - m / z 1000) was carried out with a scan time of 0.73 seconds and a 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. All data were obtained using Xcalibur software (version 2.1.0, Thermo Fisher Scientific, Waltham, MA).

[0204]

Table 3

[0205] Data-dependent scans were utilized to collect MS / MS spectra of the maximum mass in the Orbitrap (15,000 resolution) full scan mass spectra.

[0206] HPLC Conditions: For chromatographic separation of the HCM-1NG compound and the corresponding glutathione adduct, the incubation extract was chromatographed on a Phenomenex Kinetex®, 2.6 μm, C18, 100 Å, 100 x 2.1 mm reverse-phase column at a column oven temperature of 30 °C. Chromatographic separation was performed with a reverse-phase gradient elution at a flow rate of 0.3 mL / min for 30 minutes using an ESI source. Solvent A of the gradient aqueous mobile phase was water (containing 0.1% formic acid (v / v)), and the organic mobile phase (solvent B) was composed of acetonitrile (containing 0.1% formic acid (v / v)). Elution was started with 95% of the initial aqueous solvent A mobile phase and linearly decreased to 50% of solvent A over 20 minutes, then linearly decreased to 0% of solvent A over 3.5 minutes, and held at 0% for 1 minute. Finally, the gradient was linearly increased to 95% solvent A over 0.5 minutes, and then equilibrated with 95% solvent A for 5 minutes before the next analysis. [Table 4]

[0207] Table of Biological Evaluation [Table 5] In the column of "Inhibition Rate of FS at 0.3 μM" in Table 1B, + represents inhibition of the left ventricular internal diameter shortening rate of less than 33%, ++ represents inhibition of the left ventricular internal diameter shortening rate from 33% to 66%, and +++ represents inhibition of the left ventricular internal diameter shortening rate of 66% or more (i.e., the maximum inhibition is represented by +++).

[0208] [Table 6] [Table 7]

[0209] As shown above, these compounds showed that the amount of reactive metabolites was minimal or no reactive metabolites were generated.

[0210] Powder X-ray diffraction (XRPD) XRPD analysis was performed by scanning the sample in the range of 3 - 35° 2θ using a PANalytical X'pert pro. The sample was lightly pulverized to remove aggregates, and the sample was supported with Kapton or Mylar polymer film and placed on a multi-well plate. Next, this multi-well plate was set on a diffractometer and analyzed using a Cuκ ray (α1λ = 1.54060 Å; α2 = 1.54443 Å; β = 1.39225 Å; α1:α2 ratio = 0.5) operating in transition mode (step size 0.0130° 2θ) with a generator setting of 40 kV / 40 mA.

[0211] Thermogravimetric analysis (TGA) Approximately 5 mg of the material was weighed into an open pan made of aluminum, placed in a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA), and held at room temperature. Then, the sample was heated from 20 °C to 400 °C at a rate of 10 °C / min, and the change in sample weight and differential thermal phenomenon (DTA) during that time were recorded. Nitrogen was used as the purge gas at a flow rate of 300 cm 3 / min.

[0212] Differential scanning calorimetry (DSC) Approximately 5 mg of the material was weighed into an aluminum DSC pan and hermetically sealed non-thermally with a perforated aluminum lid. Then, the sample pan was placed in a Seiko DSC6200 (equipped with a cooler) cooled to 20 °C and held. After a stable heat flow response was obtained, the sample and the reference were heated to a maximum of 330 °C at a scan rate of 10 °C / min, and the resulting heat flow response was monitored. Nitrogen was used as the purge gas at a flow rate of 50 cm 3 / min. Modulated DSC was performed at an amplitude = 0.32 °C and a frequency = 0.017 Hz.

[0213] This specification also includes the following items: Item 1. Formula:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0214] Item 25. A pharmaceutical composition comprising the compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable excipient. Item 26. The pharmaceutical composition according to Item 25, wherein the composition substantially does not contain another isomer at the carbon atom in the phenyl ring. Item 27. The pharmaceutical composition according to Item 25 or 26, wherein the composition substantially does not contain another isomer at the carbon atom adjacent to the fluorine in the phenyl ring. Item 28. A treatment method, characterized by administering an effective amount of the compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of Items 25 to 27, to a subject in need of treatment. Item 29. A treatment method for hypertrophic cardiomyopathy (HCM) or a heart disease (for example, a heart disease having the pathophysiological characteristics of HCM), characterized by administering an effective amount of the compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of Items 25 to 27, to a subject in need of treatment. Item 30. A treatment method for 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, characterized by administering an effective amount of the compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of Items 25 to 27, to a subject in need of treatment. Item 31. A method for treating a disease or disorder characterized by left ventricular hypertrophy (e.g., left ventricular hypertrophy due to volume or pressure overload), wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; in combination with a treatment method (e.g., valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main cause of volume or pressure overload, administering to a subject in need of treatment an effective amount of the compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of Items 25 to 27. A treatment method, characterized by this. Item 32. A method for treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological characteristics related to HCM), wherein an effective amount of the compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of Items 25 to 27 is administered to a subject in need of treatment to downregulate cardiac neurohormonal stimulation to slow the progression of heart failure and prevent cardiac remodeling. Therapeutic agents (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neprilysin inhibitors, etc.); therapeutic agents that improve cardiac function by stimulating myocardial contraction (e.g., positive inotropic agents such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor); and / or therapeutic agents that reduce the preload of the heart (e.g., diuretics such as furosemide) or therapeutic agents that reduce the afterload of the heart (including, but not limited to, vasodilators of all classifications, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). A treatment method, characterized by administering in combination. Item 33. The compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of Items 25 to 27, for use as a pharmaceutical. Item 34. The compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of Items 25 to 27, for use in the treatment of hypertrophic cardiomyopathy or heart disease (for example, heart disease having the pathophysiological characteristics of HCM). Item 35. The compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of Items 25 to 27, 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. Item 36. 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) in combination with a treatment method (for example, valve repair / replacement or effective antihypertensive therapy) aimed at modifying or alleviating the main causes of volume or pressure overload, wherein the disease or disorder is selected from the group consisting of chronic mitral valve regurgitation, chronic aortic valve stenosis, and chronic systemic hypertension. The compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of Items 25 to 27. Item 37. A compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of Items 25 to 27, for use in the treatment of hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological characteristics associated with HCM), wherein the compound is a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a β-blocker, an aldosterone receptor antagonist or a neprilysin inhibitor, etc.) that attempts to delay the progression of heart failure and prevent cardiac remodeling by down-regulating the neurohormonal stimulation of the heart; a therapeutic agent (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or a therapeutic agent (e.g., a diuretic such as furosemide) that reduces the preload of the heart or a therapeutic agent (including, but not limited to, vasodilators of any classification, e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators) that reduces the afterload of the heart, for use in combination therewith. Item 38. A compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of Items 25 to 27, for use in the manufacture of a pharmaceutical. Item 39. Use of a compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of Items 25 to 27, for the manufacture of a therapeutic pharmaceutical for hypertrophic cardiomyopathy or a heart disease (e.g., a heart disease having pathophysiological characteristics of HCM). Item 40. Use of a compound according to any one of Items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of Items 25 to 27, for the manufacture of a therapeutic pharmaceutical for a disease or disorder selected from the group consisting of diastolic heart failure (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris and restrictive cardiomyopathy. Use of a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 25 to 27, for the manufacture of a medicament for the treatment of a disease or disorder characterized by left ventricular hypertrophy (e.g., left ventricular hypertrophy due to volume or pressure overload), in combination with a treatment method (e.g., valve repair / replacement, effective antihypertensive therapy) aimed at correcting or alleviating the main cause of volume or pressure overload, wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension). Use of a compound according to any one of items 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of items 25 to 27, for the manufacture of a medicament for the treatment of hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological characteristics related to HCM), in combination with a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor antagonist (ARB), a β-blocker, an aldosterone receptor antagonist, or a neprilysin inhibitor, etc.) that attempts to delay the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation; a therapeutic agent (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload of the heart (including, but not limited to, vasodilators of all classifications, such as calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). Item 43. At least one of the following: a. A powder X-ray diffraction pattern represented by an angle 2θ ± 0.2° and having two or more peaks 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°; b. A DSC thermogram showing endotherms at about 226.05 °C, about 302.47 °C, and about 310.13 °C; or c. An X-ray crystal structure substantially the same as that of Figure 4, characterized by a polymorph of Form 1 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. Item 44. A polymorph according to Item 43, characterized by a powder X-ray diffraction pattern represented by an angle 2θ ± 0.2° and having three or more peaks 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°. Item 45. A polymorph according to Item 43, characterized by a powder X-ray diffraction pattern represented by an angle 2θ ± 0.2° and having four or more peaks 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°. Item 46. A polymorph according to Item 43, characterized by a powder X-ray diffraction pattern having peaks at 11.3, 12.4, and 13.3° represented by 2θ ± 0.2°. Item 47. A polymorph according to Item 43, characterized by a powder X-ray diffraction pattern having peaks at 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, and 29.5° represented by 2θ ± 0.2°. Item 48. A polymorph according to Item 43, characterized by onset of dissolution at about 221.51 °C, about 299.53 °C, and about 308.81 °C. Item 49. A polymorph according to Item 43, wherein the polymorph has a powder X-ray diffraction pattern substantially the same as that of Figure 1A. Item 50. The polymorph of Form 1 substantially does not contain another form 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 is the polymorph according to any one of Items 43 to 49. Item 51. A pharmaceutical composition comprising the polymorph according to any one of Items 43 to 50 and a pharmaceutically acceptable excipient. Item 52. The composition of Item 51, wherein the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or more than 80:20. Item 53. The composition of Item 51, wherein the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or more than 90:10. Item 54. The composition of Item 51, wherein the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or more than 95:5. Item 55. The composition of Item 51, wherein the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or more than 97:3. Item 56. The composition of Item 51, wherein the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or more than 98:2. Item 57. The composition of Item 51, wherein the ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or more than 99:1. Item 58. A method for treating hypertrophic cardiomyopathy (HCM) or a heart disease having pathophysiological characteristics of HCM, which comprises administering to a subject in need of treatment an effective amount of the polymorph according to any one of Items 43 to 50 or the pharmaceutical composition according to any one of Items 51 to 57. Item 59. A method for treating a disease or disorder characterized by left ventricular hypertrophy (e.g., left ventricular hypertrophy due to volume or pressure overload), which comprises administering an effective amount of a polymorph according to any one of Items 43 to 50 or a pharmaceutical composition according to any one of Items 51 to 57 in combination with a treatment method (e.g., valve repair / replacement, effective antihypertensive therapy) aimed at correcting or alleviating the main cause of volume or pressure overload to a subject in need of treatment, wherein the disease or disorder is selected from the group consisting of chronic mitral valve regurgitation, chronic aortic valve stenosis, and chronic systemic hypertension. Item 60. To a subject in need of treatment, an effective amount of a polymorph according to any one of Items 43 to 50 or a pharmaceutical composition according to any one of Items 51 to 57 is administered in combination with a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor antagonist (ARB), a β-blocker, an aldosterone receptor antagonist, or a neprilysin inhibitor, etc.) that attempts to delay the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation; a therapeutic agent (e.g., a positive inotropic agent such as dobutamine, a β-adrenergic agonist, or milrinone, a phosphodiesterase inhibitor) that improves cardiac function by stimulating myocardial contraction; and / or a therapeutic agent that reduces the preload of the heart (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces the afterload of the heart (including, but not limited to, vasodilators of any classification, e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). A method for treating hypertrophic cardiomyopathy (HCM) or a heart disease having pathophysiological characteristics associated with HCM.

[0215] In the definition of the variable groups herein, the listing of chemical groups includes the definitions of those variables as any single group or combination of the listed groups.

[0216] Although the above disclosure has been described in detail by way of explanation and examples for the purpose of clear understanding, it will be understood by those skilled in the art that some changes and modifications can be made within the scope of the appended claims. Further, each reference provided herein is incorporated by reference in its entirety as if each reference were individually incorporated by reference. In the event of any inconsistency between the present invention and the references provided herein, the content of the present invention shall prevail.

Claims

**Claim 1** A polymorph of form 1 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 a powder X-ray diffraction pattern represented by an angle 2θ ± 0.2° and having two or more peaks 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°. **Claim 2** The polymorph according to claim 1, characterized by a powder X-ray diffraction pattern represented by an angle 2θ ± 0.2° and having three or more peaks 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°. **Claim 3** The polymorph according to claim 1, characterized by a powder X-ray diffraction pattern represented by an angle 2θ ± 0.2° and having four or more peaks 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°. **Claim 4** The polymorph according to claim 1, characterized by a powder X-ray diffraction pattern having peaks at 11.3, 12.4, and 13.3° represented by an angle 2θ ± 0.2°. **Claim 5** The polymorph according to claim 4, characterized by a powder X-ray diffraction pattern having peaks at 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, and 29.5° represented by an angle 2θ ± 0.2°. **Claim 6** The polymorph according to any one of claims 1 to 5, characterized by a DSC thermogram showing endotherms at 226.05°C ± 2°C, 302.47°C ± 2°C, and 310.13°C ± 2°C. **Claim 7** Figure 4: The polymorph according to any one of claims 1 to 6, characterized by the X-ray crystal structure shown in **Claim 8** The polymorph according to any one of claims 1 to 7, characterized by the onset of dissolution at 299.53°C ± 2°C. **Claim 9** The polymorph according to any one of claims 1 to 8, wherein the polymorph has a powder X-ray diffraction pattern shown in Figure 1A: ​

10. The polymorph of Form 1 does not contain another form 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 the polymorph according to any one of Claims 1 to 9.

11. A pharmaceutical composition comprising the polymorph according to any one of Claims 1 to 10 and a pharmaceutically acceptable excipient.

12. The pharmaceutical composition according to Claim 11, wherein the weight ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 80:

20.

13. The pharmaceutical composition according to Claim 11, wherein the weight ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 90:

10.

14. The pharmaceutical composition according to Claim 11, wherein the weight ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 95:

5.

15. The pharmaceutical composition according to Claim 11, wherein the weight ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 97:

3.

16. The pharmaceutical composition according to Claim 11, wherein the weight ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 98:

2.

17. The pharmaceutical composition according to Claim 11, wherein the weight ratio of the amount of the polymorph of Form 1 to the total amount of other forms is equal to or greater than 99:

1.

18. The pharmaceutical composition according to any one of Claims 11 to 17 for treating hypertrophic cardiomyopathy (HCM).

19. The pharmaceutical composition according to Claim 18, wherein the HCM is obstructive HCM.

20. The pharmaceutical composition according to Claim 18, wherein the HCM is non-obstructive HCM.

21. The pharmaceutical composition according to any one of Claims 11 to 17 for treating heart failure with preserved ejection fraction.

22. The pharmaceutical composition according to any one of Claims 11 to 17 for treating left ventricular hypertrophy.

23. The polymorph according to any one of Claims 1 to 10 for treating hypertrophic cardiomyopathy (HCM).

24. The polymorph according to Claim 23, wherein the HCM is obstructive HCM.

25. The polymorph according to Claim 23, wherein the HCM is non-obstructive HCM.

26. The polymorph according to any one of Claims 1 to 10 for treating heart failure with preserved ejection fraction.

27. The polymorph according to any one of claims 1 to 10 for treating left ventricular hypertrophy.

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