Tetrahydropyran (THP)-substituted bicyclic-pyrimidinedione compounds

Abstract

To provide compounds useful for the treatment of hypertrophic cardiomyopathy (HCM), conditions associated with left ventricular hypertrophy, conditions associated with diastolic dysfunction, and / or symptoms associated therewith.SOLUTION: Tetrahydropyran (THP)-substituted bicyclic pyrimidinedione compounds, for example represented by the following formula, are provided. The synthesis and characterization of the compounds, as well as methods for treating HCM and other forms of heart disease, are also provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 752,278, filed October 29, 2018, entitled "Tetrahydropyran (THP)-Substituted Bicyclic-Pyrimidinedione Compounds," the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Genetic (hereditary) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, 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, the functional unit of cardiac muscle. Approximately 1 in 500 people in the general population present with left ventricular hypertrophy that cannot be explained by other known etiologies (e.g., hypertension or valvular disease), and many of these are shown to be HCM once other genetic causes (e.g., lysosomal storage diseases) and metabolic or infiltrative causes have been ruled out.

[0003] Mutations in sarcomere genes that cause HCM are highly penetrant, yet clinical severity and course vary widely. Some genotypes are associated with an increasingly aggressive course, but there is considerable variability between and even within families with the same mutation. Gender differences have also been noted, with male patients generally being more severely affected than female patients. While many patients with HCM have minimal or no symptoms over time, HCM is a progressive disease associated with significant cumulative suffering from the condition. Symptoms of exertion intolerance are predominant and may be exacerbated by exercise or other movements that increase heart rate and / or reduce preload. As with many other disorders, symptoms tend to worsen with age. For patients with HCM, the most common clinical burden is exertional dyspnea, which limits activities of daily living and can be debilitating.

[0004] Patients with HCM often present without confirmed hemodynamic abnormalities, such as left ventricular outflow tract obstruction (with or without mitral regurgitation). Their symptoms of exertional dyspnea can rapidly worsen with the emergence of atrial fibrillation, a common complication of HCM that can induce acute pulmonary edema, increasing the risk of systemic arterial thromboembolic disease, including stroke. Other adverse events associated with HCM include hypovolemia or hypervolemia intolerance and syncope. Concomitant coronary artery disease confers a higher risk of acute coronary syndromes than patients without HCM. Sudden cardiac death (SCD) in patients with HCM, although rare and difficult to predict, is a leading cause of non-traumatic death in young adults. For survivors of SCD, ICD replacement is standard practice, and risk profiling in other HCM patients is unclear, but it is used to identify those who should be considered for ICD replacement for primary prevention.

[0005] Medical therapies for HCM are limited to treating symptoms and do not address the underlying underlying cause of the disease—the disruption of normal sarcomere function. Currently available treatments vary in efficacy in alleviating symptoms and typically demonstrate diminishing effectiveness with increasing disease duration. Patients are therefore empirically managed with beta-blockers, non-dihydropyridine calcium channel blockers, and / or disopyramide. None of these medications have a labeled indication for treating HCM, and essentially no rigorous clinical trial evidence is available to support their use. This unfortunate situation is compounded by the fact that no new medical therapies for HCM have been identified for many years. For patients with hemodynamically significant outflow tract obstruction (resting gradient >30 mmHg), surgical myectomy or alcohol septal ablation is usually required in appropriately selected patients to relieve the hemodynamic obstruction. Provided herein are novel therapeutic agents and methods that alleviate the long-felt need for improved treatments for HCM and related cardiac disorders. DETAILED DESCRIPTION OF THE INVENTION

[0006] (Summary of the Invention) In one embodiment, a compound of formula (I): [ka] [In the formula, The subscript n is 1 or 2; Each R 1 is a member selected from the group consisting of fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl; wherein at least one R 1 is fluoro; and R 2a and R 2b One of the is fluoro and R 2a and R 2b The other is H] or a pharmaceutically acceptable salt thereof.

[0007] In one embodiment, a compound of formula (I): [ka] [In the formula, The subscript n is 1 or 2; Each R 1 is a member selected from the group consisting of fluoro, chloro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 haloalkoxy, optionally substituted C2-C4 alkynyl; wherein at least one R 1 is fluoro; and R 2a and R 2b One of the is fluoro and R 2a and R 2b The other is H] or a pharmaceutically acceptable salt thereof.

[0008] In another embodiment, a polymorphic 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 ("polymorphic Form 1"). In another embodiment, polymorphic Form 1 is characterized by at least one of the following: a. A powder X-ray diffraction pattern expressed in terms of angles 2θ±0.2° and having two or more peaks selected from the following: 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. X-ray crystal structure essentially the same as in Figure 4.

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

[0010] In some embodiments, the present disclosure provides a method for treating cardiac disease or disorder in a subject in need of treatment, comprising administering to the subject an effective amount of a compound described herein.In certain embodiments, diastolic dysfunction is a characteristic of, and / or associated with, cardiac disease or disorder.For example, cardiac disease or disorder can be cardiomyopathy (e.g., hypertrophic cardiomyopathy), heart failure (e.g., heart failure with preserved ejection fraction, heart failure with intermediate ejection fraction), valvular disease (e.g., valvular aortic stenosis), congenital heart disease (e.g., tetralogy of Fallot), left ventricular hypertrophy, angina pectoris (e.g., refractory angina pectoris) or Chagas disease.

[0011] In certain aspects, provided herein are methods of treating a cardiac disease or disorder, comprising administering to a subject in need thereof 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 cardiac disease or disorder is selected from the group consisting of diastolic dysfunction, hypertrophic cardiomyopathy, nHCM, oHCM, heart failure, HFpEF, HFmREF, valvular disease, aortic stenosis, left ventricular hypertrophy, restrictive cardiomyopathy, inflammatory cardiomyopathy, Loeffler endocarditis, 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 embodiments, the cardiac disease or disorder is selected from the group consisting of nHCM, oHCM, HFpEF, HFmREF, aortic stenosis, Loeffler's endocarditis, endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, tetralogy of Fallot, angina pectoris, refractory angina pectoris, and Chagas' disease.

[0012] In certain aspects, the present specification provides a method of treating a cardiac disease or disorder, comprising administering to a subject in need thereof 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 thereof, or pharmaceutical composition thereof is administered as monotherapy.

[0013] In certain aspects, the present specification provides a method of treating a cardiac disease or disorder, comprising administering to a subject in need thereof 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 thereof, or pharmaceutical composition thereof is administered as a combination therapy, wherein an additional therapeutic agent is administered in the combination therapy. In certain embodiments, the additional therapeutic agent is a beta-adrenergic blocker (beta-blocker), a renin-angiotensin-aldosterone system (RAAS) inhibitor (e.g., angiotensin receptor blockers such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers), angiotensin receptor neprilysin inhibitors (ARNIs) (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), an orthotropic inotropic agent (e.g., digoxin, pimobendan, beta-adrenergic receptor antagonists, agonists; for example, dobutamine, phosphodiesterase (PDE)-3 inhibitors such as milrinone, or calcium sensitizers such as levosimendan), potassium, magnesium, proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitors, vasodilators (for example, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators), diuretics (for example, furosemide), antiarrhythmic drugs, anticoagulants (for example, warfarin), antithrombotic agents, antiplatelet agents, sodium-glucose cotransporter 2 inhibitors (SGLT2) (for example, empagliflozin, dapagliflozin, sotagliflozin), or combinations thereof.In some embodiments, the additional therapeutic agent is an angiotensin II receptor blocker (ARB), including A-81988, A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, candesartan, candesartan cilexetil, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, E-4177, elisartan EMD-66397, EMD-73495, eprosartan, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan , Isoteorin, KRI-1177, KT3-671, KW-3433, Losartan, LR-B / 057, L-158809, L-158978, L-159282, L-159874, L-161177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LR B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin acetate, S-8307, S-8308, SC-52458, saprisartan, saralasin, 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 subject's cardiovascular condition. In certain embodiments, the additional therapeutic agent is selected from the group consisting of a beta-blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor antagonist, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, an antiarrhythmic agent, and an SGLT2 inhibitor.

[0014] In another aspect, the present disclosure provides a method for preventing or treating a disease or disorder in which diastolic dysfunction is present or a key feature (e.g., but not limited to, hypertrophic cardiomyopathy (HCM) or a cardiac disease having pathophysiological features of or symptoms of HCM). The method comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In yet another aspect, the disease is selected from the group consisting of obstructive HCM, non-obstructive HCM, heart failure with preserved ejection fraction (HFpEF) (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 IHCM, class IInHCM, class IIInHCM, class IIoHCM, and class IIIoHCM.

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

[0016] In another aspect, the description provides a method for preventing or treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload, characterized by 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 aimed at correcting or alleviating the primary cause of volume or pressure overload, e.g., valve repair / replacement or effective antihypertensive therapy, wherein said disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension.

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

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

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

[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 said disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension, comprising administering to a subject in need thereof an effective amount of the Form 1 polymorph or a pharmaceutical composition comprising the Form 1 polymorph in combination with a treatment aimed at correcting or alleviating the primary cause of the volume or pressure overload, e.g., valve repair / replacement or effective antihypertensive therapy.

[0021] In another aspect, there is provided a method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disease having pathophysiological features associated with HCM, comprising administering to a subject in need thereof an effective amount of the polymorph of Form 1, or a pharmaceutical composition comprising the polymorph of Form 1, in combination with a therapeutic agent that seeks 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 beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., an orthotropic inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (e.g., a vasodilator of any class, such as a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator). The present invention is intended to include all isotopically labeled analogs of the compounds 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) and carbon isotopes include 13 C and 14 C. Isotopically labeled compounds of formula (I) can be prepared according to methods generally known in the art. Such compounds have a variety of uses, including but not limited to, as standards or reagents in determining biological / pharmacological activity. Stable isotope-labeled compounds of formula (I) can also be used to favorably adjust biological, pharmacological, or pharmacokinetic properties. [Brief explanation of the drawings]

[0022] [Figure 1] 1A-1C show X-ray powder diffraction (XRPD) data for the Form 1 polymorph of the compounds of Examples 1-3 (also designated Compound 3). [Figure 2] FIG. 2 shows a differential scanning calorimetry (DSC) plot for the Form 1 polymorph of the compound of Examples 1-3 (also designated as Compound 3). [Figure 3] FIG. 3 shows the thermogravimetric analysis (TGA) for the Form 1 polymorph of the compound of Examples 1-3 (also designated Compound 3). [Figure 4] FIG. 4 shows the crystal structure of the Form 1 polymorph of the compounds of Examples 1-3 (also designated Compound 3) obtained by single crystal X-ray diffraction. Detailed Description of the Invention

[0023] A series of tetrahydropyran (THP)-substituted bicyclic pyrimidinedione compounds have been shown to suppress excessive contractile force during hypercontraction and / or promote cardiac relaxation in hearts with diastolic dysfunction. Without being bound by theory, these compounds are believed to stabilize the conformation of beta cardiac myosin after ATP hydrolysis before it tightly binds to actin filaments and releases phosphate, thereby reducing the proportion of myosin molecules available for the "power stroke" portion of the muscle contraction cycle. Thus, these 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 patients with HCM, helping to eliminate the debilitating exertional dyspnea and / or symptoms associated with left ventricular outflow obstruction (presyncope, dizziness, or syncope) that often accompany these diseases. Preferred compounds of the present invention are optimally designed to have a relatively short half-life in humans. For example, certain compounds of the present invention are projected to have a half-life of less than 7 days (e.g., less than 5 days, less than 4 days) in humans. The compounds described herein are designed to produce fewer reactive metabolites during testing, to be less dependent on polymorphic CYP enzymes (e.g., CYP 2C19), and / or to have no or reduced risk of CYP induction (e.g., CYP3A4 induction). Other advantages of the present compounds include selectivity for inhibiting cardiac myosin over skeletal myosin and / or a desirable time course of efficacy in response to a given drug dose. Additionally, the present compounds have beneficial solubility, e.g., a micromolar solubility of 50 or more, e.g., 70 or more, at pH 7.4. In some cases, the present compounds have a micromolar solubility of 80 or more, e.g., 90 or more. The present compounds can also be used to treat other cardiac diseases.

[0024] As used herein, the term "about" is used to describe a range (e.g., temperature, mass, weight) and refers to the ordinary meaning in the art, typically referring to the error associated with the instrument used to collect the measurement or reading. Generally, the term "about" when referring to temperature 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. 1-2 , C 1-3 , C 1-4 , C 2-3 , C 2-4 and C 3-4 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, alkyl groups can be optionally substituted. In some embodiments, alkyl groups are unsubstituted. In some embodiments, alkyl groups are substituted. Substituents for alkyl groups include, but are not limited to, any of the substituents described herein that result in the formation of a stable group. In certain embodiments, the substituents can 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 set forth above, in which at least one hydrogen atom of the hydrocarbon portion has been replaced 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. The 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" refers to a saturated or partially unsaturated monocyclic ring containing 3 to 4 ring atoms or a specified number of atoms. Examples of saturated monocyclic cycloalkyl rings include cyclopropyl or cyclobutyl. Cycloalkyl groups may be partially unsaturated, having one or more double bonds within the ring. Representative partially unsaturated cycloalkyl groups include cyclobutene. Unless otherwise specified, cycloalkyl groups are unsubstituted.

[0028] As used herein, the term "alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: i.e., alkyl-O-. For alkyl moieties, alkoxy groups include C 1-2 or C 1-4 Alkoxy groups can have any suitable number of carbon atoms, such as , ...

[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 defined above, in which at least one hydrogen atom of the hydrocarbon moiety is replaced with a halogen atom. Additionally, the terms can 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 range of numerical values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C 1-6 "Alkyl" refers to 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 is intended to be included.

[0032] It will be understood that the groups and / or compounds described herein may be optionally substituted with any number of substituents or functional groups. That is, any of the above groups may be optionally 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 permissible substituents of organic compounds, with "permissible" meaning within the chemical rules of valency known to those of ordinary skill in the art. In general, the term "substituted," whether preceded by the term "optionally" or not, and included in formulas herein, refers to the replacement of hydrogen radicals in a given structure with the specified substituent group. When one or more positions of any given structure are optionally substituted with one or more substituents selected from a specified group, the substituents may be the same or different at all positions. "Substituted" is also understood to include those substitutions that result in stable compounds, e.g., compounds that do not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. In some cases, "substituted" generally refers to the replacement of hydrogen with a substituent described herein. However, as used herein, "substituted" does not encompass the substitution and / or modification of functional groups that are significant to the identity of the molecule, such that the "substituted" functional group becomes a different functional group upon substitution. For example, a "substituted phenyl group" must still consist of a phenyl moiety; this definition does not allow for the substitution to result in, for example, a pyridine ring. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Examples of substituents include, for example, those described herein. Permissible substituents can be one or more and can be the same or different for appropriate organic compounds.For purposes of this specification, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatom. Furthermore, this specification is not intended to be limited in any manner by the permissible substituents of organic compounds. As used herein, the term "stable" preferably refers to a compound that is stable enough to permit its manufacture and maintains its integrity for a period of time sufficient to be detected, preferably for a period of time 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, amido, 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, Examples of such alkyl groups include azide, amino, halide, alkylthio, nitride, acylalkyl, carboxyester, -carboxamido, acyloxy, aminoalkyl, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkoxyaryl, arylamino, aralkylamino, alkylsulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl, and arylalkyloxyalkyl.

[0034] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable substances will be compatible not only with the compound of Formula (I), but also with other ingredients with which the compound is formulated.

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

[0036] Certain embodiments of the compounds of the present invention may contain one or more basic functional groups and therefore may 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. These salts can be prepared in situ in the administration vehicle or formulation process, or by separately reacting a purified compound of the present invention in its free base form with a suitable organic or inorganic acid and then isolating the salt 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 lauryl sulfonate (see, e.g., 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 the 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 salts obtained from 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, isothioic acid, etc.

[0038] In some cases, the compounds of the present application may contain one or more acidic functional groups and therefore 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 prepared in situ in the administration vehicle or formulation process, or can be prepared by separately reacting the purified compound in free acid form with a suitable base (e.g., 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, sodium, potassium, calcium, magnesium, and aluminum salts. Non-limiting examples of organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.

[0039] Additional information regarding suitable pharmaceutically acceptable salts is 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 forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent compound forms may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

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

[0042] As used herein, the term "pharmaceutical composition" refers to a product comprising a mixture of a compound of formula (I) and one or more other chemical components. A pharmaceutical composition may include any product that results directly or indirectly from combining the specified amounts of the excipients and / or other optional ingredients as defined herein, as well as the specified amounts of the specified ingredients.

[0043] As used herein, the term "excipient" refers to a substance that assists in the effective administration of a drug to a subject. Pharmaceutical excipients useful herein include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, and coloring agents. 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 of success in treating or mitigating pathology, damage, symptoms, or signs associated with a disease or disorder (e.g., a cardiac disease having the pathophysiological characteristics of HCM), including any objective or subjective parameter, such as, for example, relief, remission, or reduction of symptoms; making the pathology, damage, symptom, or sign more tolerable to the patient; or reducing the frequency or duration of the pathology, damage, symptom, or sign. Treatment or mitigation 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 the prophylactic treatment of a subject who does not have or has not 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 the pathology, injury, symptom, or sign, or who has exhibited a pathology, injury, symptom, or sign, or who does not exhibit a pathology, injury, symptom, or sign but is at risk of recurrence of the pathology, injury, symptom, or sign. In some embodiments, the subject has an increased risk of developing a pathology, injury, symptom, or sign, or an increased risk of recurrence of a pathology, injury, symptom, or sign, compared to the average healthy member of the population. In some embodiments, prevention refers to preventing the onset of a pathology, injury, symptom, or sign.

[0046] An "effective amount" or "pharmaceutically effective amount" is an amount sufficient to achieve a stated purpose (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, reduce one or more symptoms of a disease or condition, reduce intracellular viral replication, etc.). An example of an "effective amount" is an amount sufficient to contribute to the treatment of a disease or the alleviation of symptoms, also referred to as a "therapeutically effective amount." "Alleviation" of symptoms means a reduction in the severity or frequency of symptoms or the elimination of symptoms.

[0047] A "subject" to which administration is intended refers to a human (i.e., male or female of any age, e.g., a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged adult, or elderly adult) or a non-human animal. A "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 etiology in the absence of known causes such as pressure overload, systemic disease, or infiltrative processes. One phenotype of HCM is myocardial hypercontractility accompanied by decreased LV compliance, which manifests clinically as reduced ventricular volumes, frequent excess ejection fraction, increased wall thickening, and diastolic dysfunction. Symptoms or signs of HCM 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 heart rate, a flutter or pounding sensation, and heart murmurs.

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

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

[0051] Heart failure is a clinical syndrome in which a patient's heart is unable to supply enough blood to the body. In some people with heart failure, the heart has difficulty pumping enough blood to support other organs in the body. In other people, the heart muscle itself stiffens and hardens, blocking or reducing blood flow to the heart. Heart failure can affect the right or left side of the heart, or both at the same time. Heart failure can be either acute (short-term) or chronic (ongoing). Symptoms of heart failure include, but are not limited to, excessive fatigue, rapid weight gain, loss of appetite, persistent cough, irregular heartbeat, palpitations, abdominal swelling, shortness of breath, swelling of the legs and ankles, prominent neck veins, and edema.

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

[0053] Stable diastolic heart failure refers to patients with diastolic heart failure without acute symptomatic deterioration. These patients have reduced diastolic function and can have their symptoms controlled or stabilized with available treatments.

[0054] Diastolic dysfunction refers to abnormalities in diastolic function. Abnormalities in diastolic function include impaired left ventricular relaxation, filling, diastolic distensibility, or stiffness. These characteristics can be measured using echocardiography. Additional determinants for diagnosing diastolic dysfunction using echocardiography are described in J Am Soc EchocardIogr. 29(4):277-314 (2016), the contents of which are incorporated by reference. Left ventricular stiffness can be measured using cardiac magnetic resonance imaging. Cardiac magnetic resonance imaging is used to measure peak filling velocity, time to peak filling, and peak diastolic strain rate. Subjects with diastolic dysfunction may also have elevated levels of biomarkers in their blood. For example, brain natriuretic peptide (BNP) or N-terminal fragment of brain natriuretic peptide precursor (NT-pro BNP) are present at elevated levels in the blood of individuals with diastolic dysfunction.

[0055] Diastolic dysfunction is a spectrum of diseases, including, but not limited to, hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF) - including both disorders related to active relaxation and disorders related to ventricular stiffening (e.g., diabetic HFpEF); ischemic cardiomyopathy, cardiac transplant allograft vasculopathy, restrictive cardiomyopathy (e.g., genetic mutations in one or more sarcomeric proteins), inflammatory cardiomyopathy (e.g., Löffler's syndrome and EMF), infiltrative cardiomyopathies (e.g., amyloid, sarcoid, and XRT), storage diseases (e.g., hemochromatosis, Fabry and glycogen storage diseases, etc.), congenital heart disease (e.g., pressure-overloaded RV, tetralogy of Fallot (e.g., pre- and early post-operative diastolic dysfunction), valvular heart disease (e.g., aortic stenosis), etc.

[0056] Class I HCM 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 the NYHA.

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

[0059] NYHA Class I refers to a classification in which the patient or subject has no limitations on physical activity and does not experience excessive fatigue, palpitations, or dyspnea (shortness of breath) with everyday physical activity.

[0060] NYHA class II refers to a classification in which the patient or subject has slight limitations in physical activity, is not in pain at rest, and experiences fatigue, palpitations, and dyspnea (shortness of breath) during everyday physical activity.

[0061] NYHA class III refers to a classification in which a patient or subject has significant limitations in physical activity, but is not in pain at rest, and experiences fatigue, palpitations, or dyspnea with less than normal physical activity.

[0062] NYHA class IV refers to a classification in which a patient or subject is unable to perform any physical activity at rest without suffering from pain accompanied by symptoms of heart failure, and any physical activity results in increased pain.

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

[0064] III.Compound In one aspect, provided herein is a compound of formula (I): [ka] [In the formula, The subscript n is 1 or 2; Each R1 is a member independently selected from the group consisting of fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl; wherein at least one R 1 is fluoro; and R 2a and R 2b One of the is fluoro and R 2a and R 2b The other is H] or a pharmaceutically acceptable salt thereof. R 2a R may be fluoro. 2b R may be fluoro. 2a When n is 1, R may be fluoro. 2a When n is 2, R may be fluoro. 2b When n is 1, R may be fluoro. 2b When n is 2, it may be fluoro.

[0065] In one aspect, provided herein is a compound of formula (I): [ka] [In the formula, The subscript n is 1 or 2; Each R 1 is a member independently selected from the group consisting of fluoro, chloro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 haloalkoxy, optionally substituted C2-C4 alkynyl; wherein at least one R 1 is fluoro; and R 2a and R 2b One of the is fluoro and R 2a and R 2b The other one is H] or a pharmaceutically acceptable salt thereof. R 2a R may be fluoro. 2b R may be fluoro. 2a When n is 1, R may be fluoro. 2a When n is 2, R may be fluoro. 2b When n is 1, R may be fluoro. 2b When n is 2, it may be fluoro.

[0066] Pharmaceutically acceptable salts of the compounds of formula (I) are also provided.

[0067] In some embodiments, the compound of formula (I) has the formula: [ka] wherein the subscript n is 1; and R 1 is a member independently selected from the group consisting of fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C2-C4 alkynyl; and R 2a and R 2b One of the is fluoro and R 2a and R 2b The other is H] or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the compound of formula (I) has the formula: [ka] wherein the subscript n is 1; and R 1is a member independently selected from the group consisting of fluoro, chloro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 haloalkoxy, and optionally substituted C2-C4 alkynyl; and R 2a and R 2b One of the is fluoro and R 2a and R 2b The other is H] or a pharmaceutically acceptable salt thereof.

[0069] In some examples, n in the compound of formula (I) is 1. The compound of formula (I) has the formula: [ka] (In the formula, R 2a and R 2b One of the is fluoro and R 2a and R 2b and the other is H).

[0070] Pharmaceutically acceptable salts of the compounds of formula (Ib) are also provided.

[0071] In some examples, n in the compound of Formula (I) is 2. In some examples, n is 2 and 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, n is 2 and one R 1is fluoro and the other may be selected from the group consisting of 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).

[0073] The compounds of formula (I) have the formula: [ka] (In the formula, R 2a and R 2b One of the is fluoro and R 2a and R 2b the other is H; and Each R 1 are members independently selected from the group consisting of fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl. may have:

[0074] The compounds of formula (I) have the formula: [ka] [In the formula, R a and R 2b One of the is fluoro and R 2a and R 2b the other is H; and Each R 1 are members independently selected from the group consisting of fluoro, chloro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 haloalkoxy, and optionally substituted C2-C4 alkynyl. may have:

[0075] In some examples, for formula (I), one R 1is 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).

[0076] In some examples, for formula (I), one R 1 is fluoro and the other may be 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) have the formula: [ka] [In the formula, R 1 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); and R 2a and R 2b One of the is fluoro and R 2a and R 2b The other is H] may have:

[0079] The compounds of formula (I) have the formula: [ka] [In the formula, R 1 may be selected from the group consisting of fluoro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkynyl; optionally fluoro, methyl, methoxy and ethynyl (-C≡CH), optionally methyl, methoxy and ethynyl (-C≡CH); and R 2a and R 2b One of the is fluoro and R 2a and R 2b The other is H] In some embodiments, R 1 is hydroxymethyl.

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

[0081] The compounds of formula (I) have the formula: [ka] In some embodiments, R 2a and R 2b One of the is fluoro and R 2a and R 2b The other is H.

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

[0083] The compounds of formula (I) have the formula: [ka] In some embodiments, R 2a and R 2b One of the is fluoro and R2a and R 2b The other is H. Pharmaceutically acceptable salts of the compounds are also provided.

[0084] The compounds of formula (I) have the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0085] The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0086] The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0087] The compound or a pharmaceutically acceptable salt thereof may be provided (e.g., in a pharmaceutical composition) substantially free of other isomers at the carbon atom bearing the phenyl ring (i.e., having an absolute configuration different from that disclosed and depicted herein). Alternatively, or additionally, the compound or a pharmaceutically acceptable salt thereof may be provided substantially free of other isomers at the carbon atom bearing the fluorine adjacent to the carbon atom bearing the phenyl ring. For example, when provided as a pharmaceutical composition, the composition may be substantially free of other isomers at the carbon atom bearing the phenyl ring. Similarly, the composition may alternatively or additionally be substantially free of other isomers at the carbon atom bearing the fluoro atom adjacent to the carbon atom bearing the phenyl ring. In some embodiments, substantially free refers to an enantiomeric excess (ee) at the carbon atom bearing the phenyl ring of 95% or greater, 98% or greater, 99% or greater, or 100%. In some embodiments, substantially free refers to an ee at the carbon atom bearing the fluoro atom adjacent to the carbon atom bearing the phenyl ring of 95% or greater, 98% or greater, 99% or greater, or 100%. In some embodiments, substantially free refers to a diastereomeric excess (de) of 95% or greater, 98% or greater, 99% or greater, 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. Form 1 polymorph has at least one of: a. A powder X-ray diffraction pattern expressed in terms of angles 2θ±0.2° and having two or more peaks selected from the following: 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. X-ray crystal structure essentially the same as Figure 4 In another embodiment, the Form 1 polymorph is characterized by a powder X-ray diffraction pattern, expressed in degrees 2θ ± 0.2 degrees, 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 degrees. In certain embodiments, the Form 1 polymorph is characterized by an X-ray powder diffraction pattern expressed in degrees 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 degrees. In certain embodiments, the Form 1 polymorph is characterized by an X-ray powder diffraction pattern expressed in degrees 2θ±0.2° and having four or more peaks selected from 11.3, 12.4, and 13.3 degrees, respectively. In another embodiment, the Form 1 polymorph is characterized by an X-ray powder diffraction pattern having peaks expressed in degrees 2θ±0.2° at 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, and 29.5°, respectively. In another embodiment, the Form 1 polymorph is characterized by onset melting temperatures at about 221.51°C, about 299.53°C, and about 308.81°C. In some embodiments, the Form 1 polymorph has an X-ray powder diffraction pattern substantially the same as Figure 1A. In some embodiments, the Form 1 polymorph is substantially free of other forms of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

[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. Those skilled in the art will understand that the compound of formula (I) can be prepared using other synthetic methods, including, for example, transformations such as those described in Larock, Comprehensive Organic Transformations, A Guide to Functional Group Preparations, Wiley, 1999.

[0090] In another embodiment, provided herein is a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may comprise a pharmaceutically acceptable excipient. The composition is useful for treating conditions such as hypertrophic cardiomyopathy in humans and other subjects. In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. Non-limiting examples of additional therapeutic agents include 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), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); agents that improve cardiac function by stimulating cardiac contractility (e.g., orthotropic inotropes such as the beta-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, e.g., 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 further embodiments, exemplary additional therapeutic agents include beta-adrenergic blockers (beta-blockers), renin-angiotensin-aldosterone system (RAAS) inhibitors (e.g., angiotensin receptor blockers such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers), angiotensin receptor neprilysin inhibitors (ARNIs) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (MRAs) [e.g., aldosterone inhibitors such as potassium-sparing diuretics (e.g., eplerenone, spironolactone, or canrenone)], cholesterol-lowering drugs (e.g., statins), and neutral endopeptidase inhibitors (NEPi). , orthotropic inotropic agents [e.g., digoxin, pimobenzene, 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 drugs, anticoagulants (e.g., warfarin), antithrombotic drugs, antiplatelet drugs 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, elisartan, EMD-66397, EMD-73495, eprosartan, EXP-063, EXP-929, EXP- 3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, Irbesartan, Isoteorin, KRI-1177, KT3-671 , KW-3433, losartan, LR-B / 057, L-158809, L-158978, L-159282, L-159874, L-16117 7, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LR B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin acetate, S-8307, S-8308, SC-52458, saprisartan, saralasin, saprisartan These include Lumesin, 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 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®, etc.), dapagliflozin (Farxiga®, etc.), 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.

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

[0092] In some embodiments, the pharmaceutical composition comprising the Form 1 polymorph further comprises an additional therapeutic agent. Non-limiting examples of additional therapeutic agents include drugs that slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); drugs that improve cardiac function by stimulating cardiac contractility (e.g., orthotropic inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or drugs that reduce cardiac preload (diuretics 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 modulators). In some embodiments, the additional therapeutic agent in the pharmaceutical composition is a cardiovascular therapeutic agent.In further embodiments, examples of additional therapeutic agents include beta-adrenergic blockers (beta-blockers), renin-angiotensin-aldosterone system (RAAS) inhibitors (e.g., angiotensin receptor blockers such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers), angiotensin receptor neprilysin inhibitors (ARNIs) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (MRAs) (e.g., aldosterone inhibitors such as potassium-sparing diuretics such as eplerenone, spironolactone, or canrenone), cholesterol-lowering drugs (e.g., statins), neutral endopeptidase inhibitors (NEPi), orthotropic Examples of the therapeutic agent include a cardiac inotropic agent (e.g., digoxin, pimobendan, a beta-adrenergic receptor agonist (e.g., dobutamine), a phosphodiesterase (PDE)-3 inhibitor (e.g., milrinone), or a calcium sensitizer (e.g., 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 modulator), a diuretic (e.g., furosemide), an antiarrhythmic agent, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent, or a combination thereof.Suitable angiotensin II receptor blockers (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, DuP-532, E-4177, elisartan, EMD-66397, EMD-73495, eprosartan, EXP-063, and EXP-9. 29, 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, Isoteorin, KRI-1177, KT3- 671, KW-3433, Losartan, LR-B / 057, L-158809, L-158978, L-159282, L-159874, L-161 177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LR B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin acetate, S-8307, S-8308, SC-52458, saprisartan, saralasin, saprisartan These may include Lumesin, 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 certain embodiments, the additional therapeutic agent may be an ARNI, e.g., sacubitril / valsartan (Entresto®), or a sodium-glucose cotransporter 2 inhibitor (SGLT2), e.g., 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.

[0093] Pharmaceutical compositions for administering the compound of Formula (I) or a pharmaceutically acceptable salt or polymorph thereof provided herein are preferably in unit dosage form and can be prepared by any of the methods known in the art of pharmacy and drug delivery. All methods include combining the compound of Formula (I) or a pharmaceutically acceptable salt thereof with a carrier containing one or more additional ingredients. Generally, pharmaceutical compositions are prepared by uniformly and intimately admixing the compound of Formula (I) or a pharmaceutically acceptable salt thereof with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the mixture into the desired formulation. In the pharmaceutical compositions of the present invention, the 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., reducing supranormal contractility often seen in HCM) and / or improve left ventricular relaxation during diastole. Such improved relaxation can alleviate symptoms in hypertrophic cardiomyopathy and / or other etiologies of diastolic dysfunction. Alternatively or additionally, the pharmaceutical compositions of the present invention may alleviate the effects of diastolic dysfunction, which causes impaired coronary artery blood flow, thereby improving the latter as an adjunct to angina pectoris and / or ischemic heart disease.Alternatively or additionally, the pharmaceutical compositions of the present invention may provide benefits in beneficial left ventricular remodeling in HCM and / or other etiologies of left ventricular hypertrophy resulting from chronic volume or pressure overload, for example, due to valvular heart disease and / or systemic hypertension.

[0094] Pharmaceutical compositions containing a compound of Formula (I) or a pharmaceutically acceptable salt or polymorph thereof may be in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gum, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide a pharmaceutically elegant and palatable formulation. Tablets contain a compound of Formula (I) or a pharmaceutically acceptable salt thereof in admixture with non-toxic pharmaceutically acceptable excipients 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, etc.; granulating and disintegrating agents such as corn starch and alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, and talc. Tablets may be uncoated, or may be enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, sustained-release materials such as glyceryl monostearate or glyceryl distearate may be used. Osmotically treated tablets may also be coated to control release.

[0095] Oral pharmaceutical compositions can also be provided as hard gelatin capsules in which the 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, or as soft gelatin capsules in which the compound of formula (I) or a pharmaceutically acceptable salt thereof is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil. Additionally, emulsions can be prepared using water-immiscible ingredients such as oils and stabilized with surfactants such as monodiglycerides, PEG esters, and the like.

[0096] Aqueous suspensions contain the compound of formula (I) or its pharmaceutically acceptable salt or polymorph thereof in admixture with excipients suitable for the manufacture of aqueous suspensions.Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and acacia gum; dispersing or wetting agents are natural phosphates (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), partial esters obtained from ethylene oxide with fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, for example, ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0097] Oily suspensions can be prepared by suspending the compound of formula (I) or its pharmaceutically acceptable salt or polymorph in vegetable oil, such as peanut oil, olive oil, sesame oil, coconut oil, or mineral oil, such as liquid paraffin.Oily suspensions can contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol.Sweeteners and flavorings, such as those mentioned above, can be added to provide a palatable oral preparation.These compositions can be preserved by adding antioxidants, such as ascorbic acid.

[0098] Dispersible powders and granules suitable for preparing an aqueous suspension by the addition of water are provided by mixing 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, and suspending agents are exemplified by those described above. Additional excipients, such as sweeteners, flavorings, 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 emulsifiers may be natural gums, such as acacia gum or tragacanth gum, natural phosphatides, such as soybean, lecithin, and esters or partial esters obtained from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0100] Syrups and elixirs may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain antifoaming agents, preservatives, flavoring agents, and coloring agents. Oral solutions may be prepared by combining, for example, cyclodextrin, PEG, surfactants, etc.

[0101] Pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. Such suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as 1,3-butanediol solutions. Acceptable vehicles and solvents can be used, including water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic mono- or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0102] The compounds of Formula (I) provided herein, or their pharmaceutically acceptable salts or polymorphs, can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum to release the drug. Such materials include cocoa butter or polyethylene glycol. Additionally, the compounds can be administered ophthalmically via solutions or ointments. Furthermore, transdermal delivery of the target compounds 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 includes the use of mouthwashes and gargles.

[0103] The compounds of Formula (I) provided herein, or pharmaceutically acceptable salts or polymorphs thereof, can also be bound to a carrier that is a polymer suitable as a targetable drug carrier. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of Formula (I) provided herein, or pharmaceutically acceptable salts thereof, can be bound to a carrier that is a biodegradable polymer useful for achieving sustained drug release, 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. Polymers and semipermeable polymer matrices can also be formed into shaped articles, such as valves, stents, tubes, and prostheses.

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

[0105] Accordingly, provided herein are methods for treating hypertrophic cardiomyopathy (HCM) or cardiac diseases having one or more pathophysiological characteristics associated with HCM. The methods involve administering to a subject in need of treatment an effective amount of a compound provided herein or a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The methods involve administering to a subject in need of treatment an effective amount of a compound provided herein or a pharmaceutical composition containing polymorphic 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] The present disclosure also provides a method for treating hypertrophic cardiomyopathy (HCM) or heart disease. The method comprises administering to a subject in need of treatment an effective amount of a compound provided herein or a pharmaceutical composition containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The method comprises administering to a subject in need of treatment an effective amount 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 or a pharmaceutical composition containing 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.

[0107] Diastolic dysfunction is present or is a key feature of a range of diseases, including, but not limited to, hypertrophic cardiomyopathy (HCM), heart failure with preserved ejection fraction (HFpEF) - e.g., both impaired active relaxation and impaired ventricular stiffening (e.g., diabetic HFpEF), ischemic cardiomyopathy, cardiac transplant allograft vasculopathy, restrictive cardiomyopathy (e.g., genetic mutations in one or more sarcomeric proteins), inflammatory cardiomyopathy (e.g., Löffler syndrome, EMF), infiltrative cardiomyopathies (e.g., amyloid, sarcoid, and X-ray), storage diseases (e.g., hemochromatosis, Fabry disease, and glycogen storage diseases), congenital heart disease (e.g., pressure-overloaded RV, tetralogy of Fallot (e.g., pre- and early postoperative diastolic dysfunction), and valvular heart disease (e.g., aortic stenosis).

[0108] The present disclosure provides a method for treating a cardiac disease or disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein or a salt thereof, or Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. In some embodiments, diastolic dysfunction is a characteristic of and / or associated with a cardiac disease or disorder. For example, the cardiac disease or disorder may be cardiomyopathy (e.g., hypertrophic cardiomyopathy), heart failure (e.g., heart failure with preserved ejection fraction, heart failure with intermediate ejection fraction), valvular disease (e.g., valvular aortic stenosis), congenital heart disease (e.g., tetralogy of Fallot), left ventricular hypertrophy, angina pectoris (e.g., refractory angina pectoris), or Chagas disease. In certain embodiments, a normal or preserved ejection fraction (e.g., an ejection fraction of about 50% or greater) is characteristic of a cardiac disease or disorder. In some such cases, the cardiac disease or disorder characteristics include a normal or preserved ejection fraction and diastolic dysfunction. For example, a subject in need of treatment for a cardiac disease or disorder (e.g., HCM, HFpEF, valvular aortic stenosis) may have diastolic dysfunction and an ejection fraction of about 50% or greater. In certain embodiments, a moderate ejection fraction (e.g., an ejection fraction of about 40% to about 50%) is characteristic of a cardiac disease or disorder. In some such cases, a subject in need of treatment for a cardiac disease or disorder may have a moderate ejection fraction and diastolic dysfunction. For example, a subject in need of treatment for a cardiac disease or disorder (e.g., heart failure with a moderate ejection fraction) may have diastolic dysfunction and an ejection fraction of about 40% to about 50%.

[0109] In some embodiments, a method for treating diastolic dysfunction in a subject in need of treatment is provided.In some embodiments, the method is characterized by administering to the subject an effective amount of the compound of formula (I) or its salt, or 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 some examples, 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 embodiments, a subject in need of treatment for diastolic dysfunction may be suffering from one or more diseases or disorders selected from the group consisting of hypertrophic cardiomyopathy (e.g., oHCM, nHCM), restrictive cardiomyopathy, heart failure (e.g., HFpEF, diabetic HFpEF, HFmrEF), infiltrative cardiomyopathy (e.g., due to amyloidosis, sarcoidosis, and / or x-ray therapy), inflammatory cardiomyopathy (e.g., Loeffler's endocarditis, endomyocardial fibrosis), hemochromatosis, Fabry's 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 some embodiments, the subject in need of diastolic dysfunction treatment may be suffering from one or more diseases or disorders selected from the group consisting of hypertrophic cardiomyopathy (e.g., oHCM, nHCM), heart failure (e.g., HFpEF, diabetic HFpEF, HFmrEF), valvular heart disease (e.g., aortic stenosis), congenital heart disease (e.g., tetralogy of Fallot), and left ventricular hypertrophy (e.g., due to mitral regurgitation, aortic stenosis, aortic regurgitation, and / or chronic systemic hypertension). In some embodiments, the subject in need of diastolic dysfunction treatment 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 surgery to correct congenital heart disease such as tetralogy of Fallot.In some embodiments, the subject in need of treatment for diastolic dysfunction may use a prosthetic heart valve (e.g., a prosthetic aortic valve). In some embodiments, the 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, the subject in need of treatment for diastolic dysfunction has a normal or preserved ejection fraction. In another example, the subject in need of treatment for diastolic dysfunction has a moderate ejection fraction.

[0110] In some embodiments, a method for treating cardiomyopathy (e.g., hypertrophy) in a subject in need of treatment is provided. In some embodiments, the method comprises administering to the subject an effective amount of a compound of formula (I) or a salt thereof, or 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. 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 some embodiments, the cardiomyopathy is hypertrophic cardiomyopathy. In some embodiments, the hypertrophic cardiomyopathy is nHCM. The method may include administering an effective amount of the compound of Formula (I) or a salt thereof, or Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to a subject in need of treatment for nHCM. The subject in need of treatment for nHCM may have NYHA class II, III, or IV heart failure. In another example, the hypertrophic cardiomyopathy is oHCM. The method can include administering to a subject in need of treatment for oHCM an effective amount of the compound of Formula (I) or a salt thereof, or 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. The subject in need of treatment for oHCM can have NYHA Class II, III, or IV heart failure.

[0111] In some embodiments, the cardiomyopathy is restrictive cardiomyopathy. The method may include administering an effective amount of the compound of Formula (I) or a salt thereof, or the Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione to a subject in need of treatment for restrictive cardiomyopathy. In some embodiments, the restrictive cardiomyopathy may be caused by, for example, one or more mutations (e.g., genetic mutations) in sarcomeric proteins. In some embodiments, the cardiomyopathy is infiltrative cardiomyopathy. Infiltrative cardiomyopathy may be caused by amyloidosis, sarcoidosis, and / or X-ray therapy. In some instances, a characteristic of infiltrative cardiomyopathy may be diastolic dysfunction. A method for treating infiltrative cardiomyopathy can include administering an effective amount of the compound of formula (I) or a salt thereof, or the 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 to a subject in need of treatment. In some embodiments, the cardiomyopathy is inflammatory cardiomyopathy. Non-limiting examples of inflammatory cardiomyopathy include Loeffler's endocarditis and endocardial fibrosis. In some examples, a characteristic of inflammatory cardiomyopathy can be diastolic dysfunction. A method for treating inflammatory cardiomyopathy can include administering an effective amount of the compound of Formula (I) or a salt thereof, or 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 to a subject in need of treatment.

[0112] In some embodiments, a method for treating heart failure (e.g., HFpEF, HFmrEF) in a subject in need of treatment is provided. The method may include administering an effective amount of the compound of formula (I) or a salt thereof, or the 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. 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 heart failure treatment may have NYHA class II, III, or IV heart failure. Non-limiting examples of heart failure that can be treated using the compounds described herein include HFpEF, diabetic HFpEF, and HFmrEF. In some embodiments, the heart failure is HFpEF. In some embodiments, a subject in need of HFpEF treatment may have normal contractile force or high contractile force (e.g., measured by echocardiogram). In some cases, a subject in need of HFpEF treatment may have abnormal longitudinal global strain (e.g., less than -15%). In some embodiments, a subject in need of HFpEF treatment may suffer from diabetes (type I, type II) and / or valvular disease (e.g., aortic stenosis). In some examples, a subject in need of HFpEF treatment may have a prosthetic valve (e.g., aortic valve) due to valvular disease (e.g., aortic stenosis). A method for treating HFpEF (e.g., diabetic HFpEF) in a subject in need of such treatment can include administering to the subject an effective amount of the compound of formula (I) or a salt thereof, or the 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. In some embodiments, the heart failure is HFmrEF.The method can include administering an effective amount of the compound of Formula (I) or a salt thereof, or 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 to a subject in need of treatment for HFmrEF. The subject in need of treatment for HFmrEF can have NYHA Class II, III, or IV heart failure.

[0113] In some embodiments, a method for treating left ventricular hypertrophy in a subject in need thereof is provided. The method comprises administering to the subject an effective amount of a compound of formula (I) or a salt thereof, or Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. In some embodiments, the subject in need of left ventricular hypertrophy treatment has an abnormal left ventricular wall thickness. The subject's left ventricular wall thickness may be thicker than normal but below the diagnostic criteria for hypertrophic cardiomyopathy. For example, the subject in need of left ventricular hypertrophy treatment 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., about 14 mm or less, about 13 mm or less). In some embodiments, the subject who needs to treat left ventricular hypertrophy has left ventricular hypertrophy without hypertrophic cardiomyopathy.In some embodiments, the subject who needs to treat left ventricular hypertrophy can be suffering from hypertension (for example, chronic and / or systemic).In some embodiments, left ventricular hypertrophy can be caused by, for example, chronic mitral regurgitation, chronic aortic regurgitation, chronic aortic stenosis and / or chronic systemic hypertension.

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

[0115] Subjects in need of treatment for diastolic dysfunction include subjects in the patient population with non-obstructive hypertrophic cardiomyopathy (nHCM) or subjects with heart failure with preserved ejection fraction (HFpEF). Subjects in need of treatment for diastolic dysfunction include subjects who have demonstrated left ventricular stiffness measured by echocardiography or cardiac magnetic resonance.

[0116] In some embodiments, the subject in need of treatment is selected from a patient population with 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, 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 a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0118] The compound of formula (I) can be administered as a single agent or as a combination therapy.In combination therapy, the compound of formula (I) is used in combination with another therapeutic regimen, for example, the standard of care (SOC) for the cardiac condition of the subject or another therapy useful for treating related diseases or disorders.The additional therapeutic agent can be administered by the route and amount commonly used for the drug, or in a reduced amount, and can be administered simultaneously, sequentially or simultaneously with the compound of formula (I).

[0119] In some embodiments, the compound of Formula (I) is administered in addition to a SOC for symptoms of diastolic dysfunction, such as diastolic heart failure. In further embodiments, the subject is administered, in addition to the compound of Formula (I), an additional therapeutic agent, such as a beta-blocker, a 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-sparing diuretic such as eplerenone, spironolactone, or canrenone), a cholesterol-lowering agent (e.g., a statin), a neutral endopeptidase inhibitor (NEPi), a cardiac inotropic agent (e.g., , beta-adrenergic receptor agonists such as digoxin, pimobendan, dobutamine, phosphodiesterase (PDE)-3 inhibitors such as milrinone or calcium sensitizers such as 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 drugs, anticoagulants (e.g., warfarin), antithrombotic drugs, antiplatelet drugs or combinations thereof may be administered.

[0120] Suitable 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, DuP-532, E-4177, elisartan, EMD-66397, EMD-73495, eprosartan, EXP-063, EXP-929, EXP-31 74, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, Irbesartan, Isoteorin, KRI-1177, KT3-671, KW-3433, Losartan, LR-B / 057, L-158809, L-158978, L-159282, L-159874, L-161177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LR B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin acetate, S-8307, S-8308, SC-52458, saprisartan, saralasin, These include 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 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®, etc.), dapagliflozin (e.g., Farxiga®, etc.), 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, the 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] Also provided herein is 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, comprising administering to a subject in need thereof an effective amount 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. Also provided herein is 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, comprising administering to a subject in need thereof an effective amount 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.

[0122] The polymorphic 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 a monotherapy or a combination therapy. In a combination therapy, the polymorphic 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 a subject's cardiac disease or another therapy useful for treating related diseases and disorders. The additional therapeutic agent may be administered by a route and in an amount commonly used for said agent or in a reduced amount, and may be administered simultaneously, sequentially, or concurrently with 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. In some embodiments, 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 is administered in addition to a SOC for symptoms of diastolic dysfunction, such as diastolic heart failure.In a further embodiment, the subject is receiving, 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, for example, a beta-blocker, a RAAS inhibitor (e.g., angiotensin receptor agonists such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists), angiotensin receptor neprilysin inhibitors (ARNIs) (e.g., sacubitril / valsartan), a mineralocorticoid receptor antagonist (e.g., an aldosterone inhibitor; a potassium-sparing diuretic such as eplerenone, spironolactone, canrenone, etc.). ), cholesterol-lowering drugs (e.g., statins), neutral endopeptidase inhibitors (NEPi), orthotropic inotropes (e.g., beta-adrenergic receptor agonists such as digoxin, pimobenzene, dobutamine, phosphodiesterase (PDE)-3 inhibitors such as milrinone, or calcium sensitizers such as 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 drugs, anticoagulants (e.g., warfarin), antithrombotic drugs, antiplatelet drugs, or combinations 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®) or dapagliflozin (Farxiga®). In some embodiments, 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 is administered and the subject is administered an additional therapeutic agent to improve a 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, the subject receiving treatment for heart failure with 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 is also receiving treatment with an ARNI, a beta-blocker, and an MRA.

[0123] Also provided herein is a method for treating 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, in combination with a therapy aimed at correcting or alleviating the primary cause of volume or pressure overload (e.g., including valve repair / replacement or effective antihypertensive therapy), comprising administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating 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, in combination with a therapy aimed at correcting or alleviating the primary cause of volume or pressure overload (e.g., including valve repair / replacement or effective antihypertensive therapy), comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0124] Also provided herein is a method for treating 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, in combination with a therapy aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., including valve repair / replacement or effective antihypertensive therapy), comprising administering to a subject in need of treatment an effective amount 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. Also provided herein is a method for treating 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, in combination with a therapy aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., including valve repair / replacement or effective antihypertensive therapy), comprising administering to a subject in need of treatment an effective amount 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.

[0125] Also described herein is a method for treating hypertrophic cardiomyopathy (HCM) or cardiac disease (e.g., cardiac disease having pathophysiological characteristics associated with HCM), comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof, in combination with (1) a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, angiotensin receptor blocker (ARB), beta-blocker, aldosterone receptor antagonist, neuroendopeptidase inhibitor, etc.); (2) a therapeutic agent that stimulates myocardial contraction by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, angiotensin receptor blocker (ARB), beta-blocker, aldosterone receptor antagonist, neuroendopeptidase inhibitor, etc.); and / or (3) a therapy that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (a vasodilator of any class, e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

[0126] Also described herein is a method for treating hypertrophic cardiomyopathy (HCM) or cardiac disease (e.g., cardiac disease having pathophysiological characteristics associated with HCM), comprising administering a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof, in combination with (1) a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); (2) a therapeutic agent that stimulates myocardial contraction by downregulating cardiac neurohormonal stimulation, thereby preventing cardiac remodeling. and / or (3) a therapy that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (vasodilators of any class, including, but not limited to, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, smooth muscle myosin modulators, etc.) to a subject in need of such treatment.

[0127] Also described herein is a method for treating hypertrophic cardiomyopathy (HCM) or cardiac disease (e.g., cardiac disease having pathophysiological characteristics associated with HCM), comprising administering 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 in combination with (1) a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, angiotensin receptor blocker (ARB), beta-blocker, aldosterone inhibitor, or aldosterone inhibitor). (2) a therapy that improves cardiac function by stimulating myocardial contraction (e.g., an orthotropic inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or (3) a therapy that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (a vasodilator of any class, including, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

[0128] Also described herein is a method for treating hypertrophic cardiomyopathy (HCM) or cardiac disease (e.g., cardiac disease having pathophysiological characteristics associated with HCM), comprising administering an effective amount of a pharmaceutical composition comprising Form 1 of polymorphic (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 that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, angiotensin receptor blocker (ARB), beta-blocker, or alveolar steroid). (2) a therapy that improves cardiac function by stimulating myocardial contraction (e.g., an orthotropic inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or (3) a therapy that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (a vasodilator of any class, including, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

[0129] The present disclosure also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical. The present disclosure also provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical. The present disclosure 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 pharmaceutical. The present disclosure 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 pharmaceutical.

[0130] The present disclosure also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease having pathophysiological characteristics associated with HCM). The present disclosure also provides a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease having pathophysiological characteristics associated with HCM). The present disclosure 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 treating hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease having pathophysiological characteristics associated with HCM). Also provided herein is 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 use in treating hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease having pathophysiological characteristics associated with HCM).

[0131] The present specification also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in 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 present specification also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in 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. Also 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 for use in the treatment of 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. Also provided herein is 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 use in 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.

[0132] Also provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating 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 aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., including valve repair / replacement or effective antihypertensive therapy). Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in treating 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 aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., including valve repair / replacement or effective antihypertensive therapy). Also 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 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 aimed at correcting or alleviating the primary cause of the volume or pressure overload (including, for example, valve repair / replacement or effective antihypertensive therapy).Also provided herein is 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 use in treating 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 aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., including valve repair / replacement or effective antihypertensive therapy).

[0133] The present specification also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease having pathophysiological characteristics of HCM), wherein the compound is selected from the group consisting of (1) a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); (2) a therapeutic agent that inhibits myocardial contraction; (3) for use in combination with a therapy that improves cardiac function by stimulating cardiac function (e.g., an orthotropic inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or (4) a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (including, but not limited to, any class of vasodilator, e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). The present specification also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease having pathophysiological characteristics of HCM), the compound being selected from the group consisting of (1) a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); (2) a therapeutic agent that inhibits cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); (3) for use in combination with a therapy that improves cardiac function by stimulating muscle contraction (e.g., an orthotropic inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or (4) a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (including, but not limited to, any class of vasodilator, e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators).

[0134]

[0013] Also 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 for use in treating hypertrophic cardiomyopathy (HCM) or cardiac disease (e.g., cardiac disease having pathophysiological characteristics of HCM), wherein the compound is incompatible with 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), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); therapeutic agents that improve cardiac function by stimulating myocardial contraction (e.g., orthotropic inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapeutic agents that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (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 modulators).Also provided herein is 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 treating hypertrophic cardiomyopathy (HCM) or cardiac disease (e.g., cardiac disease having pathophysiological characteristics of HCM), wherein the compound is incompatible with therapeutic agents (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs)) that slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation. RB), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); therapeutic agents that improve cardiac function by stimulating myocardial contraction (e.g., orthotropic inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapeutic agents that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (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 modulators).

[0135] The present disclosure also provides the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. The present disclosure 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. The present disclosure 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. The present disclosure 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.

[0136] The present disclosure also provides use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease having the pathophysiological characteristics of HCM). The present disclosure also provides 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 or cardiac disease (e.g., cardiac disease having the pathophysiological characteristics of HCM). The present disclosure also provides 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 treating hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease having the pathophysiological characteristics of HCM). Also provided herein is the use of a pharmaceutical composition comprising the Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for the treatment of hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease having pathophysiological characteristics of HCM).

[0137] The present specification also provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament 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 present specification also provides 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 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. Also provided herein is 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 the treatment of 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. Also provided herein is the use of a pharmaceutical composition comprising the Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for the treatment of 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.

[0138] Also provided herein is 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), a disease or disorder (selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension) in combination with a therapy aimed at correcting or alleviating the primary cause of volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy). Also provided herein is 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), a disease or disorder (selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension) in combination with a therapy aimed at correcting or alleviating the primary cause of volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy). Also provided herein is 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 regurgitation, chronic aortic stenosis, and chronic systemic hypertension) in combination with a therapy aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy).Also provided herein is the use of a pharmaceutical composition comprising the 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 left ventricular hypertrophy (e.g., due to volume or pressure overload), a disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension, in combination with a therapy aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy).

[0139] Also provided herein is 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 cardiac disease (e.g., a cardiac disease having pathophysiological features associated with HCM) in combination with a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., an orthotropic inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or cardiac afterload (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 modulators). Also provided herein is 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 cardiac disease (e.g., a cardiac disease having pathophysiological characteristics associated with HCM) in combination with a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., an orthotropic inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or cardiac afterload (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 modulators).

[0140] Also described herein are 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), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); therapeutic agents that improve cardiac function by stimulating myocardial contraction (e.g., orthotropic inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapeutic agents that reduce cardiac preload (e.g., diuretics such as furosemide) or cardiac afterload (e.g., vasodilators of any class). and (c) 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 hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease having pathophysiological features associated with HCM) in combination with an anti-inflammatory drug, such as, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator.Also described herein are 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), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); therapeutic agents that improve cardiac function by stimulating myocardial contraction (e.g., orthotropic inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapeutic agents that reduce cardiac preload (e.g., diuretics such as furosemide) or cardiac afterload (vasodilators of any class, e.g., ... and (c) 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 treating hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease having pathophysiological features associated with HCM) in combination with a therapeutic agent (e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

[0141] The compound of formula (I) or a pharmaceutically acceptable salt thereof can not only alleviate symptoms but also alter the natural course of diseases such as HCM. 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 can not only alleviate symptoms but also alter the natural course of HCM and other diseases. The mechanisms that provide clinical benefit to HCM patients may also extend to patients with other forms of heart disease with similar pathophysiology, regardless of whether genetic influences are present. For example, an effective treatment for HCM by improving ventricular relaxation during diastole may also be effective in a broader population characterized by diastolic dysfunction. The compound of formula (I) or a pharmaceutically acceptable salt thereof can specifically target the underlying cause of the symptoms or act on another downstream pathway. The polymorphic 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 underlying cause of a condition or to act on another downstream pathway. Thus, 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 polymorphic 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 also benefit patients suffering from heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris or restrictive cardiomyopathy.Additionally, the compounds of formula (I) or pharmaceutically acceptable salts thereof, when combined with treatments aimed at correcting or alleviating the primary cause of volume or pressure overload (e.g., valve repair / replacement, effective antihypertensive therapy), can promote healthy ventricular remodeling in left ventricular hypertrophy due to volume or pressure overload; for example, chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension. 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 promote healthy ventricular remodeling in patients with volume- or pressure-overload-induced left ventricular hypertrophy (e.g., chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension) when combined with treatments aimed at correcting or alleviating the primary cause of volume or pressure overload (valve repair / replacement, effective antihypertensive therapy). By reducing left ventricular filling pressure, the risk of pulmonary edema and respiratory failure can be reduced. By reducing or eliminating functional mitral regurgitation and lowering left atrial pressure, the risk of paroxysmal or permanent atrial fibrillation can be reduced, thereby reducing the risk of arterial thromboembolism (including, but not limited to, cerebral arterial embolism) complications. By reducing or eliminating dynamic and / or static left ventricular outflow tract obstruction, the likelihood of requiring surgical or percutaneous septal reduction therapy, which carries the risk of short- and long-term complications, can be reduced. The compound of formula (I) or a pharmaceutically acceptable salt thereof can reduce the severity of the chronic ischemic condition associated with HCM, thereby reducing the risk of sudden cardiac death (SCD) or its equivalent (frequent and / or repetitive ICD discharges) and / or the need for potentially toxic antiarrhythmic drugs in patients with implantable cardioverter-defibrillators.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 may reduce the severity of the chronic ischemic condition associated with HCM, thereby reducing the risk of sudden cardiac death (SCD) or its equivalent (frequent and / or repetitive ICD discharges) and / or the need for potentially toxic antiarrhythmic medications in patients with implantable cardioverter-defibrillators. The compound of formula (I) or a pharmaceutically acceptable salt thereof may be of value in reducing or eliminating the need for concomitant medications with potential toxicities, drug-drug interactions, and / or side effects. The polymorphic 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 valuable in reducing or eliminating the need for concomitant medications with potential toxicities, drug-drug interactions, and / or side effects. The compound of formula (I) or a pharmaceutically acceptable salt thereof may result in a reduction of interstitial myocardial fibrosis and / or slowing its progression, and inhibiting or reversing left ventricular hypertrophy. 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 can reduce and / or slow the progression of interstitial myocardial fibrosis, and inhibit or reverse left ventricular hypertrophy.

[0142] Depending on the disease to be treated and the condition of the subject, the compounds of formula (I) or pharmaceutically acceptable salts thereof provided herein may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intrapleural injection or infusion, subcutaneous injection or implantation), by implant (e.g., when the compound is attached to a stent device), by inhalation spray, intranasal, intravaginal, rectal, sublingual, or topical administration routes, and can be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each administration route.

[0143] Depending on the disease to be treated and the condition of the subject, the 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 provided herein may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intrapleural injection or infusion, subcutaneous injection or implantation), by implant (e.g., when the compound is attached to a stent device), by inhalation spray, intranasal, intravaginal, rectal, sublingual, or topical administration routes, and can be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate 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 on a regimen of 1 to 4 times per day, preferably once or twice per 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 the Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

[0145] However, it will be understood that the specific dosage range and frequency of administration for a particular patient will vary and will depend upon a variety of factors, including the activity of the particular compound or pharmaceutically acceptable salt employed, the metabolic stability and duration of action of the 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, excretion rate, drug combination, and the severity of the particular condition of the subject being treated.

[0146] The compounds of Formula (I), pharmaceutically acceptable salts of the compounds of Formula (I), and / or pharmaceutical compositions provided herein may 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 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 pharmaceutical compositions provided herein may be used in combination with other drugs used in the treatment, prevention, suppression, or alleviation of diseases or conditions for which the compounds and compositions provided herein are effective. Such additional therapeutic agents may be administered simultaneously or sequentially with the compounds or compositions provided herein, by a route and in an amount commonly used for that purpose. When the compounds or compositions provided herein are used concurrently with one or more other drugs, pharmaceutical compositions containing not only the compounds or compositions provided herein but also such other drugs are preferred. Therefore, the pharmaceutical compositions provided herein also include those that contain one or more other active ingredients or therapeutic agents in addition to the compounds or compositions provided herein.Suitable additional effective drugs include, for example, therapeutic agents that slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (for example, ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists or neuroendopeptidase inhibitors); therapeutic agents that improve cardiac function by stimulating myocardial contraction (for example, orthotropic inotropic agents such as beta-adrenergic agonist dobutamine or phosphodiesterase inhibitor milrinone); and therapeutic agents that reduce cardiac preload (for example, diuretics such as furosemide) or reduce cardiac afterload (all classes of vasodilators, for example, calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators).The weight ratio of the compound of Formula (I) provided herein or a pharmaceutically acceptable salt thereof to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each is used.

[0147] When the compound of the present invention is administered in combination with another therapeutic agent, the other therapeutic agent can be administered simultaneously, separately, or sequentially with the compound of formula (I). The exact dosage regimen is compatible with the properties of the therapeutic agent. When the compound of the present invention is administered in combination with another therapeutic agent, the other therapeutic agent can be administered simultaneously, separately, or sequentially 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. The exact dosage regimen is compatible with the properties of the therapeutic agent. [Example]

[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 (reactions performed 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; SOCl: thionyl chloride; TFA: trifluoroacetic acid; THF: tetrahydrofuran; THP: tetrahydropyran or tetrahydropyranyl; and Zn: zinc powder. All experiments were performed in a fume hood equipped with specific safety precautions and necessary personal protective equipment.

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

[0150] Step 1. Synthesis of (S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (1-2) A 1000 mL round-bottom flask was charged with 3-fluorobenzaldehyde (50 g, 0.40 mol), (S)-2-methylpropane-2-sulfinamide (50 g, 0.41 mol), CsCO (157 g, 0.48 mol), and dichloromethane (500 mL) under an Ar atmosphere. After stirring at room temperature for 4 h, the reaction mixture was diluted with methyl tert-butyl ether (MTBE) (1000 mL). The mixture was then filtered, and the filtrate was concentrated to give 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 H 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) To a suspension of Zn (38 g, 0.58 mmol) in tetrahydrofuran (600 mL), 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 with stirring under an Ar atmosphere at 70 °C for 40 min. After stirring at 70 °C for an additional 30 min, the reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with EtOAc (1000 mL). The resulting mixture was then washed with saturated aqueous citric acid (500 mL) and dried over anhydrous NaSO. The solvent was removed, and the residue was dried in vacuo to give 1-3 (50 g, 60%) as a yellow oil. LC-MS (ES, m / z): 352 [M+H] + .

[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) in 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 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). The combined organic extracts were then washed with brine (500 mL) and dried over anhydrous NaSO. The solvent was removed, and the residue was purified by Flash-Prep-HPLC (column: C18 silica gel; mobile phase: CHCN / HO = 10 / 90 (v / v) increased to CHCN / HO = 95 / 5 (v / v) over 60 minutes; detector: UV 254 nm) to give 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 [ka]

[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) was added isocyanatotrimethylsilane (30 g, 0.26 mol) 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). The suspension was then filtered, and the solid was washed with ether (500 mL × 3) and dried in vacuo to give 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) was added 2-2 (34 g, 0.24 mol) at room temperature under an Ar atmosphere, followed by the addition of 1,3-dimethylpropanedioate (470 g, 0.36 mol). After stirring at 80 °C overnight, the reaction mixture was concentrated, and the residue was diluted with water (50 mL). The pH of the resulting mixture was then adjusted to 2 by adding concentrated aqueous HCl at 0 °C. The suspension was filtered, and the solid was washed with water and dried in vacuo at 45 °C for 24 h to give 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) A solution of 2-4 (30 g) in DCM (45 mL) was added to a mixture of saturated aqueous ammonia (50 mL) and DCM (50 mL) 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 give 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, and 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 [ka]

[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 CsCO (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 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 min at −78 °C under an Ar atmosphere. After stirring at −78 °C for 1 h, the reaction was quenched by the addition of 2 N aqueous HCl (45 mL) at −78 °C. The reaction mixture was concentrated to remove most of the THF and then extracted with EtOAc (100 mL × 3). The combined organic extracts were then washed with brine and dried over anhydrous NaSO. The solvent was removed, and the residue was dried in vacuo to give 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 crude product 3-2 (6 g, 18 mmol) in THF (60 mL) was added 1N aqueous NaOH solution (36 mL, 36 mmol) 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 with saturated aqueous citric acid, and the resulting mixture was extracted with EtOAc (200 mL x 3). The combined organic extracts were then 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, 5 μm; mobile phase: water (0.05% TFA (v / v)) and ACN (from 3.0% (v / v) to 17.0% (v / v) in 8 min; detector: UV 220 nm) to give 3-3 (1.5 g, 27%) as a white solid. LC-MS (ES, m / z): 306 [M+H] + ; 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 [ka]

[0163] Step 1. Synthesis of (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-methylpropane-2-sulfinamide (CA) 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 dropwise DIEA (2.15 g, 16.63 mmol) at 0 °C. After stirring overnight at room temperature, the reaction mixture was diluted with saturated aqueous NaHCO (100 mL) and ice water (100 mL). The mixture was extracted with EtOAc (100 mL x 3), and the combined organic extracts were washed with brine and dried over anhydrous NaSO. The solvent was removed, and the residue was dried in vacuo to give crude CA (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] Step 2. Synthesis of (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-methylpropane-2-sulfinamide (CB) A mixture of CA (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. Then, 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 CB (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] Step 3. Synthesis of 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 (CC) To a solution of crude CB (1.28 g) in ethanol (18 mL) was added thionyl chloride (2.7 mL) over 3 min at 0° C. After stirring at room temperature for 1 h, the reaction mixture was concentrated and dried in vacuo to give crude CC (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] Step 4. Synthesis of (S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (C-1) A mixture of crude CC (800 mg) and CHCN (10 mL) in a sealed vial was stirred at 120 °C in a microwave reactor for 20 min. The mixture was then 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 NaSO. 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: Water (0.05% (v / v) NH3·H2O) / CH3CN = 11.0% (v / v) to 30.0% (v / v) within 8 min; Detector: UV 254 nm) to give C-1 (197 mg, 27% in three steps from CA) as a white solid. LC-MS (ES, m / z): 382 [M+H] + ; 1 H 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 [ka]

[0168] Steps 1 to 4. Synthesis of (6S,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1) Following the same method as described for preparing (S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (C-4), (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) to give 1 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 [ka]

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

[0171] Steps 3 to 6. Synthesis of (6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2) Following the same method as described for preparing (S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (C-4), (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 give 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] Example 1-3: Preparation of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3) Scheme 3 [ka] Step 1. Synthesis of (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide (3B) A mixture of 2-fluoro-5-methylbenzaldehyde (3A) (5 g, 36.2 mmol), CsCO (17.6 g, 54.0 mmol), and (R)-2-methylpropane-2-sulfinamide (4.6 g, 38.0 mmol) in DCM (100 mL) was stirred at room temperature overnight under an Ar atmosphere. The reaction mixture was filtered, and the filtrate was diluted with ether (150 mL). The resulting suspension was then filtered. The filtrate was concentrated, and the residue was dried in vacuo to give 3B (8.7 g, 97%) as a yellow oil. LC-MS (ES, m / z): 242 [M+H] + ; 1 H NMR (400 MHz, d 6 -DMSO): δ 8.87 (s, 1H), 7.76 (m, 1H), 7.29 (m, 1H), 7.03 (m, 1H), 2.37 (d, J = 1.0 Hz, 3H), 1.27 (s, 9H).

[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) was added LiHMDS (1 M in THF, 24.6 mL, 24.6 mmol) dropwise over 30 min at −78 °C under an Ar atmosphere. After stirring at −78 °C for 1 h, the reaction was quenched by adding 1 N aqueous HCl (50 mL) while maintaining the internal temperature of the mixture at < −20 °C. The mixture was then concentrated to remove most of the organic solvent and then extracted with EtOAc (100 mL × 3). The combined organic extracts were washed with brine (100 mL) and dried over anhydrous NaSO. The solvent was removed, and the residue was dried in vacuo to give crude 3C (6.0 g) as a yellow oil, which was used in the next step without further purification. LC-MS(ES, m / z):348[M+H] + .

[0174] Step 3. Synthesis of (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(2-fluoro-5-methylphenyl)propanoic acid (3D) To a solution of 3C (6.0 g, 17.3 mmol) in THF (40 mL) was added 1N aqueous NaOH (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 with saturated aqueous citric acid and then extracted with EtOAc (100 mL x 3). The combined organic extracts were then 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, 5 um; Mobile phase: Water (0.05% TFA) and ACN (28.0% ACN to 36.0% in 10 min; Detector: UV 220 nm) to give 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 (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-methylpropane-2-sulfinamide (3E) To a solution of 3D (700 mg, 2.19 mmol), 2-2 (698 mg, 3.29 mmol), and HATU (1.25 g, 3.29 mmol) in DMF (10 mL) was added DIEA (849 mg, 6.57 mmol) at 0 °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 × 3). The combined organic extracts were washed with brine (50 mL × 2) and dried over anhydrous Na2SO4. The solvent was removed, and the residue was dried in vacuo to give 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-fluoro-5-methylphenyl)-3-(2,4,6-trioxo-1-(tetrahydro-2H-pyran-4-yl)hexahydropyrimidin-5-yl)propyl)-2-methylpropane-2-sulfinamide (3F) A solution of crude product 3E (1.3 g, 2.53 mmol) in AcOH (10 mL) was added to NaBHCN (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 × 3). The combined organic extracts were then washed with brine (50 mL) and dried over anhydrous NaSO. 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 CHCN (15 mL) was placed in a microwave reactor with stirring at 120 °C for 30 min. The mixture was then concentrated, and the residue was purified by preparative HPLC (column: C18 silica gel; mobile phase: CHCN:HO = 20:80 (v / v) increasing to CHCN:HO = 80:20 (v / v) within 40 min; detector: UV 254 nm) to obtain compound 3 (302 mg, 32%) as a white solid, which was identified as Form 1 polymorph (see Example 2). LC-MS (ES, m / z): 378 [M+H] + ; 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] Example 1-4: Preparation of (6R,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4) Scheme 4 [ka]

[0180] Step 1-7. Synthesis of (6R,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4) Following the same procedure as described for preparing (6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2), 3-fluorobenzaldehyde (1-1) was replaced with 2-fluoro-5-methylbenzaldehyde (3A) to give 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] Examples 1-5: Preparation for 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 [ka]

[0182] Steps 1 to 6. Synthesis of (6R,7R)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (5) Following the same procedure as described for preparing (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3), substituting (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide (4B) for (3B), 5 was obtained 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 [ka]

[0184] Steps 1 to 6: (6S,7R)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6) Following the same procedure as described for preparing (6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2), substituting (S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (1-2) with (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfinamide (3B), 6 was obtained as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 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 methods similar to those described above. [Table 1] [Table 2]

[0186] Example 2 Single Crystal X-ray Analysis - Morphology 1 SXRD analysis was performed on an Agilent Technologies (Dual Source) SuperNova diffractometer using monochromated Cu Kα (λ 1.54178 Å) radiation generated in a sealed tube. The diffractometer was equipped with an Oxford Cryosystems cryostat capable of data collection at 120(1) K, and the crystals were protected with Paratone oil. The collected data were corrected for absorption effects based on Gaussian integration for a polyhedral crystal model implemented as part of the CrysAlisPro software package (Agilent Technologies, 2014).

[0187] The structure is direct method (SHELXS97) 1 F analyzed by and interfaced through the OLEX2 software package 2 Exact least squares method (SHELXL97) 1 The image was developed using OLEX2 (see Figure 4). 2 was treated according to Data were collected, analyzed, and refined to the orthotropic space group P212121, and PLATON 4 ADDSYMM 3Routines were used to search for higher metric symmetries, but none were evident. All non-hydrogen atoms were placed in a Fourier map, their positions refined, and the thermal motion of all non-hydrogen atoms was then anisotropically described. Within this structure, one complete molecule of 3 (also referred to as the compound of Example 3) was located only in the asymmetric unit. Due to the weak diffraction data obtained, the Flack parameter was calculated to be -0.0657 and the esd to be 0.7497 (calculated from 1477 Bijovet pairs, indicating 97.6% completeness). Attempts to refine the structure using the TWIN and BASF commands failed to produce any further improvement. All hydrogen atoms were placed in calculated positions using a riding model with fixed Uiso, with all CH, CH2, and NH groups fixed at 1.2 times, and all CH3 groups fixed at 1.5 times. The highest residual Fourier peak was from C(16) at 1.34 e.Å. -3 about 0.68 Å, and the deepest Fourier hole is O(2) to -0.89 e.Å. -3 It was found to be about 0.58 Å.

[0188] Crystal data - Morphology 1 C 19 H 21 F2N3O3 (M=377.39g / mol): orthotropic 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)=0.964mm -1 , Dcalc=1.456g / cm 3 , 30202 reflection measurement (10.18° < 2θ < 153.36°), 3570 unique (R int =0.1117,R sigma =0.0636) (these were used for all calculations). The final R 1 was 0.1591 (>2Sigma(I)) and wR2 was 0.3889 (all data).

[0189] 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 assessing 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, including but not limited to myosin ATPase assays (bovine cardiac myofibrillar (bcMF) with and without serum, rabbit skeletal myofibrillar (rbskMF), cardiomyocyte contractility, and reactive metabolite identification).

[0191] Because a shorter half-life allows for a faster time to steady-state exposure, compounds with shorter half-lives were selected to allow for more rapid dose adjustment. Furthermore, eliminating or minimizing the dependency of drug candidates on polymorphic cytochrome P450 (CYP) enzymes, such as CYP2C19, for metabolic clearance may reduce the variability in human PK between slow and fast metabolizers. Eliminating or minimizing strong CYP enzyme-inducing properties of new drug candidates has the advantage of avoiding potential drug interactions. Drug candidates with higher selectivity for cardiac myosin over skeletal myosin have demonstrated advantages for the targeted human pharmacokinetics of myosin modulator candidates related to drug distribution. Myosin modulator candidates with lower potency for skeletal myosin are predicted to have reduced distribution to skeletal muscle tissue due to reduced binding to skeletal myosin, resulting in a reduced volume of distribution and a reduced half-life in humans. In preclinical studies, pharmacokinetic / pharmacodynamic studies were conducted to optimally select compounds that could be administered orally 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 The solubility of small molecule drugs in PBS (pH 7.4) at room temperature was evaluated using reserpine (solubility <15 μM in PBS at 7.4°C) as a negative control and verapamil (solubility >200 μM in PBS at 7.4°C) as a positive control. To each well of a 96-well plate, 2 μL of a 20 mM DMSO stock solution of the compound was added, followed by 198 μL of PBS at room temperature. After shaking for 1.5 h 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. 70 μL of the filtrate was then added to a 96-well reading plate well, which had previously contained 70 μL of DMSO per well. The concentration of the sample in each well was determined based on the integration of the LC with UV detection, compared to a standard curve established for each compound 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 assessed using a biochemical assay in which the release of ADP (adenosine diphosphate) from cardiac myosin was monitored as a function of time by coupling it to an enzyme-linked system consisting of pyruvate kinase and lactate dehydrogenase (PK / LDH). PK converts PEP (phosphoenolpyruvate) to pyruvate, which then converts ADP to ATP (adenosine triphosphate). Pyruvate is then converted to lactate by LDH, which converts NADH (nicotinamide adenine dinucleotide) to oxidized NAD (nicotinamide adenine dinucleotide). Cardiac myosin was obtained from skinned bovine hearts in the form of myofibrils. Prior to testing small molecule drugs, the calcium responsiveness of bovine myofibrils was assessed, and the calcium concentration achieving 50% activation of the myofibril lineage was selected as the final condition for evaluating the inhibitory activity of small molecule drugs. All enzyme activities were measured in a pH 6.8 buffer (PM12 buffer) containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), 2 mM magnesium chloride, and 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 antifoam, 2 mM BME, 0.5 mM NADH, and 1.5 mM PEP, which was the desired free calcium concentration required for 50% myofibril activation.

[0194] A dilution series of compounds was prepared in DMSO to obtain a final compound concentration in a volume of 30 μL, with the DMSO concentration fixed at 3.3% (v / v). Typically, 1 μL of the dilution series was added to a 384-well plate to obtain a 10-point dose-response pattern. After adding 14 μL of a solution containing bovine cardiac muscle fibrils, PK / LDH, and calcium solution (to achieve 50% activation), the enzyme reaction was initiated by adding 15 μL of a solution containing ATP, PEP, and NADH. The reaction progress was monitored at room temperature using a PerkinElmer Envision plate reader with a clear bottom. The plate reader was set to read absorbance at 340 nm in kinetic mode for 15 minutes. Data were recorded as the slope of the absorbance response versus time. The slope of the absorbance response versus time was normalized to the slope of the plate containing DMSO. This normalized rate was then plotted as a function of small molecule concentration, and the data were fitted with a four-parameter fit using Excel XLfit. I C 50 is the concentration at which 50% of the total response is inhibited. Drugs that do not achieve 50% inhibition at the highest concentration tested have IC values ​​higher than the highest concentration tested. 50 reported as (i.e., IC 50 >50 μM).

[0195] Myosin Inhibition Assay (bcMF) Serum pCa IC 50 (μM) In the presence of 10% human serum, the enzyme activity of bovine cardiac myosin, which is associated with ADP (adenosine diphosphate) release, was inhibited at a calcium concentration that achieved 50% activation of bovine cardiac myofibrillar cells. This method was identical to the bovine cardiac myosin inhibition assay (bcMF pCa 6 IC), except that 10% human serum was added. 50 (μM)).

[0196] Myosin inhibition assay (rbskMF pCa IC 50 (μM) The enzyme activity of rabbit skeletal myosin, associated with ADP (adenosine diphosphate) release, was inhibited at a calcium concentration that achieved 50% activation of rabbit skeletal myofibrils. The bovine cardiac myosin inhibition assay (bcMF pCa 6 IC) was performed using rabbit skeletal myofibrils instead of bovine cardiac myofibrils. 50 The same method was used as in (μM).

[0197] Pharmacokinetic / Pharmacodynamic (PK / PD) Relationships The ability of small molecule compounds to dose-dependently modulate systolic cardiac function was assessed noninvasively using echocardiography in isoflurane-anesthetized SD rats. Cardiac function and heart rate were continuously measured before and during (~every 3 minutes) a 30-60-minute continuous intravenous infusion at 2.0 mg / kg / hr. Conscious rats were then 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). Cardiac function and cardiac morphology were recorded under isoflurane anesthesia at two different time points / days: once before administration (i.e., baseline, day 2) and 2 hours after administration (day 0), a time known to approach steady state upon exposure and expected to peak. 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 imaging (Vevo2100, Visual Sonic Inc.). FS was defined as the change in left ventricular size / diameter between end-systole (LVESd) and end-diastole (LVEDd) normalized to end-diastole (i.e., FS = 100 x [LVEDd - LVESd] / LVEDd). LV volume was calculated using the Teichholz model (LVV = 7 x [2.4 + LVid]). -1 xLVid 3 In all cases, blood samples were collected (by tail vein microsampling) at each echocardiographic time point to establish pharmacokinetic / pharmacodynamic (PK / PD) relationships.

[0198] Cardiomyocyte contractile force assay Contractility of adult rat ventricular myocytes was determined by edge detection using the IonOptix contractility system. Aliquots of myocytes in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl2, 1.5 mM CaCl2, 4 mM HEPES, 11 mM glucose) were placed in a perfusion chamber (Series 20 RC-27NE; Warner Instruments) and allowed to adhere to a coverslip. They were then perfused with Tyrode's buffer at 37°C. Myocytes were stimulated and recorded at 1 Hz and 10 V. Only myocytes with clear striations in the resting state before pacing, with cell lengths of 120–180 μm, basal shortening fractions corresponding to 3–8% of the cell length, and contraction velocities greater than 100 μm per second, were used for contraction experiments. To measure the response to compounds (at a concentration of 0.3 μM), cardiomyocytes were first perfused with Tyrode's buffer for 60 seconds, then administered with compound for 5 minutes, followed by a 140-second washout with Tyrode's buffer. Data were continuously recorded using IonOptix software. Contractile force data were analyzed using Ionwizard software (IonOptix). For each cell, 10–20 contractile force transients were averaged to compare baseline (no compound) and compound-treated conditions. Compound activity was measured by its effect on fractional shortening (FS), which is the ratio of the peak length of the cell during contraction divided by the baseline cell length, normalized to 100% for untreated cells. Percent inhibition was calculated by subtracting the FS value from 100%.

[0199] Identification of reactive metabolites The formation of small molecule reactive metabolites is determined in vitro by detecting glutathione adducts formed during incubation with human liver microsomes stimulated with NADPH and glutathione.

[0200] Methods: Metabolism of small molecules (30 μM) to form glutathione adducts was assessed in 96-well plates (2 mL well volume) incubated with human liver microsomes (1 mg / mL protein) in potassium phosphate buffer (0.1 M, pH 7.4) at 37°C for 1 h (200 μL volume, n = 3 incubations / treatment, 60 min incubation time) in the absence of NADPH (used as a negative control) and in the presence of NADPH (1 mM) and glutathione (GSH, 10 mM). Incubations with liver microsomes were performed in a shaking water bath incubator with slow horizontal shaking (30 rpm). To achieve a compound incubation concentration of 30 μM, a 3 mM substrate stock solution in DMSO was used. The final incubation mixture contained 148 μL of potassium phosphate buffer, 10 μL of liver microsome solution (20 mg protein / mL), and 2 μL of 3 mM substrate solution. The incubation was initiated by the addition of 40 μL of 5 mM NADPH solution in potassium phosphate buffer. For incubations without NADPH, 40 μL of potassium phosphate buffer was added. After incubation, the reaction was terminated by adding 20 nM carbamazepine internal standard and an equal volume of acetonitrile containing 3% formic acid. After centrifugation (4,600 rpm, 4°C, 10 min), 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 in aluminum foil before analysis by liquid chromatography / mass spectrometry (LC-MS / MS).

[0201] Analyte identification: LC-MS / MS detection (with in-line UV detection at 280 nm) of test compounds and potential GSH-adducts was performed using Xcalibur software (version 2.1.0, Thermo Fisher Scientific, Waltham, MA) by extracting selected ion chromatographic profiles using 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 abundance of in vitro GSH adducts in liver microsomal extracts was assessed using Xcalibur software (version 2.1.0) by calculating the LC / UV absorbance ratio at 280 nm between the GSH adduct detected in the incubation extracts supplemented with NADPH and GSH and the corresponding LC / UV peak area of ​​the parent compound from the incubation extract containing NADPH. The extent of GSH adduct formation was determined by LC-MS / MS analysis with in-line LC-UV detection at 280 nm by dividing the LC / UV peak area of ​​the glutathione adduct by the LC / UV peak area of ​​the corresponding parent HCM-1NG analogue, determined from analysis of the control (-NAPDH, -GSH) incubation extract.

[0202] Materials: Pooled human male 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 chromatographic grade.

[0203] LC-MS Conditions: Liver microsomes and extracts incubated with hepatocytes were characterized by LC-MS and LC-MS / MS on a Thermo Electron LTQ Orbitrap XL mass spectrometer coupled to a Dionex UltiMate 3000 UHPLC with an in-line diode array detector and an OAS-3300TXRS autosampler (40 μL injection volume). Electrospray ionization (ESI) was performed in positive ion mode at 5.01 kV, with a sheath flow rate of 35.02, an aux flow rate of 9.99, a current of 2.6 μA, a capillary temperature of 325 °C, and a capillary voltage hold of 15.99. Vacuum conditions were used, and an ion gauge pressure of 2.33 × 10 was used. -5 The pressure was 0.90 Torr, and the reflux gauge pressure was 0.90 Torr. LC-MS analysis was performed in positive ion mode with a full scan (m / z 100–m / z 1000) of 0.73 s 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 acquired using Xcalibur software (version 2.1.0, Thermo Fisher Scientific, Waltham, MA).

[0204] [Table 3]

[0205] A data-dependent scan was used to collect MS / MS spectra of the highest mass in the Orbitrap (15,000 resolution) full scan mass spectrum.

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

[0207] Biological Evaluation Table [Table 5] In the "FS Inhibition Rate at 0.3 μM" column in Table 1B, + indicates inhibition of left ventricular fractional shortening of less than 33%, ++ indicates inhibition of left ventricular fractional shortening of 33% to 66%, and +++ indicates inhibition of left ventricular fractional shortening of 66% or more (i.e., +++ indicates maximal inhibition).

[0208] [Table 6] [Table 7]

[0209] As shown above, these compounds demonstrated minimal or no reactive metabolites.

[0210] X-ray powder diffraction (XRPD) XRPD analysis was performed using a PANalytical X'pert Pro, scanning the sample from 3 to 35° 2θ. Samples were lightly ground to remove aggregates and mounted in a multiwell plate, supported by Kapton or Mylar polymer film. The multiwell plate was then placed in the diffractometer and analyzed using Cu κ radiation (αλ = 1.54060 Å; α = 1.54443 Å; β = 1.39225 Å; α:α 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 material was weighed into an open aluminum pan and placed in a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and kept at room temperature. The sample was then heated from 20 to 400 °C at a rate of 10 °C / min, during which the change in sample weight and the differential thermal analysis (DTA) were recorded. Nitrogen was used as a purge gas at 300 cm. 3 A flow rate of 1 / min was used.

[0212] Differential scanning calorimetry (DSC) Approximately 5 mg of material was weighed into an aluminum DSC pan and athermally sealed with a perforated aluminum lid. The sample pan was then placed in a Seiko DSC6200 (with a cooler) cooled to 20 °C and maintained there. After a stable heat flow response was obtained, the sample and reference were heated up to 330 °C at a scan rate of 10 °C / min, and the resulting heat flow response was monitored. The purge gas was nitrogen at 50 cm. 3 A flow rate of 1 / min was used. Modulated DSC was performed at an amplitude of 0.32°C and a frequency of 0.017 Hz.

[0213] This specification also includes the following items: Item 1. Formula: [ka] [In the formula, The subscript n is 1 or 2; Each R 1 is a member selected from the group consisting of fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl; wherein at least one R 1 is fluoro; and R 2a and R 2b One of the R is fluoro and the other R 2a and R 2b is H; or, optionally, the subscript n is 1 or 2; Each R 1 is a member selected from the group consisting of fluoro, chloro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 haloalkoxy, optionally substituted C2-C4 alkynyl; wherein at least one R 1 is fluoro; and R 2a and R 2b One of the groups is fluoro, and R 2a and R 2b the other is H] or a pharmaceutically acceptable salt thereof. Item 2.R 2a or a pharmaceutically acceptable salt thereof. Item 3.R 2b or a pharmaceutically acceptable salt thereof. Item 4.R 2a is fluoro and n is 1, or a pharmaceutically acceptable salt thereof. Item 5.R 2a is fluoro and n is 2, or a pharmaceutically acceptable salt thereof. Item 6.R 2b is fluoro and n is 1, or a pharmaceutically acceptable salt thereof. Item 7.R 2b is fluoro and n is 2, or a pharmaceutically acceptable salt thereof. Item 8. The compound according to any one of items 1 to 3, wherein n is 1, or a pharmaceutically acceptable salt thereof. Item 9. Formula: [ka] [In the formula, The subscript n is 1; and R 1 is a member independently selected from the group consisting of fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C2-C4 alkynyl; and R 2a and R 2b One of the is fluoro and R 2a and R 2b the other is H; or, optionally, n is 1; R 1 is a member independently selected from the group consisting of fluoro, chloro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 haloalkoxy, optionally substituted C2-C4 alkynyl; and R 2a and R 2b One of the groups is fluoro, and R 2a and R 2b the other is H] 2. The compound of claim 1, wherein: Item 10. Formula: [ka] 9. The compound of claim 8, wherein: Item 11. n is 2; optionally one R 1 is fluoro and the other is selected from the group consisting of fluoro, C1-C4 alkyl, C2-C4 alkoxy and C2-C4 alkynyl; optionally one R 1 is fluoro and the other is selected from the group consisting of fluoro, methyl, methoxy, and ethynyl; or, optionally, n is 2; and optionally one R 1 is fluoro and the other is selected from the group consisting of fluoro, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkoxy and optionally substituted C2-C4 alkynyl; optionally one R 1 is fluoro and the other is selected from the group consisting of fluoro, hydroxymethyl, methyl, methoxy and ethynyl, or a pharmaceutically acceptable salt thereof. Item 12. n is 2 and optionally the formula: [ka] 4. The compound according to any one of items 1 to 3, wherein: Item 13. One R 1 is 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); or optionally, one R 1is fluoro and the other is selected from the group consisting of fluoro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkynyl; optionally fluoro, hydroxymethyl, methoxy and ethynyl (-C≡CH), optionally methyl, methoxy and ethynyl (-C≡CH), or a pharmaceutically acceptable salt thereof. Item 14. Formula: [ka] 4. The compound according to any one of items 1 to 3, or a pharmaceutically acceptable salt thereof. Item 15.R 1 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); or optionally, R 1 is selected from the group consisting of fluoro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy, optionally substituted C2-C4 alkynyl; optionally fluoro, methyl, methoxy and ethynyl (-C≡CH), optionally methyl, hydroxymethyl, methoxy and ethynyl (-C≡CH), or a pharmaceutically acceptable salt thereof. Item 16. Formula: [ka] 2. The compound of claim 1, wherein: Item 17. Compounds [ka] or a pharmaceutically acceptable salt thereof. Item 18. The compound is [ka] or a pharmaceutically acceptable salt thereof. Item 19. Formula: [ka] 2. The compound of claim 1, wherein: Item 20. Formula: [ka] 2. The compound of claim 1, wherein: Item 21. Formula: [ka] 2. The compound of claim 1, wherein: Item 22. Formula: [ka] 2. The compound of claim 1, wherein: Item 23. Formula: [ka] 2. The compound of claim 1, wherein: Item 24. Formula: [ka] 2. The compound of claim 1, wherein:

[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 is substantially free of alternative isomers at carbon atoms in the phenyl ring. Item 27. The pharmaceutical composition according to Item 25 or 26, wherein the composition is substantially free of alternative isomers at the carbon atom adjacent to the fluorine on the phenyl ring. Item 28. A method for treatment, comprising 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 method for treating hypertrophic cardiomyopathy (HCM) or a heart disease (e.g., a heart disease having pathophysiological characteristics of HCM), comprising 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 the pharmaceutical composition according to any one of Items 25 to 27. Item 30. 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, comprising 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 the pharmaceutical composition according to any one of Items 25 to 27. 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; the method comprising 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 the pharmaceutical composition according to any one of Items 25 to 27, in combination with a therapy aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy). Item 32. A method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease having pathophysiological characteristics associated with HCM), comprising administering to a subject in need of treatment an effective amount 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, in combination with a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptide). and / or a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., an orthotropic inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or cardiac afterload (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 modulators). Item 33. 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 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 treating hypertrophic cardiomyopathy or a cardiac disease (e.g., a cardiac disease having 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 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. Item 36. 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 characterized by left ventricular hypertrophy (e.g., left ventricular hypertrophy due to volume or pressure overload), in combination with a therapy aimed at correcting or alleviating the primary cause of volume or pressure overload (e.g., valve repair / replacement or effective antihypertensive therapy), wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension. 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 treating hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease having pathophysiological characteristics associated with HCM), wherein the compound is administered in combination with a therapeutic agent (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptide) that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation. thrombolytic inhibitors, etc.); therapeutic agents that improve cardiac function by stimulating myocardial contraction (e.g., orthotropic inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapeutic agents that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (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 modulators). 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 product. 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 medicament for treating hypertrophic cardiomyopathy or a cardiac disease (e.g., a cardiac disease having the pathophysiological characteristics of HCM). Item 40. Use 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, for the manufacture of a pharmaceutical 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. Item 41. 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), 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 therapeutic method aimed at correcting or alleviating the primary cause of volume or pressure overload (e.g., valve repair / replacement, effective antihypertensive therapy). Item 42. Therapeutic drugs that slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); therapeutic drugs that improve cardiac function by stimulating myocardial contraction (e.g., orthotropic inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapeutic drugs that reduce cardiac preload (e.g., furosemide). 28. 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 cardiac disease (e.g., a cardiac disease having pathophysiological features associated with HCM), in combination with a therapeutic agent that reduces cardiac afterload (a vasodilator of any class, including, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator). Item 43. At least one of the following: a. A powder X-ray diffraction pattern expressed in terms of angles 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. X-ray crystal structure substantially the same as in Figure 4; 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: Item 44. The polymorph of Item 43, characterized by a powder X-ray diffraction pattern expressed in terms of angles 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. The polymorph of Item 43, characterized by a powder X-ray diffraction pattern having four or more peaks expressed in terms of angles 2θ±0.2° and selected from the following: 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. The polymorph of item 43, characterized by a powder X-ray diffraction pattern having peaks at 11.3, 12.4, and 13.3 degrees expressed in 2θ±0.2 degrees. Item 47. The polymorph of 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 degrees expressed in θ±0.2 degrees. Item 48. The polymorph of item 43 characterized by melting onsets at about 221.51°C, about 299.53°C, and about 308.81°C. Item 49. The polymorph of item 43, wherein the polymorph has a powder X-ray diffraction pattern substantially the same as that shown in FIG. 1A. Item 50. The polymorph of any one of items 43 to 49, wherein Form 1 polymorph is substantially free of other forms of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. 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 Form 1 polymorph to the total amount of another form is equal to or greater than 80:20. Item 53. The composition of item 51, wherein the ratio of the amount of Form 1 polymorph to the total amount of another form is equal to or greater than 90:10. Item 54. The composition of item 51, wherein the ratio of the amount of Form 1 polymorph to the total amount of another form is equal to or greater than 95:5. Item 55. The composition of item 51, wherein the ratio of the amount of Form 1 polymorph to the total amount of another form is equal to or greater than 97:3. Item 56. The composition of item 51, wherein the ratio of the amount of Form 1 polymorph to the total amount of another form is equal to or greater than 98:2. Item 57. The composition of item 51, wherein the ratio of the amount of Form 1 polymorph to the total amount of another form is equal to or greater than 99:1. Item 58. A method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disease having pathophysiological characteristics of HCM, comprising administering to a subject in need thereof 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), characterized by administering to a subject in need thereof an effective amount of the polymorph of any one of Items 43 to 50 or the pharmaceutical composition of any one of Items 51 to 57 in combination with a treatment aimed at correcting or alleviating the primary cause of volume or pressure overload (e.g., valve repair / replacement, effective antihypertensive therapy), wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension. Item 60. A subject in need of treatment is administered an effective amount of the polymorph of any one of Items 43 to 50 or the pharmaceutical composition of any one of Items 51 to 57 in combination with a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a beta-adrenergic agonist, dobutamine, or orthotropic inotropic agents such as the phosphodiesterase inhibitor milrinone; and / or a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or cardiac afterload (including, but not limited to, a vasodilator of any class, e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

[0215] The recitation of a list of chemical groups in a definition of a variable herein includes definitions of those variables as any single group or combination of listed groups.

[0216] Although the above disclosure has been described in detail by way of illustration and example for clarity of understanding, it will be understood by those skilled in the art that certain changes and modifications may be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a discrepancy between the present invention and the references provided herein, the contents of the present invention shall prevail.

Claims

1. formula: 【Chemical 1】 [In the formula, The subscript n is 1 or 2; Each R １ is fluoro, chloro, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ haloalkyl, optionally substituted C １ -C ４ Alkoxy, optionally substituted C １ -C ４ Haloalkoxy and optionally substituted C ２ -C ４ alkynyl; wherein at least one R １ is fluoro; and R ２ａ and R ２ｂ one of which is fluoro, and R ２ａ and R ２ｂ The other is H] or a pharmaceutically acceptable salt thereof.

2. formula: 【Chemistry 2】 [In the formula, The subscript n is 1 or 2; Each R １ is fluoro, chloro, C １ -C ４ Alkyl, C １ -C ４ Haloalkyl, C １ -C ４ Alkoxy, C １ -C ４ Haloalkoxy and C ２ -C ４ alkynyl; wherein at least one R １ is fluoro; and R ２ａ and R ２ｂ one of which is fluoro, and R ２ａ and R ２ｂ The other is H] or a pharmaceutically acceptable salt thereof.

3. R ２ａ is fluoro and R ２ｂ is H or R ２ａ is H and R ２ｂ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is fluoro.

4. R ２ａ 3. The compound of claim 1 or 2, wherein is fluoro and n is 1, or a pharmaceutically acceptable salt thereof.

5. R ２ａ 3. The compound of claim 1 or 2, wherein is fluoro and n is 2, or a pharmaceutically acceptable salt thereof.

6. R ２ｂ 3. The compound of claim 1 or 2, wherein is fluoro and n is 1, or a pharmaceutically acceptable salt thereof.

7. R ２ｂ 3. The compound of claim 1 or 2, wherein is fluoro and n is 2, or a pharmaceutically acceptable salt thereof.

8. 3. The compound according to claim 1 or 2, wherein n is 1, or a pharmaceutically acceptable salt thereof.

9. formula: 【Chemistry 3】 [In the formula, The subscript n is 1; R １ is fluoro, chloro, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ haloalkyl, optionally substituted C １ -C ４ Alkoxy, optionally substituted C １ -C ４ Haloalkoxy and optionally substituted C ２ -C ４ alkynyl; and R ２ａ and R ２ｂ one of which is fluoro, and R ２ａ and R ２ｂ The other is H] 3. The compound according to claim 1 or 2, wherein:

10. n is 1 and the formula: 【Chemistry 4】 3. The compound according to claim 1 or 2, wherein:

11. n is 2 and one R １ is fluoro and the other R １ is fluoro, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ - ４ Alkoxy and optionally substituted C ２ -C ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which may be selected from the group consisting of: alkynyl.

12. n is 2 and the formula: 【Chemistry 5】 3. The compound according to claim 1 or 2, wherein:

13. formula: 【Chemistry 6】 (In the formula, R １ is fluoro, optionally substituted C １ -C ４ Alkyl, optionally substituted C １ -C ４ Alkoxy and optionally substituted C ２ -C ４ alkynyl) 3. The compound according to claim 1 or 2, wherein:

14. R １ 14. The compound of any one of claims 1 to 13, wherein is hydroxyalkyl (e.g., hydroxymethyl).

15. The compound is 【Chemistry 7】 3. The compound of claim 1 or 2, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

16. formula: 【Chemistry 8】 3. The compound according to claim 1 or 2, wherein:

17. formula: 【Chemistry 9】 3. The compound according to claim 1 or 2, wherein:

18. formula: 【Chemistry 10】 3. The compound according to claim 1 or 2, wherein:

19. formula: 【Chemistry 11】 3. The compound according to claim 1 or 2, wherein:

20. formula: 【Chemistry 12】 3. The compound according to claim 1 or 2, wherein:

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

22. The compound has the formula Ia: 【Chemistry 13】 22. The pharmaceutical composition of claim 21, wherein

23. The compound has the formula Ib: 【Chemistry 14】 22. The pharmaceutical composition of claim 21, wherein

24. The compound has the formula Ic: 【Chemistry 15】 22. The pharmaceutical composition of claim 21, wherein

25. The compound has the formula Id: 【Chemistry 16】 22. The pharmaceutical composition of claim 21, wherein

26. The compound is 【Chemistry 17】 22. The pharmaceutical composition of claim 21, selected from the group consisting of:

27. A method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disease having pathophysiological characteristics of HCM, comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

28. A method for treating a disease or disorder selected from the group consisting of heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, comprising administering an effective amount of the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

29. 21. A method for treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload, comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof in combination with a therapeutic method aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., valve repair / replacement, effective antihypertensive therapy), wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension.

30. A method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disease having pathophysiological characteristics associated with HCM, comprising administering to a subject in need thereof a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a beta-adrenergic agonist, dobutamine, or phosphatase); 21. A method of treatment comprising administering an effective amount of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, in combination with an orthotropic inotropic agent such as the phosphodiesterase inhibitor milrinone; and / or a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (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 modulators).

31. At least one of the following: a. a powder X-ray diffraction pattern expressed in terms of angles 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. X-ray crystal structure substantially the same as in Figure 4; 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:

32. 32. The polymorph of claim 31 characterized by a powder X-ray diffraction pattern expressed in angles 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°.

33. 32. The polymorph of claim 31, characterized by a powder X-ray diffraction pattern expressed in degrees 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°.

34. 32. The polymorph of claim 31, characterized by a powder X-ray diffraction pattern having peaks at 11.3, 12.4 and 13.3 degrees, expressed in degrees 2θ±0.2 degrees.

35. 44. The polymorph of claim 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 degrees, expressed in degrees 2θ±0.2 degrees.

36. 32. The polymorph of claim 31, characterized by an onset of melting at about 221.51°C, about 299.53°C, and about 308.81°C.

37. 32. The polymorph of claim 31 , wherein the polymorph has a powder X-ray diffraction pattern substantially the same as FIG. 1A.

38. 38. The polymorph of any one of claims 31-37, wherein the Form 1 polymorph is substantially free of other forms of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

39. 39. A pharmaceutical composition comprising the polymorph of any one of claims 31 to 38 and a pharmaceutically acceptable excipient.

40. 40. The composition of claim 39, wherein the ratio of the amount of Form 1 polymorph to the total amount of the other forms is equal to or greater than 80:

20.

41. 40. The composition of claim 39, wherein the ratio of the amount of Form 1 polymorph to the total amount of the other forms is equal to or greater than 90:

10.

42. 40. The composition of claim 39, wherein the ratio of the amount of Form 1 polymorph to the total amount of the other forms is equal to or greater than 95:

5.

43. 40. The composition of claim 39, wherein the ratio of the amount of Form 1 polymorph to the total amount of the other forms is equal to or greater than 97:

3.

44. 40. The composition of claim 39, wherein the ratio of the amount of Form 1 polymorph to the total amount of the other forms is equal to or greater than 98:

2.

45. 40. The composition of claim 39, wherein the ratio of the amount of Form 1 polymorph to the total amount of the other forms is equal to or greater than 99:

1.

46. 46. ​​A method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having pathophysiological characteristics of HCM, comprising administering to a subject in need thereof an effective amount of the polymorph of any one of claims 31 to 38 or the pharmaceutical composition of any one of claims 39 to 45.

47. 46. ​​A method for treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload in combination with a therapeutic method aimed at correcting or alleviating the primary cause of the volume or pressure overload (e.g., valve repair / replacement, effective antihypertensive therapy), characterized by administering to a subject in need thereof an effective amount of the polymorph of any one of claims 31 to 38 or the pharmaceutical composition of any one of claims 39 to 45, wherein the disease or disorder is selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis and chronic systemic hypertension.

48. An effective amount of the polymorph of any one of claims 31 to 38 or the pharmaceutical composition of any one of claims 39 to 45 is administered to a subject in need of treatment in combination with a therapeutic agent that slows the progression of heart failure and prevents cardiac remodeling by downregulating neurohormonal stimulation of the heart (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor); a therapeutic agent that improves cardiac function by stimulating myocardial contraction (e.g., a beta-adrenergic agonist dobutamine or and / or a therapeutic agent that reduces cardiac preload (e.g., a diuretic such as furosemide) or a therapeutic agent that reduces cardiac afterload (including, but not limited to, a vasodilator of any class, e.g., a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

49. 46. ​​A method for treating a cardiac disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to any one of claims 21 to 26, a polymorph according to any one of claims 31 to 38, or a pharmaceutical composition according to any one of claims 39 to 45, wherein the cardiac disease or disorder is selected from the group consisting of diastolic dysfunction, hypertrophic cardiomyopathy, nHCM, oHCM, heart failure, HFpEF, HFmREF, valvular disease, aortic stenosis, left ventricular hypertrophy, restrictive cardiomyopathy, inflammatory cardiomyopathy, Loeffler's endocarditis, endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, angina pectoris, refractory angina pectoris, and Chagas' disease.

50. 50. The method of claim 49, wherein the cardiac disease or disorder is selected from the group consisting of nHCM, oHCM, HFpEF, HFmREF, aortic stenosis, Loeffler's endocarditis, endocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry's disease, glycogen storage disease, tetralogy of Fallot, angina pectoris, refractory angina pectoris, and Chagas' disease.

51. 51. The method of any one of claims 49-50, wherein the compound or a pharmaceutically acceptable salt, polymorph or pharmaceutical composition thereof is administered as a monotherapy.

52. 51. The method of any one of claims 49-50, wherein the compound or a pharmaceutically acceptable salt, polymorph, or pharmaceutical composition thereof is administered as a combination therapy, wherein an additional therapeutic agent is administered.

53. The additional therapeutic agent may be a beta-adrenergic blocker (beta-blocker), a renin-angiotensin-aldosterone system (RAAS) inhibitor (e.g., angiotensin receptor blockers such as angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers), angiotensin receptor neprilysin inhibitors (ARNIs) (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), an orthotropic inotropic agent (e.g., digoxin, pimobendan, beta-adrenergic receptor agonist; e.g., 53. The method of claim 52, wherein the therapeutic agent is selected from the group consisting of dobutamine, a phosphodiesterase (PDE)-3 inhibitor such as 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 antiarrhythmic agent, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent, a sodium-glucose cotransporter 2 (SGLT2) inhibitor (e.g., empagliflozin, dapagliflozin, sotagliflozin), or a combination thereof.

54. Angiotensin II receptor blockers (ARBs) include A-81988, A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, candesartan, candesartan cilexetil, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, E-4177, elisartan, EMD-66397, EMD-73495, eprosartan, EXP-063, EXP-929, EXP- 3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, Irbesartan, Isoteorin, KRI-1177, KT3-671 , KW-3433, losartan, LR-B / 057, L-158809, L-158978, L-159282, L-159874, L-16117 7, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LR B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin acetate, S-8307, S-8308, SC-52458, saprisartan, saralasin, salmesin, SL-91 54. The method of claim 53, wherein the steroid hormone is selected from the group consisting of .0102, tasosartan, telmisartan, UP-269-6, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360, X-6803, valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155, ZD-8731 and zolasartan.

55. 54. The method of claim 53, wherein the ARNI is selected from the group consisting of sacubitril, valsartan, or a combination of sacubitril and valsartan (sacubitril / valsartan).

56. 54. The method of claim 53, wherein SGLT2 is selected from the group consisting of empagliflozin, dapagliflozin, and sotagliflozin.

57. 53. The method of claim 52, wherein the additional therapeutic agent improves a cardiovascular condition in the subject.

58. 58. The method of any one of claims 52, 53 and 57, wherein 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.

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