Bicyclic pyrimidinedione compounds substituted with tetrahydropyran (THP)

Abstract

The present application provides novel tetrahydropyran (THP) substituted bicyclic pyrimidinedione compounds which are useful for treating hypertrophic cardiomyopathy (HCM), conditions associated with left ventricular hypertrophy, conditions associated with diastolic dysfunction and / or symptoms associated therewith. The synthesis and characterization of the compounds are described, as well as methods for treating HCM and other forms of heart disease.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 62 / 752,278, filed on October 29, 2018, entitled “Tetrahydropyran (THP)-Substituted Bicyclic-pyrimidinedione Compounds,” which is incorporated herein by reference in its entirety. Existing technology

[0003] Genetic (inherited) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, monogenic, autosomal dominant heart muscle disorders. HCM is caused by one or more of the more than 1,000 known point mutations in any of the genes for structural proteins that contribute to the sarcomere, the functional unit of the heart muscle. Approximately 1 in 500 individuals in the general population are found to have left ventricular hypertrophy that is unexplained by other known causes (such as hypertension or valvular disease), and many of these individuals may be shown to have HCM once other genetic (such as lysosomal storage diseases), metabolic, or infiltrative causes have been ruled out.

[0004] The sarcomere gene mutations that cause HCM are highly penetrant, but there is wide variability in clinical severity and clinical course. Some genotypes are associated with more malignant processes, but there is considerable variability between families carrying the same mutation and even within families. Gender differences have also been noted, with male patients generally being more severely affected than female patients. Although many HCM patients report minimal symptoms or no symptoms for extended periods of time, HCM is a progressive disease with a significant cumulative burden of morbidity. Symptoms of effort intolerance are dominant and can be aggravated by exercise and other actions that increase heart rate and / or reduce preload. Like many other diseases, symptoms tend to worsen with age. To date, the most common clinical burden for HCM patients is exercise-induced dyspnea, which limits the patient's daily activities and can be debilitating.

[0005] HCM patients often have symptoms without documented hemodynamic abnormalities, such as left ventricular outflow tract obstruction (with or without mitral regurgitation). Patients' symptoms of exertional dyspnea can rapidly worsen with the onset of atrial fibrillation, a common HCM complication that can precipitate acute pulmonary edema and increase the risk of systemic arterial thromboembolic disease, including stroke. Other adverse events associated with HCM include intolerance to hypovolemia or hypervolemia, and syncope. Concomitant coronary artery disease confers a higher risk of acute coronary syndrome compared to patients without HCM. Sudden cardiac death (SCD) in HCM patients is uncommon and difficult to predict, but is the leading cause of non-traumatic death in adolescents. For SCD survivors, ICD implantation is standard practice, and risk profiling in other HCM patients is not accurately used to identify those patients for whom ICD implantation for primary prevention is considered prudent.

[0006] Medical therapies for HCM are limited to symptomatic treatment and do not address the underlying underlying cause of the disease - the destruction of normal sarcomere function. Currently available therapies can variably effectively alleviate symptoms, but typically show that efficacy decreases as the disease duration increases. Patients are therefore empirically managed with beta-blockers, non-dihydropyridine calcium channel blockers and / or disopyramide. None of these agents carry a labeling indication for the treatment of HCM, and essentially no rigorous clinical trial evidence is available for guiding its use. The fact that new medical therapies for HCM have not yet been identified over the years exacerbates this unfortunate situation. For patients with hemodynamically significant outflow tract obstruction (resting gradient>30mmHg), surgical myectomy or alcohol septal ablation is usually required in appropriately selected patients to alleviate hemodynamic obstruction. The present application provides new therapeutic agents and methods for remedying the long-term needs for the treatment of improving HCM and related cardiac disorders and / or diseases. Summary of the Invention

[0007] In one aspect, a compound having formula (I) is provided:

[0008]

[0009] or a pharmaceutically acceptable salt thereof, wherein

[0010] Subscript n is 1 or 2;

[0011] Each R 1 is a member selected from the group consisting of fluorine, chlorine, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl; wherein at least one R 1 is fluorine; and

[0012] R 2aand R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0013] In one aspect, a compound having formula (I) is provided:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein

[0016] Subscript n is 1 or 2;

[0017] 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, and optionally substituted C2-C4 alkynyl; wherein at least one R 1 is fluorine; and

[0018] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0019] In another aspect, provided is Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione ("Form 1 polymorph"). In another aspect, the Form 1 polymorph is characterized by at least one of the following:

[0020] a. a powder X-ray diffraction pattern having two or more peaks expressed in degrees 2θ ± 0.2° 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;

[0021] b. a DSC thermogram showing endotherms at about 226.05 ° C, at about 302.47 ° C, and at about 310.13 ° C; or

[0022] c. X-ray crystal structure essentially the same as that in FIG4 .

[0023] In another aspect, the present application 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.

[0024] In some aspects, the present application provides a method for treating a cardiac disease or condition in an individual in need thereof, the method comprising administering an effective amount of a compound as described herein to the individual. In some aspects, diastolic dysfunction is a characteristic of a cardiac disease or condition and / or is associated with a cardiac disease or condition. For example, a cardiac disease or condition may be cardiomyopathy (e.g., hypertrophic cardiomyopathy), heart failure (e.g., ejection fraction-preserving heart failure, ejection fraction mid-range heart failure), valvular disease (e.g., valvular aortic stenosis), congenital heart disease (e.g., tetralogy of Fallot), left ventricular hypertrophy, angina (e.g., refractory angina), or Chagas disease.

[0025] In certain aspects, the present application provides a method of treating a cardiac disease or condition, comprising administering to a subject in need thereof an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition as described herein, or a polymorph as described herein, wherein the cardiac disease or condition is selected from the group consisting of: diastolic dysfunction, hypertrophic cardiomyopathy, nHCM, oHCM, heart failure, HFpEF, HFmREF, valvular disease, aortic stenosis, left ventricular hypertrophy, restrictive cardiomyopathy, inflammatory cardiomyopathy, Loeffler endocarditis, endomyocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, angina pectoris, refractory angina, and Chagas' disease. In certain aspects, the cardiac disease or disorder is selected from the group consisting of nHCM, oHCM, HFpEF, HFmREF, aortic stenosis, Loeffler's endocarditis, endomyocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, tetralogy of Fallot, angina pectoris, refractory angina, and Chagas' disease.

[0026] In some aspects, the present application provides a method of treating a cardiac disease or condition, comprising administering to a subject in need thereof an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition as described herein, or a polymorph as described herein, wherein the compound or its pharmaceutically acceptable salt, polymorph, or pharmaceutical composition is administered as a monotherapy.

[0027] In some aspects, the present application provides a method of treating a cardiac disease or condition, comprising administering to a subject in need thereof an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition as described herein, or a polymorph as described herein, wherein the compound or its pharmaceutically acceptable salt, polymorph, or pharmaceutical composition is administered as a combination therapy, wherein an additional therapeutic agent is administered. In certain aspects, the additional therapeutic agent is selected from the group consisting of: beta-adrenergic blockers (β-blockers), renin-angiotensin-aldosterone system (RAAS) inhibitors (e.g., angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor antagonists, such as 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, spironolact ... ironolactone or canrenone), cholesterol-lowering drugs (e.g., statins), neutral endopeptidase inhibitors (NEPi), inotropic agents (e.g., digoxin; pimobendane; beta-adrenergic receptor agonists such as dobutamine; phosphodiesterase (PDE)-3 inhibitors such as milrinone; or calcium sensitizers such as levosimendan), potassium, magnesium, proprotein convertase subtilisin (Kexin) 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), arrhythmia drugs, anticoagulants (e.g., warfarin), antithrombotic agents, antiplatelet agents, sodium-glucose co-transporter 2 inhibitors (SGLT2) (e.g., empaglifozin, dapagliflozin, sotagliflozin), or any combination thereof. In some aspects, the additional therapeutic agent is an angiotensin II receptor blocker (ARB) selected from the group consisting of: A-81988, A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, candesartan, candesartan cilexetil,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-0 056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan, isoteoline, KRI-1177, KT3-671, KW-3433, losartan, LR-B / 057, L-158809, L-158978, L-159282, L-159874, L-161177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LR B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralamin acetateacetate), S-8307, S-8308, SC-52458, saprisartan, saralasin, sarmesin, SL-91.0102, tasosartan, telmisartan, UP-269-6, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360, X-6803, valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155, ZD-8731, and zolasartan. In some aspects, the additional therapeutic agent is an ARNI selected from the group consisting of: sacubitril, valsartan, or a combination of sacubitril and valsartan (sacubitril / valsartan). In some aspects, the additional therapeutic agent is an SGLT2 selected from the group consisting of: empagliflozin, dapagliflozin and sogliaflozin. In some aspects, the additional therapeutic agent improves the cardiovascular conditions of the individual. In certain aspects, 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 blockers, mineralocorticoid receptor antagonists, ARNI, RAAS inhibitors, arrhythmia drugs and SGLT2 inhibitors.

[0028] In another aspect, the present application provides a method for preventing or treating a disease or condition in which diastolic dysfunction exists or is an important feature, including but not limited to hypertrophic cardiomyopathy (HCM), or a cardiac disease with the pathophysiological characteristics of HCM, or a symptom thereof. The method comprises administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need. In yet another aspect, the disease is selected from the group consisting of obstructive HCM, non-obstructive HCM, heart failure with preserved ejection fraction (HFpEF) (including but not limited to diabetic HFpEF) and hypertension. The disease may be acute, chronic and / or stable. In yet another aspect, the disease is selected from the group consisting of Class I HCM, Class II nHCM, Class III nHCM, Class II oHCM and Class III oHCM.

[0029] In another aspect, the present application provides a method for preventing or treating a disease or condition selected from the group consisting of heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris and restrictive cardiomyopathy, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0030] In another aspect, the present application provides a method for preventing or treating a disease or condition characterized by left ventricular hypertrophy due to volume or pressure overload, wherein the disease or condition is selected from the group consisting of chronic mitral valve 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, including valve repair / replacement or effective antihypertensive therapy, the method comprising administering to an individual in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0031] In another aspect, the present application provides a method for preventing or treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder with pathophysiological features associated with HCM, or its symptoms, 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 the following therapies: therapies that delay the progression of heart failure and attempt to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and therapies that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). HCM can be obstructive HCM (oHCM) or non-obstructive HCM (nHCM).

[0032] In another aspect, a pharmaceutical composition is provided, comprising the Form 1 polymorph and a pharmaceutically acceptable excipient.

[0033] In another aspect, a method of treating hypertrophic cardiomyopathy (HCM) or a cardiac condition with pathophysiological features of HCM is provided, the method 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.

[0034] In another aspect, a method of treating a disease or condition characterized by left ventricular hypertrophy due to volume or pressure overload selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension is provided; in combination with a therapy directed to correcting or alleviating the primary cause of volume or pressure overload, including valve repair / replacement or effective antihypertensive therapy, the method 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.

[0035] In another aspect, a method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder with pathophysiological features associated with HCM is provided, the method 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 therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart (e.g., an ACE inhibitor, angiotensin receptor blocker (ARB), a beta-blocker, aldosterone receptor antagonist, or a neuropeptidase inhibitor); a therapy that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotrope, such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapy that reduces cardiac preload (e.g., a diuretic, such as furosemide) or afterload (a vasodilator of any kind, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). This application is intended to include all isotopically labeled analogs of compounds of formula (I). Isotopes include those atoms having the same atomic number but different masses. For example, hydrogen isotopes include 2 H(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 various uses, such as, but not limited to, standards and reagents for determining biological / pharmacological activity. For those stable isotopically labeled compounds of Formula (I), they can also advantageously modulate biological, pharmacological, or pharmacokinetic properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] 1A to 1C show X-ray powder diffraction (XRPD) data for the Form 1 polymorph of the compound of Examples 1-3 (also referred to as Compound 3).

[0037] FIG2 shows a dynamic scanning calorimetry (DSC) graph of Form 1 polymorph of the compound of Examples 1-3 (also referred to as Compound 3).

[0038] Figure 3 shows the thermogravimetric analysis (TGA) of the Form 1 polymorph of the compound of Examples 1-3 (also referred to as Compound 3).

[0039] FIG4 shows the crystal structure of the Form 1 polymorph of the compound of Examples 1-3 (also referred to as Compound 3) obtained by single crystal X-ray diffraction.

[0040] Implementation Method

[0041] A series of tetrahydropyran (THP)-substituted bicyclic pyrimidinedione compounds have been found to reduce excessive contractile force in hypercontractile states and / or promote cardiac relaxation in hearts with diastolic dysfunction. Without being bound by theory, it is believed that these compounds stabilize the conformation of beta cardiac myosin after ATP hydrolysis but before it binds strongly to actin filaments and releases phosphate, thereby reducing the proportion of myosin molecules available to participate in the "power stroke" portion of the muscle contraction cycle. Thus, the compounds can improve cardiac elasticity, reduce dynamic and / or static left ventricular outflow obstruction, improve diastolic left ventricular relaxation, reduce left ventricular diastolic (filling) pressure, reduce functional mitral valve regurgitation, and / or reduce left atrial and pulmonary capillary wedge pressure in HCM patients, helping to overcome the debilitating exertional dyspnea and / or symptoms attributable to left ventricular outflow obstruction (presyncope or syncope) that often accompanies the disease. The preferred compounds of the present application have been optimally designed to have a relatively short half-life in humans. For example, certain compounds of the present application are expected to have a half-life of less than 7 days (e.g., less than 5 days, less than 4 days) in humans. The compounds described herein have been designed to reduce the appearance of reactive metabolites after testing, reduce dependence on polymorphic CYP enzymes (such as CYP 2C19), and / or eliminate or reduce the risk of CYP induction (such as CYP3A4 induction). Some other benefits of the compounds of the present application relate to the selectivity of cardiac myosin inhibition compared to skeletal myosin and / or the desired time course of the intensity of action in response to the administered drug dose. In addition, the compounds of the present application have beneficial solubility, for example, a micromolar solubility of greater than 50, such as greater than 70, at pH 7.4. In some cases, the compounds of the present application have a micromolar solubility of greater than 80, such as greater than 90. The compounds may also be used to treat other cardiac conditions.

[0042] As used herein, the term "about" is used to describe a range (e.g., a temperature range, a mass range, a weight range) and is given its ordinary meaning in the art, typically relating to the error associated with the instrument used to collect the measurement or reading. Generally, the term "about" provides a deviation of ±0-2°C when referring to temperature.

[0043] As used herein, the term "alkyl" refers to a straight or branched chain, saturated, aliphatic group having the indicated number of carbon atoms. Alkyl groups may include any number of carbon atoms, such as C 1-2 、C 1-3 、C 1-4 、C 2-3 、C 2-4 and C 3-4 For example, C 1-4Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In some cases, an alkyl group is optionally substituted. In some cases, an alkyl group is unsubstituted. In some aspects, an alkyl group is substituted. Alkyl substituents include, but are not limited to, any of the substituents described herein that form a stable moiety. In certain aspects, a substituent may be one or more hydroxyl groups. In some such cases, an alkyl group may also be referred to as a hydroxyalkyl group. As used herein, the term "hydroxyalkyl" refers to an alkyl group as provided above, in which at least one hydrogen atom of the hydrocarbon portion is replaced by a hydroxyl group (-OH). Thus, "hydroxyalkyl" refers to, for example, hydroxymethyl, 2-hydroxyethyl, and 2-hydroxypropyl.

[0044] As used herein, the term "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight or branched aliphatic group. The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, and the like. Alkynyl groups can be substituted or unsubstituted.

[0045] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic ring containing three or four ring atoms, or the number of atoms indicated. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl or cyclobutyl. Cycloalkyl groups can also be partially unsaturated, having one or more double bonds in the ring. Representative partially unsaturated cycloalkyl groups include cyclobutene. Unless otherwise specified, cycloalkyl groups are unsubstituted.

[0046] As used herein, the term "alkoxy" refers to an alkyl group with an oxygen atom connecting the alkyl group to the point of attachment: that is, alkyl-O-. With respect to the alkyl portion, the alkoxy group can have any suitable number of carbon atoms, such as C 1-2 or C 1-4 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. Alkoxy groups may be optionally substituted (unsubstituted or substituted).

[0047] The terms "halo" and "halogen" as used herein refer to fluoro, chloro, bromo and iodo.

[0048] As used herein, the terms "haloalkyl" and "haloalkoxy" refer to alkyl and alkoxy groups as provided above, wherein at least one hydrogen atom of the hydrocarbon portion is replaced by a halogen atom. In addition, the terms may also refer to perhalogenated forms of alkyl and alkoxy groups. 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.

[0049] When a range of values ​​is listed, it is intended to include each value and sub-range within that range. For example, "C 1-6 "Alkyl" is intended to encompass 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.

[0050] It will be understood that the above-mentioned groups and / or compounds described herein may be optionally substituted with any number of substituents or functional moieties. That is, any of the above-mentioned groups may be optionally substituted. As used herein, the term "optionally substituted" is intended to include unsubstituted and / or substituted variations (that is, "optionally substituted" can be used interchangeably with "substituted or unsubstituted"). As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds, "permissible" being within the context of chemical rules of valence known to those skilled in the art. In general, the term "substituted," whether preceded by the term "optionally" or not, and the substituents contained in the formulae of this application, refers to the replacement of a hydrogen radical in a given structure with a radical of a specified substituent. When more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents at each position may be the same or different. It will be understood that "substituted" also includes substitutions that result in stable compounds, for example, compounds that do not spontaneously undergo transformations, such as by rearrangement, cyclization, elimination, etc. In some cases, "substituted" may generally refer to the replacement of a hydrogen radical with a substituent as described herein. However, as used herein, "substituted" does not encompass the replacement and / or change of key functional groups used to identify molecules, for example, such that the "substituted" functional group becomes a different functional group via substitution. For example, a "substituted phenyl" must still contain a phenyl moiety and cannot be modified to become, for example, a pyridine ring by substitution in this definition. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein. For appropriate organic compounds, permissible substituents may be one or more and the same or different. For the purposes of this application, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatoms. In addition, this application is not intended to be limited in any way by the permissible substituents of organic compounds. The term "stable" as used herein preferably refers to compounds that possess stability sufficient to allow manufacturing and maintain the integrity of the compound for a period of time sufficient to be detected and preferably for a period of time sufficient to be suitable for the purposes detailed herein.

[0051] Examples of substituents include, but are not limited to, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxy, alkoxy, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, -CF3, -CN, aryl, aryloxy, perhaloalkoxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkyl alkylamino, alkylsulfonyl, alkylaminoalkylaryl, alkylaminoalkylaryl, alkyloxyaryl, arylamino, arylalkylamino, alkylsulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxyl-, aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl, arylalkoxyalkyl and the like.

[0052] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, consistent with a reasonable benefit / risk ratio, within the scope of sound medical judgment. Pharmaceutically acceptable substances are compatible with the compound of formula (I) and any other ingredients formulated with the compound.

[0053] 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 from, for example, inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, and the like), organic acids (e.g., acetic acid, propionic acid, glutamic acid, citric acid, and the like), and quaternary ammonium ions. It should be understood that pharmaceutically acceptable salts are non-toxic.

[0054] Some aspects of the compounds of the present invention may contain one or more basic functional groups and therefore can form pharmaceutically acceptable salts with pharmaceutically acceptable acid. In such cases, pharmaceutically acceptable salts can be relatively nontoxic, inorganic and organic acid addition salts of the compound of the present application. These salts can be prepared on site during administration of a vehicle or dosage form manufacturing process, or by reacting the purified compound of the present application in the form of a free alkali independently with a suitable organic acid or inorganic acid, and separating the salt thus formed during subsequent purification to prepare. The non-limiting examples of salt include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate (napthylate), mesylate, glucoheptanoate, lactobionate and lauryl sulfonate and its analogue. (See, e.g., Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19)

[0055] Pharmaceutically acceptable salts of the compounds described herein include non-toxic salts or quaternary ammonium salts of the compounds, for example, from non-toxic organic or inorganic acids. For example, such non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and salts prepared 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, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, and the like.

[0056] In some cases, the compound of the present application may contain one or more acidic functional groups and therefore can form a pharmaceutically acceptable salt with a pharmaceutically acceptable base. In such cases, a pharmaceutically acceptable salt can be a relatively non-toxic, inorganic and organic base addition salt of the compound of the present application. These salts can also be prepared on site during the administration of a drug delivery vehicle or a dosage form manufacturing process, or by reacting the purified compound in the form of a free acid independently with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine. Non-limiting examples of alkali metal salts or alkaline earth metal salts include lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like. Non-limiting examples of organic amines suitable for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

[0057] Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, and Berge et al., “Pharmaceutical Salts”, J. Pharm. Sci. 1977, 66, 1-19, which are incorporated herein by reference.

[0058] 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 form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.

[0059] Certain compounds of the present invention have asymmetric carbon atoms (chiral centers) or double bonds; racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are intended to be encompassed within the scope of the present invention. When a stereochemical drawing is shown, it is intended that one of the isomers is present and substantially free of the other isomers. "Substantially free" of the other isomers indicates that at least about 80% of the disclosed isomer should be present, more preferably at least about 90%, such as about 95% or greater, based on the molar concentration of all isomeric forms of the disclosed isomer present. The depicted isomer may be present in an amount of at least about 99%. For example, when a disclosed isomer is provided in a pharmaceutical composition, the composition may contain at least about 99% of the disclosed isomer in the pharmaceutical composition, based on the total molar concentration of all isomeric forms of the disclosed compound present in the pharmaceutical composition (including the disclosed isomer and all other isomeric forms).

[0060] 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 an excipient as defined herein, and / or other optional ingredients in specified amounts, as well as any product that results directly or indirectly from the combination of specified ingredients in specified amounts.

[0061] As used herein, the term "excipient" refers to a substance that aids in the administration of an active agent to a subject. Pharmaceutical excipients suitable for use in the present application include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorants. One skilled in the art will recognize that other excipients may be suitable for use in the present application.

[0062] As used herein, the terms "treat" and "treatment" refer to any marker of success in treating or ameliorating a disease, injury, condition, or symptom associated with a disease or disorder (e.g., a cardiac disorder with pathophysiological features of HCM), including any objective or subjective parameter, such as elimination; remission; reduction of symptoms; making the disease, injury, condition, or symptom more tolerable to the patient; or reducing the frequency or duration of the disease, injury, condition, or symptom. Treatment or improvement can be based on any objective or subjective parameter, including, for example, the results of a physical examination.

[0063] As used herein, the terms "prevent" and "prevention" refer to the prophylactic treatment of an individual who does not have and has not yet had a disease, injury, condition, or symptom associated with a disease or disorder (e.g., a cardiac disorder with pathophysiological features of HCM), but is at risk of developing the disease, injury, condition, or symptom; or who has a disease, injury, condition, or symptom, does not have the disease, injury, condition, or symptom, but is at risk of regression of the disease, injury, condition, or symptom. In certain aspects, the individual is at a higher risk of developing the disease, injury, condition, or symptom, or is at a higher risk of regression of the disease, injury, condition, or symptom compared to an average healthy member of the population. In some aspects, prevention refers to preventing the onset of the disease, injury, condition, or symptom.

[0064] An "effective amount" or "pharmaceutically effective amount" is an amount sufficient to achieve the stated purpose (e.g., to achieve the effect for which it is administered, to treat a disease, to reduce enzyme activity, to reduce one or more symptoms of a disease or condition, to reduce viral replication in a cell). An example of an "effective amount" is an amount sufficient to contribute to the treatment or reduction of one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount." "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) means a decrease in the severity or frequency of one or more symptoms, or the elimination of one or more symptoms.

[0065] The term "subject" contemplated for administration refers to a human (i.e., a male or female of any age group, such as a pediatric subject (e.g., an infant, child, or adolescent) or an adult subject (e.g., a young adult, middle-aged, or elderly person)) or a non-human animal. A "patient" refers to a human subject in need of treatment for a disease.

[0066] Hypertrophic cardiomyopathy (HCM) is clinically identified as unresolved left ventricular (LV) hypertrophy in the absence of a known cause, such as pressure overload, systemic disease, or infiltrative process. A phenotypic characteristic of HCM is hypercontractility of the myocardium, accompanied by reduced LV compliance, which is clinically reflected in reduced ventricular cavity size, often an abnormal ejection fraction, increased wall thickness, and diastolic dysfunction. Some symptoms and signs that patients with HCM have include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), fainting (especially during or just after exercise), a sensation of rapid, trembling, or racing heartbeats, and heart murmurs.

[0067] Obstructive HCM (oHCM), also known as hypertrophic obstructive cardiomyopathy (HOCM), refers to HCM with left ventricular outflow tract obstruction (LVOT).

[0068] Non-obstructive HCM (nHCM) refers to HCM without outflow obstruction at rest or after provocation.

[0069] Heart failure refers to a clinical syndrome in which a patient's heart is unable to provide enough blood to the body. For some people with heart failure, the heart has difficulty pumping enough blood to support other organs in the body. For others, they may have hardening and stiffening of the heart muscle itself, which blocks or reduces blood flow to the heart. Heart failure can affect the right or left side of the heart, or both sides at the same time. Heart failure can be an acute (short-term) or chronic (persistent) condition. Symptoms of heart failure include, but are not limited to, excessive fatigue, sudden weight gain, loss of appetite, persistent cough, irregular pulse, palpitations, abdominal distension, shortness of breath, swelling of the legs and ankles, prominent neck veins, and edema.

[0070] Heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure or diastolic failure, refers to heart failure when the heart's ejection fraction is normal (e.g., greater than or equal to 50%). Often, the heart muscle contracts normally during ventricular filling, but the ventricles do not relax as they should, resulting in a reduced stroke volume.

[0071] Stable diastolic heart failure refers to an asymptomatic acute exacerbation of diastolic heart failure in patients with impaired diastolic function whose symptoms can be controlled or stabilized using available therapies.

[0072] Diastolic dysfunction refers to abnormal diastolic function. Abnormal diastolic function includes impaired left ventricular relaxation, filling, diastolic dilation, or stiffness. These traits can be measured using echocardiography. Further determination of factors for diagnosing diastolic dysfunction using echocardiography is 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 by cardiac magnetic resonance imaging. Cardiac magnetic resonance imaging is used to determine peak filling rate, peak filling time, and peak diastolic strain rate. Individuals with diastolic dysfunction may also exhibit increased levels of biomarkers in the blood. For example, brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-BNP pro) is present at elevated levels in the blood of individuals with diastolic dysfunction.

[0073] 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) - including both conditions of active relaxation and conditions of chamber stiffness (e.g., diabetic HFpEF); ischemic cardiomyopathy, cardiac transplant allograft vasculopathy, restrictive cardiomyopathies (e.g., genetic mutations in one or more sarcomeric proteins), inflammatory cardiomyopathies (e.g., Loefllers disease and EMF), infiltrative cardiomyopathies (e.g., amyloid, sarcoid, and XRT), storage diseases (e.g., hemochromatosis, Fabry disease, and glycogen storage diseases), congenital heart disease (e.g., pressure-overloaded RV), tetralogy of Fallot (e.g., preoperative and early postoperative diastolic dysfunction), and valvular heart disease (e.g., aortic stenosis).

[0074] Class I HCM refers to HCM classified as class I according to the New York Heart Association (NYHA).

[0075] Class II-III nHCM refers to nHCM classified as class II or III according to the NYHA.

[0076] Class II-III oHCM refers to oHCM classified as class II or III according to the NYHA.

[0077] NYHA Class I refers to a classification in which a patient or individual has no limitations in physical activity and ordinary physical activity does not cause undue fatigue, palpitations, or dyspnea (shortness of breath).

[0078] NYHA Class II refers to a classification in which a patient or individual has slight limitations in physical activity, is comfortable at rest, and in which ordinary physical activity causes fatigue, palpitations, and dyspnea (shortness of breath).

[0079] NYHA Class III refers to a classification in which a patient or individual has marked limitations in physical activity, is comfortable at rest, and has less than ordinary activity that causes fatigue, palpitations, or dyspnea.

[0080] NYHA Class IV refers to a patient or individual who cannot continue any physical activity without discomfort, has symptoms of heart failure at rest, and whose discomfort increases if any physical activity is initiated.

[0081] As used herein, "Valsalva gradient" refers to the pressure gradient across the LVOT in a subject while the subject performs the Valsalva maneuver.

[0082] III. Compounds

[0083] In one aspect, provided herein is a compound having formula (I):

[0084]

[0085] or a pharmaceutically acceptable salt thereof, wherein

[0086] Subscript n is 1 or 2;

[0087] Each R 1 is a member independently selected from the group consisting of fluorine, chlorine, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl; wherein at least one R 1 is fluorine; and

[0088] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0089] R 2a It can be fluorine. 2b It can be fluorine. When n is 1, R 2a It can be fluorine. When n is 2, R 2a It can be fluorine. When n is 1, R 2b It can be fluorine. When n is 2, R 2b It may be fluorine.

[0090] In one aspect, provided herein is a compound having formula (I):

[0091]

[0092] or a pharmaceutically acceptable salt thereof, wherein

[0093] Subscript n is 1 or 2;

[0094] 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, and optionally substituted C2-C4 alkynyl; wherein at least one R 1 is fluorine; and

[0095] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0096] R 2a It can be fluorine. 2b It can be fluorine. When n is 1, R 2a It can be fluorine. When n is 2, R 2a It can be fluorine. When n is 1, R 2b It can be fluorine. When n is 2, R 2b It may be fluorine.

[0097] Also provided are pharmaceutically acceptable salts of such compounds of formula (I).

[0098] In certain aspects, the compound of formula (I) may have the following formula:

[0099]

[0100] or a pharmaceutically acceptable salt thereof, wherein subscript n is 1; and

[0101] 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

[0102] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0103] In certain aspects, the compound of formula (I) may have the following formula:

[0104]

[0105] or a pharmaceutically acceptable salt thereof, wherein subscript n is 1; and

[0106] 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

[0107] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0108] In some cases, n of the compound of formula (I) is 1. The compound of formula (I) may have the following formula:

[0109]

[0110] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0111] Also provided are pharmaceutically acceptable salts of such compounds of formula (Ib).

[0112] In some cases, n of the compound of Formula (I) is 2. In some cases where n is 2, one R 1 is fluorine and the other R 1 It may be selected from the group consisting of fluorine, C1-C4 alkyl, C1-C4 alkoxy and C2-C4 alkynyl; optionally, fluorine, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH).

[0113] In some cases, n of the compound of Formula (I) is 2. In some cases where n is 2, one R 1 is fluorine and the other R 1 It can be selected from the group consisting of fluorine, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 alkoxy and optionally substituted C2-C4 alkynyl; optionally, fluorine, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH).

[0114] The compound of formula (I) may have the following formula:

[0115]

[0116] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other of is H; and

[0117] Each 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.

[0118] The compound of formula (I) may have the following formula:

[0119]

[0120] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other of is H; and

[0121] 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, and optionally substituted C2-C4 alkynyl.

[0122] In some cases, for Formula (I), one R 1 is fluorine and the other R 1 It may be selected from the group consisting of fluorine, C1-C4 alkyl, C1-C4 alkoxy and C2-C4 alkynyl; optionally, fluorine, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH).

[0123] In some cases, for Formula (I), one R 1 is fluorine and the other R 1 can 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 cases, for Formula (I), one R 1 is fluorine and the other R 1 can be selected from the group consisting of: optionally, fluoro, methyl, methoxy, and ethynyl (-C≡CH); optionally, methyl, methoxy, and ethynyl (-C≡CH). In some cases, for Formula (I), one R 1 is fluorine and the other R 1 is an alkyl group substituted with a hydroxyl group. In some cases, for Formula (I), one R 1 is fluorine and the other R 1 It is hydroxymethyl.

[0124] Also provided are pharmaceutically acceptable salts of such compounds of formula (Ic).

[0125] The compound of formula (I) may have the following formula:

[0126]

[0127] R 1 may be selected from the group consisting of fluorine, C1-C4 alkyl, C1-C4 alkoxy, and C2-C4 alkynyl; optionally, fluorine, methyl, methoxy, and ethynyl (-C≡CH); optionally, methyl, methoxy, and ethynyl (-C≡CH); and

[0128] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0129] The compound of formula (I) may have the following formula:

[0130]

[0131] R 1 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); and

[0132] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other of is H. In certain aspects, R 1 It is hydroxymethyl.

[0133] Also provided are pharmaceutically acceptable salts of such compounds of formula (Id).

[0134] The compound of formula (I) may have the following formula:

[0135]

[0136] In certain aspects, R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0137] Also provided are pharmaceutically acceptable salts of such compounds of formula (Ie).

[0138] The compound of formula (I) may have the following formula:

[0139]

[0140] In some aspects, R 2a and R 2b One of them is fluorine and R 2a and R 2b The other of is H. Also provided are pharmaceutically acceptable salts of such compounds.

[0141] The compound of formula (I) may have the following formula:

[0142]

[0143] or a pharmaceutically acceptable salt thereof.

[0144] The compound may be:

[0145]

[0146] or a pharmaceutically acceptable salt thereof.

[0147] The compound may be: or a pharmaceutically acceptable salt thereof.

[0148] The compounds disclosed above, or pharmaceutically acceptable salts thereof, can be provided (e.g., in pharmaceutical compositions) that are substantially free of other isomers at the carbon atom bearing a benzene ring (i.e., having an absolute configuration different from that disclosed and depicted herein). Alternatively or additionally, the compounds or pharmaceutically acceptable salts thereof can be provided that are substantially free of other isomers at carbon atoms bearing fluorine adjacent to carbon atoms bearing a benzene ring. For example, when provided in a pharmaceutical composition, the composition can be substantially free of other isomers at carbon atoms bearing a benzene ring. Similarly, alternatively or additionally, the composition can be substantially free of other isomers at carbon atoms bearing fluorine adjacent to carbon atoms bearing a benzene ring. In some aspects, substantially free refers to an enantiomeric excess (ee) of ≥95%, ≥98%, ≥99%, or 100% at carbon atoms bearing a fluorine. In some aspects, substantially free refers to an ee of ≥95%, ≥98%, ≥99%, or 100% at carbon atoms bearing fluorine adjacent to carbon atoms bearing a benzene ring. In some aspects, substantially free refers to diastereomeric excess (de) of ≥95%, ≥98%, ≥99%, or 100%.

[0149] In another aspect, provided herein is Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The Form 1 polymorph is characterized by at least one of the following:

[0150] a. a powder X-ray diffraction pattern having two or more peaks expressed in degrees 2θ ± 0.2° 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;

[0151] b. a DSC thermogram showing endotherms at about 226.05 ° C, at about 302.47 ° C, and at about 310.13 ° C; or

[0152] c. An X-ray crystal structure substantially the same as Figure 4. In another aspect, the Form 1 polymorph is characterized by a powder X-ray diffraction pattern having three or more peaks expressed in degrees 2θ ± 0.2° selected from the group consisting of 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5, 32.9, 34.3, 35.5, and 38.8 degrees. In some aspects, the Form 1 polymorph is characterized by a powder X-ray diffraction pattern having four or more peaks expressed in degrees 2θ±0.2° selected from 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5, 32.9, 34.3, 35.5, and 38.8 degrees. In some aspects, the Form 1 polymorph is characterized by a powder X-ray diffraction pattern having peaks expressed in degrees 2θ±0.2° at each of 11.3, 12.4, and 13.3 degrees. In another aspect, the Form 1 polymorph is characterized by a powder X-ray diffraction pattern having peaks at each of 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, and 29.5 degrees, expressed in degrees 2θ ± 0.2°. In another aspect, the Form 1 polymorph is characterized by melting onsets of approximately 221.51°C, approximately 299.53°C, and approximately 308.81°C. In some aspects, the Form 1 polymorph has a powder X-ray diffraction pattern substantially the same as Figure 1A. In some aspects, 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.

[0153] The compounds of formula (I) can be prepared by any suitable method. The compounds can be prepared, for example, by the routes outlined in the examples below. Those skilled in the art will appreciate that the compounds of formula (I) can be prepared using other synthetic methods, including, for example, the transformations described in Larock (Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Wiley, 1999, incorporated herein by reference).

[0154] In another aspect, a pharmaceutical composition is provided herein, which contains a compound of formula (I) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may include a pharmaceutically acceptable excipient. The composition is suitable for treating the pathology of humans and other individuals, such as hypertrophic cardiomyopathy. In some aspects, the pharmaceutical composition further includes an additional agent. Exemplary non-limiting additional agents include agents that delay the progression of heart failure by downregulating cardiac neurohormonal stimulation and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptide chain endonuclease inhibitors); agents that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as β-adrenergic agonists dobutamine or phosphodiesterase inhibitors milrinone); and / or agents that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). In certain aspects, the additional agent in the pharmaceutical composition is a cardiovascular drug. In other aspects, additional exemplary therapeutic agents include beta-adrenergic blocking agents (β-blockers), renin-angiotensin-aldosterone system (RAAS) inhibitors (e.g., angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor antagonists such as angiotensin II receptor blockers), angiotensin receptor neprilysin inhibitors (ARNI) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (MRA) (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), positive inotropic agents (e.g., digoxin; pimobendan; beta-adrenergic receptor agonists such as dobutamine; phosphodiesterase (PDE)-3 inhibitors such as milrinone; or calcium sensitizers such as levosimendan), potassium or magnesium, proprotein convertase subtilisin Kexin a 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 arrhythmia medication, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent, or any combination thereof.Suitable angiotensin II receptor blockers (ARBs) can 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-317 4. EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan, isotrine, 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, Myoproline acetate, S-8307, S-8308, SC-52458, Saprisartan, Myoproline Alaquinoxaline, samaquinoxaline, 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 aspects, the additional therapeutic agent may be an ARNI such as sacubitril / valsartan. or sodium-glucose co-transporter 2 inhibitors (SGLT2), such as empagliflozin (e.g. ), dapagliflozin (e.g. ) or sogliflozin. In some aspects, the subject is administered an additional medication for improving the subject's cardiovascular condition. The additional medication can be, for example, a beta blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor blocker, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, or an arrhythmia medication. In specific aspects, the additional medication is an ANRI, such as sacubitril / valsartan; or an SGLT2 inhibitor.

[0155] In another aspect, provided herein is a pharmaceutical composition comprising the Form 1 polymorph. In some aspects, the pharmaceutical composition comprises a pharmaceutically acceptable excipient. In some aspects, provided herein is a pharmaceutical composition wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 80:20. In another instance, the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 90:10. In certain aspects, the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 95:5. In some instances, the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 97:3. In certain instances, the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 98:2. In some instances, the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 99:1.

[0156] In some aspects, the pharmaceutical composition comprising the Form 1 polymorph further comprises an additional agent. Exemplary non-limiting additional agents include agents that delay the progression of heart failure and attempt to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); agents that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or agents that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). In certain aspects, the additional agent in the pharmaceutical composition is a cardiovascular drug. In other aspects, additional exemplary therapeutic agents include beta-adrenergic blockers (beta-blockers), renin-angiotensin-aldosterone system (RAAS) inhibitors (e.g., angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor antagonists such as 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), positive inotropes (e.g., digoxin; pimobendan; beta-adrenergic receptor agonists such as dobutamine; phosphodiesterase (PDE)-3 inhibitors such as milrinone; or calcium sensitizers such as levosimendan), potassium or magnesium, proprotein convertase subtilisin (Kexin) a 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 arrhythmia medication, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent, or any combination thereof.Suitable angiotensin II receptor blockers (ARBs) can 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-317 4. EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan, isotrine, 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, Myoproline acetate, S-8307, S-8308, SC-52458, Saprisartan, Myoproline Alaquinoxaline, samaquinoxaline, 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 aspects, the additional therapeutic agent may be an ARNI such as sacubitril / valsartan. or sodium-glucose co-transporter 2 inhibitors (SGLT2), such as empagliflozin (e.g. ), dapagliflozin (e.g. ) or sogliflozin. In some aspects, the subject is administered an additional medication for improving the subject's cardiovascular condition. The additional medication can be, for example, a beta blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor blocker, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, or an arrhythmia medication. In specific aspects, the additional medication is an ANRI, such as sacubitril / valsartan; or an SGLT2 inhibitor.

[0157] The pharmaceutical composition for administering the compound of formula (I) or its pharmaceutically acceptable salt or polymorph provided herein can be conveniently presented in unit dosage form and can be prepared by any method known in pharmaceutics and drug delivery technology. All methods include the step of associating the compound of formula (I) or its pharmaceutically acceptable salt with a carrier containing one or more auxiliary ingredients. In general, the pharmaceutical composition is prepared by associating the compound of formula (I) or its pharmaceutically acceptable salt evenly and finely with a liquid carrier or a finely powdered solid carrier or both, and then forming the product into the desired formulation when necessary. In the pharmaceutical composition, the compound of formula (I) or its pharmaceutically acceptable salt is generally included in an amount sufficient to produce the desired effect on myocardial contractility (e.g., reducing the systolic contractility that is often abnormal in HCM) and / or improving diastolic left ventricular relaxation. Such improved relaxation can alleviate the symptoms of hypertrophic cardiomyopathy and / or other causes of diastolic dysfunction. Alternatively or additionally, the pharmaceutical composition may ameliorate the effects of diastolic dysfunction that leads to impaired coronary blood flow, thereby serving as an adjunct in angina and / or ischemic heart disease. Alternatively or additionally, the pharmaceutical composition may confer benefit on beneficial left ventricular remodeling in HCM and / or other causes of left ventricular hypertrophy due to chronic volume or pressure overload, such as from valvular heart disease and / or systemic hypertension.

[0158] 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, for example, as tablets, lozenges, buccal tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colorants, antioxidants, and preservatives to provide pharmaceutically high-quality and palatable preparations. Tablets contain a compound of formula (I) or a pharmaceutically acceptable salt thereof mixed with a non-toxic, pharmaceutically acceptable excipient suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. The tablets may be uncoated, or they may be enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, time-extending materials such as glyceryl monostearate or glyceryl distearate may be used. The tablets may also be coated to form osmotic therapeutic tablets for controlled release.

[0159] Pharmaceutical compositions for oral use may also be presented as gelatin capsules, such 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 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. In addition, emulsions can be prepared with water-immiscible ingredients such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.

[0160] Aqueous suspensions contain a compound of formula (I) or a 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, gum tragacanth, and gum arabic; dispersants or wetting agents may be naturally occurring phospholipids such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of alkylene oxide with long-chain aliphatic alcohols, such as heptadecanethoxycetanol, or condensation products of alkylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of alkylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. 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.

[0161] Oily suspensions can be prepared by suspending the compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof in a vegetable oil such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners (such as those described above) and flavorings may be added to provide a palatable oral formulation. These compositions may be stored by adding an antioxidant such as ascorbic acid.

[0162] Dispersible powders and granules suitable for preparation of an aqueous suspension by addition of water provide a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof in admixture with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0163] The pharmaceutical compositions provided herein may also be in the form of an oil-in-water emulsion. The oil 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 naturally occurring gums, such as gum arabic or gum tragacanth; naturally occurring phospholipids, such as soy, lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of such partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

[0164] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. Oil solutions can be prepared in combination with, for example, cyclodextrins, PEG, and surfactants.

[0165] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated using suitable dispersants or wetting agents and suspending agents as mentioned above according to known techniques. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are commonly used as solvents or suspending media. For this purpose, any mild, non-volatile oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may be used to prepare injectables.

[0166] The compound of formula (I) provided herein, or its pharmaceutically acceptable salt or polymorph, can also be administered in the form of a suppository for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol. In addition, the compound can be delivered to the eye by means of a solution or ointment. Furthermore, transdermal delivery of the subject compound can be achieved by means of an iontophoretic patch and the like. For topical use, creams, ointments, jellies, solutions or suspensions containing the compound provided herein or its pharmaceutically acceptable salt are used. Topical application as used herein also means including the use of mouthwashes and gargles.

[0167] The compound of formula (I) provided herein, or its pharmaceutically acceptable salt or polymorph thereof, can also be coupled to a carrier, which is a suitable polymer for a targetable drug carrier. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-asparagine-phenol, or polyethylene oxide-polylysine substituted with a palmitoyl residue. In addition, the compound of formula (I) provided herein, or its pharmaceutically acceptable salt, can be coupled to a carrier, which is a biodegradable polymer suitable for achieving controlled release of the drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels. Polymers and semipermeable polymer matrices can be formed into shaped articles, such as valves, stents, conduits, prostheses, and the like.

[0168] The mutations that cause HCM cause significant disturbances in the myosin mechanism. These mutations play their role via different mechanisms depending on their position in the myosin gene. The well-studied HCM mutations R403Q and R453C are located in different regions of the motor domain and cause different mechanical disturbances, which are common results in increased force generation. Without wishing to be bound by any particular theory, it is believed that the compound of formula (I) provided herein or a pharmaceutically acceptable salt thereof can be directly bound to the mutant sarcomere protein and correct the abnormal function of the protein in cis (by affecting the same specific function) or in trans (by changing the complementary function). Therefore, it can provide therapeutic benefits for HCM patients by counteracting the hypercontraction and / or impaired relaxation associated with this disease.

[0169] Therefore, the application provides a method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disease with one or more pathophysiological features associated with HCM. The method includes administering an effective amount of a compound provided herein to an individual in need, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The method includes administering an effective amount of a compound provided herein to an individual in need, or 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 in form 1 polymorphic form.

[0170] The present application also provides a method for treating hypertrophic cardiomyopathy (HCM) or cardiac disease. The method comprises administering to a subject in need thereof an effective amount of a compound provided herein, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The method comprises administering to a subject in need thereof an effective amount of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

[0171] 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) - including both conditions of active relaxation and conditions of chamber stiffness (e.g., diabetic HFpEF); ischemic cardiomyopathy, cardiac transplant allograft vasculopathy, restrictive cardiomyopathies (e.g., genetic mutations in one or more sarcomeric proteins), inflammatory cardiomyopathies (e.g., Loeffler's disease and EMF), infiltrative cardiomyopathies (e.g., amyloid, sarcoid, and XRT), storage diseases (e.g., hemochromatosis, Fabry disease, and glycogen storage diseases), congenital heart disease (e.g., pressure-overloaded RV), tetralogy of Fallot (e.g., preoperative and early postoperative diastolic dysfunction), and valvular heart disease (e.g., aortic stenosis).

[0172] Provided herein are methods for treating a cardiac disease or condition 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 aspects, diastolic dysfunction is a characteristic of and / or associated with a cardiac disease or condition. For example, the cardiac disease or condition can be cardiomyopathy (e.g., hypertrophic cardiomyopathy), heart failure (e.g., heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction), valvular disease (e.g., valvular aortic stenosis), congenital heart disease (e.g., tetralogy of Fallot), left ventricular hypertrophy, angina (e.g., refractory angina), or Chagas' disease. In certain aspects, a normal or preserved ejection fraction (e.g., an ejection fraction of greater than or equal to about 50%) is a characteristic of a cardiac disease or condition. In some such cases, the characteristics of a cardiac disease or condition include a normal or preserved ejection fraction and diastolic dysfunction. For example, an individual in need of treatment for a cardiac disease or condition (e.g., HCM, HFpEF, valvular aortic stenosis) may have diastolic dysfunction and an ejection fraction of greater than or equal to about 50%. In certain aspects, an intermediate ejection fraction (e.g., an ejection fraction between about 40% and about 50%) is a characteristic of a cardiac disease or condition. In some such cases, an individual in need of treatment for a cardiac disease or condition (e.g., heart failure with mid-range ejection fraction) may have diastolic dysfunction and an ejection fraction between about 40% and about 50%.

[0173] In some aspects, a method of treating diastolic dysfunction in an individual in need thereof is provided. In some aspects, the method comprises administering to the individual 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 cases, the diastolic dysfunction is left ventricular diastolic dysfunction, right ventricular diastolic dysfunction, or both. The diastolic dysfunction may be chronic, stable, or acute. In some aspects, the individual 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 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 certain aspects, the individual in need of treatment for diastolic dysfunction may suffer from one or more diseases or conditions selected from the group consisting of hypertrophic cardiomyopathy (e.g., oHCM, nHCM), heart failure (e.g., HFpEF, diabetic HFpEF, HFmrEF), valvular heart disease (e.g., aortic stenosis), congenital heart disease (e.g., tetralogy of Fallot), and left ventricular hypertrophy (e.g., due to mitral regurgitation, aortic stenosis, aortic regurgitation, and / or chronic systemic hypertension). In some aspects, the individual in need of treatment for diastolic dysfunction may have undergone one or more surgical procedures. For example, the individual may have undergone valve replacement surgery (e.g., surgical aortic valve replacement, transcatheter aortic valve replacement) and / or corrective surgery for congenital heart disease, such as tetralogy of Fallot. In some aspects, the individual in need of treatment for diastolic dysfunction may be a prosthetic heart valve (e.g., a prosthetic aortic valve). In some cases, the individual in need of treatment for diastolic dysfunction has postoperative diastolic dysfunction. For example, a subject may have post-operative diastolic dysfunction (e.g., right ventricular diastolic dysfunction) following corrective surgery for a congenital condition (e.g., tetralogy of Fallot). In some cases, a subject in need of treatment for diastolic dysfunction has a normal or preserved ejection fraction. In other cases, a subject in need of treatment for diastolic dysfunction has an intermediate ejection fraction.

[0174] In some aspects, a method of treating a cardiomyopathy (e.g., hypertrophic) in an individual in need thereof is provided. In certain aspects, the method comprises administering to the individual an effective amount of a compound of formula (I) or a salt thereof, or (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. 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., with diastolic dysfunction), and inflammatory cardiomyopathy (e.g., with diastolic dysfunction). In some aspects, the cardiomyopathy is hypertrophic cardiomyopathy. In some cases, hypertrophic cardiomyopathy is nHCM. The method may include administering to a subject in need of treatment for nHCM 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. The subject in need of treatment for nHCM may have NYHA Class II, III, or IV heart failure. In other instances, the hypertrophic cardiomyopathy is oHCM. The method may comprise administering to a subject in need of treatment for oHCM 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. The subject in need of treatment for oHCM may have NYHA Class II, III, or IV heart failure.

[0175] In some aspects, the cardiomyopathy is restrictive cardiomyopathy. The method may include administering an effective amount of a compound of formula (I) or a salt thereof, or a 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 an individual in need of treating restrictive cardiomyopathy. In some aspects, restrictive cardiomyopathy may be attributed to one or more mutations (e.g., gene mutations) in, for example, sarcomeric proteins. In some aspects, the cardiomyopathy is infiltrative cardiomyopathy. Infiltrative cardiomyopathy may be attributed to amyloid degeneration, sarcoidosis, and / or X-ray therapy. In some cases, infiltrative cardiomyopathy may be characterized by diastolic dysfunction. Methods for treating infiltrative cardiomyopathy may comprise administering to a subject in need thereof 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 aspects, the cardiomyopathy is an inflammatory cardiomyopathy. Non-limiting examples of inflammatory cardiomyopathy include Loeffler's endocarditis and endomyocardial fibrosis. In some cases, the inflammatory cardiomyopathy may be characterized by diastolic dysfunction. A method for treating inflammatory cardiomyopathy may comprise administering to a subject in need thereof 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.

[0176] In some aspects, a method of treating heart failure (e.g., HFpEF, HFmrEF) in an individual in need thereof is provided. The method comprises administering to the individual 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. Heart failure may be left-sided heart failure, right-sided heart failure, or both. Heart failure may be chronic, stable, or acute. An individual in need of treatment for heart failure may have NYHA Class II, III, or IV heart failure. Non-limiting examples of heart failure that can be treated using the compounds described herein include HFpEF, diabetic HFpEF, and HFmrEF. In some aspects, heart failure is HFpEF. In some cases, a subject in need of treatment for HFpEF may have normal or elevated contractility (e.g., as measured by echocardiography). In some cases, a subject in need of treatment for HFpEF may have abnormal global longitudinal strain (e.g., less than -15%). In certain aspects, a subject in need of treatment for HFpEF may have diabetes (type I, type II) and / or valvular disease (e.g., aortic stenosis). In some cases, a subject in need of treatment for HFpEF may have a prosthetic valve (e.g., an aortic valve) due to valvular disease (e.g., aortic stenosis). A method of treating HFpEF (e.g., diabetic HFpEF) in a subject in need thereof may comprise administering 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 cases, the heart failure is HFmrEF. The method may comprise administering to a subject in need of treatment for HFmrEF 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. The subject in need of treatment for HFmrEF may have NYHA Class II, III, or IV heart failure.

[0177] In some aspects, a method of 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 aspects, the subject in need of treatment for left ventricular hypertrophy has abnormal left ventricular wall thickness. The subject's left ventricular wall thickness may be greater than normal, but less than the diagnostic criteria for hypertrophic cardiomyopathy. For example, a subject in need of treatment for left ventricular hypertrophy may have a left ventricular wall thickness greater than about 10 mm (e.g., greater than about 11 mm) and less than about 15 mm (e.g., less than or equal to about 14 mm, less than or equal to about 13 mm). In some aspects, the individual in need of treatment for left ventricular hypertrophy has left ventricular hypertrophy without hypertrophic cardiomyopathy. In certain aspects, the individual in need of treatment for left ventricular hypertrophy may suffer from hypertension (e.g., chronic and / or systemic). In some aspects, left ventricular hypertrophy may be due to, for example, chronic mitral regurgitation, chronic aortic regurgitation, chronic aortic stenosis, and / or chronic systemic hypertension.

[0178] Further determination of factors for diagnosing diastolic dysfunction using echocardiography is described in J Am Soc Echocardiogr. 29(4):277-314 (2016), the contents of which are incorporated herein for all purposes.

[0179] Individuals in need of treatment for diastolic dysfunction include individuals from a patient population with non-obstructive hypertrophic cardiomyopathy (nHCM), or individuals with heart failure with preserved ejection fraction (HFpEF). Individuals in need of treatment for diastolic dysfunction include individuals who exhibit left ventricular stiffness as measured by echocardiography or left ventricular stiffness as measured by cardiac magnetic resonance.

[0180] In some aspects, the individual in need thereof is from a patient population suffering from HFpEF.

[0181] The present application also provides a method for treating a disease or condition 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 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.

[0182] The compounds of formula (I) can be administered as monotherapy or in combination therapy. In combination therapy, the compounds of formula (I) are used in combination with additional therapeutic regimens, such as standard of care (SOC) therapy for the individual's cardiac condition or other therapies suitable for treating the related disease or condition. The additional therapeutic agent can be administered by a route and in an amount typically used for that agent, or in a reduced amount, and can be administered simultaneously, sequentially, or concurrently with the compound of formula (I).

[0183] In certain aspects, a compound of formula (I) is administered in addition to a SOC for a condition of diastolic dysfunction, such as diastolic heart failure. In other aspects, in addition to a compound of formula (I), a subject is administered another therapeutic agent, such as a beta-blocker, a RAAS inhibitor (e.g., angiotensin converting enzyme (ACE) inhibitor; angiotensin receptor antagonist, such as angiotensin II receptor blocker), angiotensin receptor neprilysin inhibitor (ARNI) (e.g., sacubitril / valsartan), a mineralocorticoid receptor antagonist (e.g., an aldosterone inhibitor, such as a potassium-sparing diuretic, such as eplerenone, spironolactone, or canrenone), a cholesterol-lowering drug (e.g., a statin), a neutral endopeptidase inhibitor (NEPi), a positive inotropic agent (e.g., digoxin; pimobendan; a beta adrenergic receptor agonist, such as dobutamine; a phosphodiesterase (PDE)-3 inhibitor, such as milrinone; or a calcium sensitizer, such as levosimendan), potassium or magnesium, proprotein convertase subtilisin Kexin a 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 arrhythmia medication, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent, or any combination thereof.

[0184] Suitable ARBs can 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-3174, EXP-63175, and the like. 155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan, isotrine, 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, Myoproline acetate, S-8307, S-8308, SC-52458, Saprisartan, Myoproline Alaquinoxaline, samaquinoxaline, 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 aspects, the additional therapeutic agent may be an ARNI such as sacubitril / valsartan or sodium-glucose co-transporter 2 inhibitors (SGLT2), such as empagliflozin (e.g. ), dapagliflozin (e.g. ) or sogliflozin. In some aspects, the subject is given an additional drug for improving the subject's cardiovascular condition. The additional drug can be, for example, a beta blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor blocker, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, or an arrhythmia drug. In a specific aspect, the additional drug is an ANRI, such as sacubitril / valsartan; or an SGLT2 inhibitor. In another aspect, the subject who is being treated for heart failure with a compound of formula (I) is also being treated with an ARNI, a beta blocker, and an MRA.

[0185] The present application also provides a method for treating a disease or condition 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 Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The present application also provides a method for treating a disease or condition 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 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.

[0186] 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 can be administered as a monotherapy or in combination therapy. In combination therapy, 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 is used in combination with an additional therapy regimen, such as standard of care (SOC) therapy for the individual's cardiac condition or other therapy suitable for treating the relevant disease or condition. The additional therapeutic agent can be administered by a route and in an amount typically used for that agent, or in a reduced amount, and can be administered simultaneously, sequentially, or concurrently with 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. In certain aspects, 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 is administered in addition to SOC for conditions of diastolic dysfunction, such as diastolic heart failure. In other aspects, in addition to 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, the subject is administered another therapeutic agent, such as a beta-blocker, a RAAS inhibitor (e.g., angiotensin converting enzyme (ACE) inhibitor; angiotensin receptor antagonist, such as angiotensin II receptor blocker), an angiotensin receptor neprilysin inhibitor (ARNI) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (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), inotropes (e.g., digoxin; pimobendan; beta-adrenergic receptor agonists, such as 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 regulators), diuretics (e.g., furosemide), arrhythmia drugs, anticoagulants (e.g., warfarin), antithrombotic agents, antiplatelet agents, or any combination thereof.Suitable ARBs are provided herein (see above). In certain aspects, the additional therapeutic agent may be an ARNI, such as sacubitril / valsartan. or sodium-glucose co-transporter 2 inhibitors (SGLT2), such as empagliflozin (e.g. ), dapagliflozin (e.g. ) or sogliflozin. In some aspects, along with administering 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, an additional drug for improving the individual's cardiovascular condition is administered to the individual. The additional drug can be, for example, a beta blocker, a diuretic, an angiotensin converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor blocker, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, or an arrhythmia drug. In specific aspects, the additional drug is an ANRI, such as sacubitril / valsartan; or an SGLT2 inhibitor. In yet another aspect, a subject being treated for heart failure with Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione is also being treated with an ARNI, a beta blocker, and an MRA.

[0187] The present application also provides a method for treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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 reducing the primary cause of volume or pressure overload, including valve repair / replacement or an effective antihypertensive therapy, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present application also provides a method for treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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 reducing the primary cause of volume or pressure overload, including valve repair / replacement or an effective antihypertensive therapy, the method 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.

[0188] The present application also provides a method for treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition selected from the group consisting of chronic mitral valve 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, including valve repair / replacement or an effective antihypertensive therapy, the method comprising administering to a subject in need thereof an effective amount of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The present application also provides a method for treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition selected from the group consisting of chronic mitral valve 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, including valve repair / replacement or an effective antihypertensive therapy, the method comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

[0189] The present application also provides a method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features 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: (1) a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); (2) a therapy that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotropic agent, such as the β-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 (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0190] The present application also provides a method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), which comprises administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with: (1) a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); (2) a therapy that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotropic agent, such as the β-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 (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0191] The present application also provides a method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), comprising administering to a subject in need thereof an effective amount of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione in combination with: (1) a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation; (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); (2) therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or (3) therapies that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0192] The present application also provides a method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, in combination with the following therapies: (1) delaying the progression of heart failure and attempting to prevent cardiac recurrence by downregulating cardiac neurohormonal stimulation; (1) therapy that reduces cardiac contractility (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); (2) therapy that improves cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or (3) therapy that reduces cardiac preload (e.g., diuretics, such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0193] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. The present application also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament. The present application also provides Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use as a medicament. The present application also provides a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use as a medicament.

[0194] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features of HCM). The present application also provides a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features of HCM). The present application also provides Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use in treating hypertrophic cardiomyopathy or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features of HCM). The present application also provides a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use in treating hypertrophic cardiomyopathy or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features of HCM).

[0195] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition 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 application also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition 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 application also provides Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use in treating a disease or condition 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 application also provides a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, for use in treating a disease or condition 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.

[0196] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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 reducing the primary cause of volume or pressure overload, including valve repair / replacement or an effective antihypertensive therapy. The present application also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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 reducing the primary cause of volume or pressure overload, including valve repair / replacement or an effective antihypertensive therapy. The present application also provides Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use in treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition selected from the group consisting of chronic mitral valve 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 volume or pressure overload, including valve repair / replacement or an effective antihypertensive therapy. The present application also provides a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use in treating a disease or condition characterized by left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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 volume or pressure overload, including valve repair / replacement or an effective antihypertensive therapy.

[0197] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), wherein the compound is used in combination with the following therapies: (1) a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); (2) a therapy that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotropic agent, such as the β-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 (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). The present application 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 disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), wherein the compound is used in combination with the following therapies: (1) a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); (2) a therapy that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotropic agent, such as the β-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 (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0198] The present application also provides Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use in treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), wherein the compound is used in combination with a therapy that delays the progression of heart failure by downregulating neurohormonal stimulation of the heart and attempts to prevent cardiac remodeling (e.g., A CE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). The present application also provides a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use in treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), wherein the compound is used in combination with a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation. therapy to improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapy to reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0199] The present application also provides a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament. The present application also provides a use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament. The present application also provides a use of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for use in the manufacture of a medicament. The present application also provides a use of a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament.

[0200] The present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hypertrophic cardiomyopathy or a cardiac condition (e.g., a cardiac condition with pathophysiological features of HCM). The present application also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hypertrophic cardiomyopathy or a cardiac condition (e.g., a cardiac condition with pathophysiological features of HCM). The present application also provides the use of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for treating hypertrophic cardiomyopathy or a cardiac condition (e.g., a cardiac condition with pathophysiological features of HCM). The present application also provides a use of a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for treating hypertrophic cardiomyopathy or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features of HCM).

[0201] The present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or condition 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 application also provides the use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a disease or condition 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 application also provides a use of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for treating a disease or condition 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 application also provides a use of a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for treating a disease or condition 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.

[0202] The present application also provides a 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), wherein the disease or condition 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, including valve repair / replacement or an effective antihypertensive therapy. The present application also provides a use of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating left ventricular hypertrophy (e.g., due to volume or pressure overload), wherein the disease or condition 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, including valve repair / replacement or an effective antihypertensive therapy. The present application also provides the use of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for treating left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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, including valve repair / replacement or effective antihypertensive therapy. The present application also provides the use of a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for treating left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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, including valve repair / replacement or effective antihypertensive therapy.

[0203] The present application also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), in combination with the following therapies: therapies that delay the progression of heart failure and attempt to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapies that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). The present application also provides a use of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), in combination with the following therapies: therapies that delay the progression of heart failure and attempt to prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapies that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0204] The present application also provides a use of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM) in combination with the following therapies: therapies that delay the progression of heart failure by downregulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators). The present application also provides a use of a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione for the manufacture of a medicament for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM) in combination with the following therapies: a therapy that delays the progression of heart failure by downregulating neurohormonal stimulation of the heart and attempts to prevent cardiac remodeling therapy to improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapy to reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0205] Compounds of formula (I), or pharmaceutically acceptable salts thereof, may alter the natural history of HCM and other diseases, rather than merely alleviating symptoms. Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione may alter the natural history of HCM and other diseases, rather than merely alleviating symptoms. The mechanisms by which clinical benefit is conferred to patients with HCM may extend to patients with other forms of heart disease that share similar pathophysiology, with or without demonstrable genetic influences. 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. Compounds of formula (I), or pharmaceutically acceptable salts thereof, may specifically target the underlying cause of the condition or act on other downstream pathways. Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione can be used to specifically target the underlying cause of a condition or act on other downstream pathways. Therefore, the compound of formula (I) or a pharmaceutically acceptable salt thereof may also provide benefits to patients suffering from heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, or restrictive cardiomyopathy. Thus, 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 also confer benefits to patients suffering from heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, or restrictive cardiomyopathy. Compounds of formula (I) or pharmaceutically acceptable salts thereof may also promote beneficial ventricular remodeling in patients with left ventricular hypertrophy due to volume or pressure overload, such as chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension, in combination with therapies aimed at correcting or alleviating the primary cause of volume or pressure overload (valve repair / replacement, effective antihypertensive therapy). Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione may also promote beneficial ventricular remodeling in patients with left ventricular hypertrophy due to volume or pressure overload, such as chronic mitral regurgitation, chronic aortic stenosis, or chronic systemic hypertension. This may be combined with therapies aimed at correcting or alleviating the primary cause of volume or pressure overload (valve repair / replacement, effective antihypertensive therapy). By reducing left ventricular filling pressures, the compound may reduce the risk of pulmonary edema and respiratory failure.Reducing or eliminating functional mitral valve regurgitation and / or reducing left atrial pressure can reduce the risk of paroxysmal or permanent atrial fibrillation and, consequently, reduce the risk of arterial thromboembolic complications, including but not limited to the associated risk of cerebral arterial embolic stroke. Reducing or eliminating dynamic and / or static left ventricular outflow obstruction can reduce the likelihood of requiring surgery or percutaneous septal volume reduction therapy and the associated risks of short-term and long-term complications. The compound of formula (I) or a pharmaceutically acceptable salt thereof can reduce the severity of chronic ischemic conditions associated with HCM and thereby reduce the risk of sudden cardiac death (SCD) or its equivalent in patients with implantable cardioverter-defibrillators (frequent and / or repetitive ICD shocks) and / or the need for potentially toxic antiarrhythmic drugs. Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione can reduce the severity of chronic ischemic conditions associated with HCM and thereby reduce the risk of sudden cardiac death (SCD) or its equivalent in patients with implantable cardioverter-defibrillators (frequent and / or repetitive ICD shocks) and / or the need for potentially toxic antiarrhythmic drugs. Compounds of formula (I) or pharmaceutically acceptable salts thereof can be valuable in reducing or eliminating the need for concomitant medications and their attendant potential toxicities, drug-drug interactions, and / or side effects. Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione may be valuable in reducing or eliminating the need for concomitant medications and their associated potential toxicities, drug-drug interactions, and / or side effects. Compounds of formula (I) or pharmaceutically acceptable salts thereof may reduce interstitial myocardial fibrosis and / or slow the progression of left ventricular hypertrophy, thereby inhibiting or reversing left ventricular hypertrophy. Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione can reduce interstitial myocardial fibrosis and / or slow down the progression of left ventricular hypertrophy, and inhibit or reverse left ventricular hypertrophy.

[0206] Depending on the disease to be treated and the condition of the individual, the compounds of formula (I) or pharmaceutically acceptable salts thereof provided herein can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneously, or implanted), by implant (e.g., when the compound is coupled to a stent device), by inhalation spray, nasally, vaginally, rectally, sublingually, or topically, and can be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles suitable for each route of administration.

[0207] Depending on the disease to be treated and the condition of the subject, 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 provided herein can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implantation), by implantation (e.g., when the compound is coupled to a stent device), by inhalation spray, nasally, vaginally, rectally, sublingually, or topically, and can be formulated, alone or together, into appropriate dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants, and vehicles suitable for each route of administration.

[0208] 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, can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutical composition comprising Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, can be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

[0209] However, it will be understood that the specific dosage level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound or pharmaceutically acceptable salt employed, the metabolic stability and duration of action of that compound or pharmaceutically acceptable salt thereof, the age, weight, genetic characteristics, general health, sex, and diet of the individual, as well as the mode and timing of administration, rate of excretion, drug combination, and the severity of the particular condition in the individual undergoing therapy.

[0210] The compounds of formula (I) provided herein, pharmaceutically acceptable salts of the compounds of formula (I) and / or pharmaceutical compositions can be used in combination with other drugs, and the other drugs are used to treat, prevent, suppress or improve the diseases or conditions for which the compounds and compositions provided herein are applicable. 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 provided herein and / or pharmaceutical compositions can be used in combination with other drugs, and the other drugs are used to treat, prevent, suppress or improve the diseases or conditions for which the compounds and compositions provided herein are applicable. Such other drugs can be administered simultaneously or sequentially with the compounds or compositions provided herein by the routes and amounts commonly used therefor. When the compounds or compositions provided herein are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs in addition to the compounds or compositions provided herein are preferred. Therefore, the pharmaceutical compositions provided herein include those containing one or more other active ingredients or therapeutic agents in addition to the compounds or compositions provided herein. Suitable additional active agents include, for example: delaying the progression of heart failure by downregulating the neurohormonal stimulation of the heart and attempting to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuropeptide chain endonuclease inhibitors); improving cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as β-adrenergic agonists dobutamine or phosphodiesterase inhibitors milrinone); and reducing cardiac preload (e.g., diuretics, such as furosemide) or afterload (any type of vasodilator, including but not limited to 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 its pharmaceutically acceptable salt to the second active ingredient can vary and will depend on the effective dose of each component. In general, the effective dose of each will be used.

[0211] Where a compound of the present invention is administered in combination with another therapeutic agent, the other therapeutic agent may be administered simultaneously, independently, or sequentially with the compound of formula (I). The precise dosing regimen is matched to the characteristics of the one or more therapeutic agents. Where a compound of the present invention is administered in combination with another therapeutic agent, the other therapeutic agent may be administered simultaneously, independently, or sequentially with Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The precise dosing regimen is matched to the characteristics of the one or more therapeutic agents. Example

[0212] Abbreviations: ACN: acetonitrile; aq: aqueous solution; Ar: argon; CH2Cl2: dichloromethane; CH3CN: acetonitrile; CH3OH: methanol; Cs2CO3: cesium carbonate; DCM: dichloromethane; DIEA: diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; equiv.: equivalent; Et2O: diethyl ether; EtOAc: ethyl acetate; EtOH: ethanol; h or hr: hour; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, N- [(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HCl: hydrogen chloride; H2O: water; IPA: isopropyl alcohol; iPr2O: diisopropyl ether; K2CO3: potassium carbonate; LiHMDS: lithium hexamethyldisilazane; MeOH: methanol; MgSO4: magnesium sulfate; min: minute; mL: milliliter; MW or μW: microwave (reaction was carried out in a microwave reactor); NaBH4: sodium borohydride; NaBH3CN: sodium cyanoborohydride; NaCl: sodium chloride; NaBH 3CN : sodium cyanoborohydride; NaH: sodium hydride; NaHCO3: sodium bicarbonate; NaOH: sodium hydroxide; NaOMe: sodium methoxide; Na2SO4: sodium sulfate; n-BuOH: n-butanol; NH4Cl: ammonium chloride; pH: -log[H + ]; RT: room temperature; SOCl2: thionyl chloride; TFA: trifluoroacetic acid; THF: tetrahydrofuran; THP, tetrahydropyran or tetrahydropyranyl; and Zn: zinc powder. All experiments were performed in a fume hood with specific safety precautions and necessary personal protective equipment.

[0213] Example 1: Synthesis

[0214] Intermediate Example 1: Preparation of (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4)

[0215] Process I-1

[0216]

[0217] Step 1. Synthesis of (S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (1-2). To a 1000-mL round-bottom flask under argon atmosphere were added 3-fluorobenzaldehyde (50 g, 0.40 mol), (S)-2-methylpropane-2-sulfinamide (50 g, 0.41 mol), Cs2CO3 (157 g, 0.48 mol) and dichloromethane (500 mL). After stirring at room temperature for 4 hours, 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 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 (300MHz, CDCl3): δ8.55 (d, 1H), 7.63-7.48 (m, 2H), 7.41-7.48 (td, J = 8.0, 5.5Hz, 1H), 7.17-7.7.26 (m, 1H), 1.26 (d, J = 2.6Hz, 9H).

[0218] Step 2. Synthesis of (S)-ethyl 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) under argon atmosphere was added a solution of 1-2 (53.5 g, 0.24 mol) and ethyl 2-bromo-2,2-difluoroacetate (120 g, 0.59 mol) in tetrahydrofuran (250 mL) while stirring at 70 ° C for 40 minutes. After stirring at 70 ° C for another 30 minutes, 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 solution (500 mL) and dried over anhydrous Na2SO4. 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] + .

[0219] Step 3. (S)-3-(((S)-tert-Butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4). To a solution of 1-3 (80 g, 0.23 mol) in tetrahydrofuran (1000 mL) was added 1N aqueous NaOH (350 mL) at room temperature under argon atmosphere. After stirring at room temperature for 30 minutes, the pH of the reaction mixture was adjusted to 5 with 1N aqueous citric acid. 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 preparative HPLC (column: C18 silica gel; mobile phase: CH3CN / H2O=10 / 90 (v / v) increasing to CH3CN / H2O=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): δ14.97(s,1H),7.48-7.36(m,2H),7.32(d,J=7.8Hz,1H),7.23-7.13(m,1H),6.56(d,J=10.1Hz,1H),4.98(m,1H),1.01(s,9H).

[0220] Intermediate Example 2: Preparation of 1-(tetrahydro-2H-pyran-4-yl)piperidine-2,4,6-trione (2-3)

[0221] Process I-2

[0222]

[0223] Step A-1. Synthesis of 1- (tetrahydro -2H- pyran -4- bases) 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 argon atmosphere. After stirring overnight at room temperature, the reactant was quenched by adding MeOH (20 mL). The solvent was removed and the residue was triturated with diethyl ether (50 mL). Subsequently, the suspension was filtered and the solid was washed with diethyl ether (500 mL x 3) and dried in vacuo to give 2-2 (34 g, 68%) as a white solid. 1 H NMR (300 MHz, d 6-DMSO): δ5.96(d,J=7.8Hz,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).

[0224] 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 argon atmosphere, followed by 1,3-dimethyl malonate (470 g, 0.36 mol). After stirring overnight at 80 ° C, the reaction mixture was concentrated and the residue was diluted with water (50 mL). Subsequently, the pH value of the resulting mixture was 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 hours to give 2-3 (30 g, 60%) as a white solid. 1 HNMR (300MHz, d 6 -DMSO): δ11.25(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).

[0225] Step B-1. Synthesis of phenyl carbamate (2-5). To a mixture of saturated aqueous ammonia solution (50 mL) and DCM (50 mL) at 0°C was added a solution of 2-4 (30 g) in DCM (45 mL). After stirring at 0°C for 4 hours, the reaction mixture was filtered and the solid was washed with water and dried in vacuo at 45°C for 12 hours 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): δ7.42-7.32(m,2H),7.24-7.15(m,1H),7.13-7.04(m,2H),6.89(br,2H).

[0226] 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 hours under argon atmosphere. Then, the suspension was filtered and the solid was washed with diethyl ether (100 mL) and dried in vacuo at 45° C. for 12 hours to give 2-2 (18.3 g, 95%) as a white solid. 1 H NMR (400 MHz, d 6 -DMSO): δ5.96(d,J=7.8Hz,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).

[0227] Intermediate Example 3: Preparation of (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (3-3)

[0228] Process I-3

[0229]

[0230] Step 1. Synthesis of (R,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfinamide (4-1). A mixture of 1-1 (5.0 g, 40.3 mmol), (R)-2-methylpropane-2-sulfinamide (5.1 g, 42.2 mmol) and Cs2CO3 (15.7 g, 48.25 mol) in DCM (60 mL) was stirred at room temperature overnight under an argon atmosphere. Subsequently, the reaction mixture was diluted with diethyl ether (200 mL) and then filtered. The filtrate was concentrated and the residue was dried in vacuo to give crude 3-1 (10 g) as a white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 228 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ8.58(s,1H),7.88-7.73(m,2H),7.60(m,1H),7.45(m,1H),1.19(s,9H).

[0231] 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 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 under argon at -78 °C over 30 minutes. After stirring at -78 °C for 1 hour, the reaction was quenched by the addition of 2N 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 x 3). The combined organic extracts were then washed with brine and dried over anhydrous Na2SO4. The solvent was removed and the residue was dried in vacuo to give crude 3-2 (4.6 g) as an off-white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 334 [M+H] + .

[0232] 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 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 solution and extracted with EtOAc (200 mL x 3). The combined organic extracts were then washed with brine (100 mL) and dried over anhydrous NaSO. 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 (3.0% (v / v) to 17.0% (v / v) in 8 minutes); 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): δ12.83(s,1H),7.53-7.44(m,1H),7.42-7.35(m,2H),7.12(m,1H),6.12(d,J=10.7Hz,1H),5.33(m,1H),4.86(m,1H),1.14(s,9H).

[0233] 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)

[0234] Process C-1

[0235]

[0236] 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 DIEA (2.15 g, 16.63 mmol) dropwise at 0° C. After stirring at room temperature overnight, the reaction mixture was diluted with saturated aqueous NaHCO solution (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 Na2SO4. 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] + .

[0237] 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 hour. Subsequently, 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] + .

[0238] 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) at 0° C. over 3 minutes. After stirring at room temperature for 1 hour, 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] + .

[0239] 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 the crude material CC (800 mg) in CHCN (10 mL) in a sealed vial was stirred at 120 ° C for 20 minutes in a microwave reactor. Subsequently, the mixture was diluted with water (50 mL) and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine and dried over anhydrous 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) NH 3 · H 2 O) / CH 3 CN = 11.0% (v / v) to 30.0% (v / v) in 8 minutes; detector: UV 254 nm) to give C-1 (197 mg, 27%, from CA in three steps) as a white solid. LC-MS (ES, m / z): 382 [M+H] + ; 1 H NMR (400 MHz, d 6 -DMSO): δ10.67(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).

[0240] 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)

[0241] Process 1

[0242]

[0243] 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). Follow the same steps as for the preparation of (S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The same procedure as described for (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (3-3) was used to replace (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) to obtain 1 as a white solid. LC-MS (ES, m / z): 364 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ10.18(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=26.8Hz,1H),3.93(m,2H),3.34(m,2H),2.74-2.53(m,4H),1.46-1.31(m,2H); 19 FNMR (376 MHz, d 6 -DMSO):δ-113.18,-192.36.

[0244] 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)

[0245] Process 2

[0246]

[0247] Steps 1 to 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 the preparation of (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) and substituting ethyl 2-bromo-2-fluoroacetate for ethyl 2-bromo-2,2-difluoroacetate, 2B was obtained as an off-white solid. LC-MS (ES, m / z): 306 [M+H] + .

[0248] 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). Follow the same procedure as for the preparation of (S)-6,6-difluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The same procedure as described for (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) was used to obtain 2 as a white solid. LC-MS (ES, m / z): 364 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ10.66(s,1H),7.51-7.37(m,1H),7.21-7.08(m,3H),6.76(d,J=4.0Hz,1H),5.29-5.01(m,1H),4 .84(d,J=10.2Hz,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.

[0249] 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).

[0250] Process 3

[0251]

[0252] 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), Cs2CO3 (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 argon atmosphere. The reaction mixture was filtered and the filtrate was diluted with diethyl 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): δ8.87(s,1H),7.76(m,1H),7.29(m,1H),7.03(m,1H),2.37(d,J=1.0Hz,3H),1.27(s,9H).

[0253] 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 at -78°C under argon atmosphere over 30 minutes. After stirring at -78°C for 1 hour, the reaction was quenched by the addition of 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 x 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] + .

[0254] 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 solution (34.6 mL, 34.6 mmol) at room temperature. After stirring at room temperature for 1 hour, ice water (50 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (100 mL x 2). The aqueous layer was adjusted to pH 5 with saturated aqueous citric acid solution and then extracted with EtOAc (100 mL x 3). The combined organic extracts were then washed with brine (100 mL) and dried over anhydrous NaSO. 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) and ACN (28.0% ACN to 36.0% in 10 minutes); 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): δ13.57(br,1H),7.55(dd,J=7.5,2.2Hz,1H),7.23-6.94(m,2H),6.04(d,J=10.8Hz,1H),5.37-4.86(m,2H),2.29(s,3H),1.12(s,9H).

[0255] 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 argon atmosphere. After stirring at room temperature for 2 hours, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate solution (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 NaSO. The solvent was removed and the residue was dried in vacuo to give crude 3E (1.3 g) as a white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 514 [M+H]+ ; 1 H NMR (400 MHz, d 6 -DMSO): δ12.16(br,1H),7.66-7.45(m,1H),7.23-6.98(m,2H),6.37(m,1H),6.13(d,J=10.7Hz,1H),5.22(m,1H),4. 79(m,1H),3.94(m,2H),3.35(t,J=11.7Hz,2H),2.52-2.39(m,2H),2.29(s,3H),1.49(d,J=12.2Hz,2H),1.04(s,9H).

[0256] 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). To a solution of crude 3E (1.3 g, 2.53 mmol) in AcOH (10 mL) was added NaBHCN (398 mg, 6.33 mmol) at 0°C under argon atmosphere. After stirring at room temperature for 1 hour, ice water (20 mL) was added to the reaction mixture and the resulting solution was extracted with EtOAc (50 mL x 3). The combined organic extracts were then washed with brine (50 mL) and dried over anhydrous 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): δ11.31(d,J=28.1Hz,1H),7.41(d,J=7.4Hz,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=2.1Hz,10H).

[0257] 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). To a solution of crude 3F (1.3 g, 2.60 mmol) in ethanol (10 mL) was added thionyl chloride (334 mg) at 0°C. After stirring at room temperature for 1 hour, 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] + .

[0258] 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 material 3G (1.0 g, 2.53 mmol) in CH3CN (15 mL) was placed in a microwave reactor while stirring at 120°C for 30 minutes. Subsequently, the mixture was concentrated and the residue was purified by preparative HPLC (column: C18 silica gel; mobile phase: CH3CN:H2O=20:80 (v / v) increasing to CH3CN:H2O=80:20 (v / v) over 40 minutes; detector: UV 254 nm) to give compound 3 (302 mg, 32%) as a white solid, which was identified as Form 1 polymorph (see Example 2). LC-MS (ES, m / z): 378 [M+H] + ; 1 HNMR (300MHz, d 6 -DMSO): δ10.20(s,1H),7.38-7.05(m,3H),6.45(s,1H),5.11-4.81(m,3H),3.89(dd,J= 10.8,3.9Hz,2H),3.34-3.27(m,3H),2.76-2.48(m,4H),2.28(s,3H),1.39-1.36(m,2H); 19 FNMR (376 MHz, d 6 -DMSO): δ-123.51(t,J=86.5Hz),-191.57(d,J=129.34Hz).

[0259] 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)

[0260] Process 4

[0261]

[0262] Steps 1 to 7. Synthesis of (6R,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (4). Following the same procedure as described for the preparation of (6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2) and substituting 2-fluoro-5-methylbenzaldehyde (3A) for 3-fluorobenzaldehyde (1-1), 4 was obtained as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 1 HNMR (400MHz, d 6 -DMSO): δ10.69(s,1H),7.19-7.09(m,2H),6.98(d,J=6.8Hz,1H),6.62(d,J=3.6Hz,1H),5.08-4.84(m,3H),3. 91(dd,J=11.2,3.6Hz,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.

[0263] Example 1-5: Preparation and 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)

[0264] Process 5

[0265]

[0266] 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). Follow the same procedure as for the preparation of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)- The same procedure as described for 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (3) and substituting (S,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfenamide (4B) for (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfenamide (3B) gave 5 as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ10.72(s,1H),7.85-7.11(m,3H),6.45(s,1H),5.14-3.93(m,3H),3.92(dd,J= 10.4,5.2Hz,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.

[0267] 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)

[0268] Process 6

[0269]

[0270] 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). Follow the same procedure as for the preparation of (6R,7S)-6-fluoro-7-(3-fluorophenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. The same procedure as described for 6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (2) and substituting (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfenamide (3B) for (S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfenamide (1-2) afforded 6 as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 1 H NMR (300 MHz, d 6 -DMSO): δ10.69(s,1H),7.21-7.09(m,2H),6.98(d,J=6.8Hz,1H),6.66(d,J=3.6Hz,1H),5.11-4.84(m,3H),3.92( dd,J=11.1,3.9Hz,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 FNMR (376 MHz, d 6 -DMSO):δ-124.36,-175.43.

[0271] Additional compounds were prepared using methods analogous to those provided above.

[0272] Characterization data of compounds

[0273] Table 1A

[0274]

[0275]

[0276]

[0277]

[0278]

[0279] Example 2

[0280] Single Crystal X-ray Analysis - Form 1

[0281] The diffractometer was an Agilent Technologies (Dual Source) SuperNova diffractometer using a sealed tube monochromated Cu Kα SXRD analysis was performed using a diffractometer equipped with an Oxford Cryosystems cryostat capable of collecting data at 120(1)K and a crystal embedded in a protective layer of paratone oil. The collected data were corrected for absorption effects based on Gaussian integration on a multifaceted crystal model, performed as part of the CrysAlisPro software package (Agilent Technologies, 2014).

[0282] By direct method (SHELXS97) 1 The structure was solved and the F 2 (SHELXL97) 1 Developed by full least squares refinement (see Figure 4). 2 The resulting image was collected, analyzed, and crystallized in the orthorhombic space group P212121 using PLATON 4 ADDSYMM 3 The routine refined the structure in a search for higher-order symmetries but failed to reveal any higher-order symmetries. All non-hydrogen atoms were located in the Fourier map and their positions refined, and their anisotropic thermal shifts were subsequently described. Within the structure, only one complete molecule of 3 (also referred to as the compound of Example 3) was located in the asymmetric unit. Due to the weak diffraction data obtained, a Flack parameter of -0.0657 with an esd of 0.7497 (calculated from 1477 Bijovet pairs at 97.6% completeness) was calculated. Attempts to refine the structure using TWIN and BASF commands did not yield further improvement. A riding model with fixed Uiso was used to place all hydrogen atoms in the calculated positions at 1.2 times for all CH, CH2, and NH groups and 1.5 times for all CH3 groups. The highest residual Fourier peak is found to be from C(16) approximation And found that the deepest Fourier hole is from O(2) approximation

[0283] Crystal Data - Form 1

[0284] C 19 H 21 F2N3O3 (M=377.39 g / mol): orthorhombic system, space group P212121 (No. 19), Z=4, T=120(1)K, μ(CuKα)=0.964mm -1 , Dcalc=1.456g / cm 3 , 30202 reflections (10.18°≤2θ≤153.36°), 3570 unique values ​​(R int =0.1117, R sigma =0.0636), which was used in all calculations. The final R1 was 0.1591 (>2sigma(I)) and wR2 was 0.3889 (all data).

[0285] The X-ray powder diffraction (XRPD), dynamic scanning calorimetry (DSC), and thermogravimetric analysis (TGA) data of Form 1 of the compounds of Examples 1-3 are shown in Figures 1A-1C, Figure 2, and Figure 3, respectively.

[0286] Biological Examples

[0287] Compounds were profiled by evaluating their physicochemical properties, biochemical activity, cell-based 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 myofibril system (bcMF), and rabbit skeletal myofibril system (rbskMF) in the presence / absence of serum), cardiomyocyte contractility, and reactive metabolite identification.

[0288] Compounds with reduced half-lives are selected to enable potentially more rapid dose adjustments, as shorter half-lives allow for a more rapid time to steady-state exposure. Removing or minimizing the dependence of a drug candidate's metabolic clearance on polymorphic cytochrome P450 (CYP) enzymes, such as CYP2C19, offers the potential advantage of reduced human PK variability, which can occur, for example, between poor and rapid drug metabolizers. Removing or minimizing the potent CYP enzyme-inducing properties of new drug candidates offers the potential advantage of avoiding drug-drug interactions. Increased selectivity of drug candidates for cardiac myosin over skeletal myosin has desirable human pharmacokinetic benefits related to myosin modulator drug distribution. Myosin modulator drug candidates with reduced potency for skeletal myosin are predicted to be less distributed in skeletal muscle tissue due to lower binding of the drug to skeletal myosin, resulting in a reduced volume of distribution and, therefore, a reduced half-life in humans. Preclinical pharmacokinetic / pharmacodynamic studies are conducted to optimize selected compounds, thereby allowing oral administration with a reduced 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.

[0289] KS Solubility Analysis

[0290] The kinetic solubility of small molecule agents in PBS (pH 7.4) was assessed at room temperature using Reserpine (kinetic solubility <15 μM in PBS (7.4)) as a negative control and Verapamil (kinetic solubility >200 μM in PBS (7.4)) as a positive control. 2 μL of a 20 mM DMSO stock solution of the compound was added to a well in a 96-well plate, followed by 198 μL of PBS at room temperature. After shaking for 1.5 hours at room temperature, the mixture was filtered under vacuum through a 96-well filter disc pre-washed with 100 μL of 70% ethanol per well. Subsequently, 70 μL of the filtrate was added to a well in a 96-well reader pre-loaded with 70 μL of DMSO per well. The concentration of the sample in the well was determined based on the integration on the LC under UV detection, compared to the standard curve of each compound established in DMSO.

[0291] Myosin inhibition assay (bcMF pCa 6IC 50 (μM)

[0292] The ability of small molecule agents to inhibit the enzymatic activity of bovine cardiac myosin was assessed using a biochemical assay that correlates the release of ADP (adenosine diphosphate) from cardiac myosin with an enzymatic coupling system consisting of pyruvate kinase and lactate dehydrogenase (PK / LDH) and monitors the decrease in absorbance of NADH (at 340 nm) over time. PK converts ADP to ATP (adenosine triphosphate) by converting PEP (phosphoenolpyruvate) to pyruvate. Pyruvate is then converted to lactate by LDH by converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide). The source of cardiac myosin was from bovine heart in the form of skinned myofibrils. Prior to testing small molecule agents, the calcium responsiveness of bovine myofibrils was assessed, and the calcium concentration that achieved 50% activation of the myofibril system was selected as the final condition for evaluating the inhibitory activity of small molecule agents. All enzymatic activities were measured in a buffer solution containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), 2 mM magnesium chloride (pH 6.8) (PM12 buffer). 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, at the desired free calcium concentration required to achieve 50% activation of the myofibrils.

[0293] A dilution series of the compound is created in DMSO so that the final desired concentration of the compound will be achieved at a fixed DMSO concentration of 3.3% (v / v) in a 30 μL volume. Typically, 1 μL of the dilution series is added to a 384-well plate to achieve a 10-point dose response. After adding 14 μL of a solution containing bovine heart myofibrils, PK / LDH, and calcium solution (to achieve 50% activation), the enzymatic reaction is started by adding 15 μL of a solution containing ATP, PEP, and NADH. The reaction progress is tracked using a transparent bottom plate in a PerkinElmer Envision plate reader at ambient temperature. The plate reader is configured to read the absorbance at 340 nm for 15 minutes in kinetic mode. Data is recorded as the slope of the absorbance reaction versus time. The slope of the absorbance reaction over time is normalized to the slope on the plate containing DMSO. This normalized rate is then plotted as a function of small molecule concentration, and the data are fitted with a four-parameter fit using EXCEL XLfit. IC 50 Any agent that failed to achieve 50% inhibition at the highest concentration tested was reported as IC 50 higher than the highest concentration tested (i.e., IC 50 >50 μM).

[0294] Myosin inhibition assay (bcMF serum pCa 6IC 50 (μM)

[0295] Inhibition of the enzymatic activity of bovine cardiac myosin associated with the release of ADP (adenosine diphosphate) at calcium concentrations that achieve 50% activation of the bovine cardiac myofibril system in the presence of 10% human serum. Procedure and bovine cardiac myosin inhibition assay (bcMF pCa 6IC 50 (μM)) were the same, but with the addition of 10% human serum.

[0296] Myosin inhibition assay (rbskMF pCa 6IC 50 (μM)

[0297] Inhibition of the enzymatic activity of rabbit skeletal myosin associated with the release of ADP (adenosine diphosphate) at calcium concentrations that achieve 50% activation of the rabbit skeletal myofibril system. The procedure was similar to the bovine cardiac myosin inhibition assay (bcMF pCa 6IC) by substituting rabbit skeletal myofibrils for bovine cardiac myofibrils. 50 (μM)) are the same.

[0298] Pharmacokinetic / pharmacodynamic (PK / PD) relationships

[0299] The ability of small molecules to modulate systolic cardiac performance in a dose-dependent manner was assessed non-invasively using echocardiography in isoflurane-anesthetized SD rats. Cardiac function / geometry was first studied before and continuously (approximately every 3 minutes) following a 30-60 minute intravenous infusion (2.0 mg / kg / h IV, n=4). Subsequently, a group of conscious rats was also treated with vehicle control (0 mg / kg PO, n=3) or three dose levels of Compound 3 via oral gavage: low (2 mg / kg PO, n=4), medium (5 mg / kg PO, n=4), or high (10 mg / kg PO, n=5). In these animals, cardiac function / geometry was recorded under isoflurane anesthesia at two separate time points / day: once before dosing (i.e., at baseline, Day -2) and 2 hours after dosing (Day 0), when exposure is known to approach steady-state and peak response is expected. In these experiments, the systolic performance index, left ventricular fractional shortening (FS), as well as LV dimensions / volumes and heart rate were measured using a high-frequency transducer and parasternal long-axis transthoracic views (Vevo 2100, VisualSonic). FS was defined as the end-diastolic normalized change in the internal dimension / diameter of the left ventricle between end-systole (LVESd) and end-diastole (LVEDd) (i.e., FS = 100 x [LVEDd - LVESd] / LVEDd). LV volume (LVV = 7 x [2.4 + LVid]) was derived using the Teichholz model. - 1 xLVid 3 In all cases, blood samples were obtained (via tail vein microsampling) at the time of each echocardiography examination to establish pharmacokinetic / pharmacodynamic (PK / PD) relationships.

[0300] Cardiomyocyte contractility analysis

[0301] 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 perfusion chambers (20RC-27NE series; Warner Instruments), allowed to adhere to a coverslip, and then perfused with Tyrode's buffer at 37°C. Myocytes were stimulated at 1 Hz and a 10 V magnetic field. Only myocytes with distinct striations, resting before pacing, a cell length of 120-180 μm, a basal fractional shortening equal to 3-8% of cell length, and a contraction velocity greater than 100 μm / s were used for contractility experiments. For determining the reaction to compound (0.3 μM concentration), first myocytes were perfused with Tyrode's buffer for 60 seconds, then perfused with compound for 5 minutes and washed out with Tyrode's buffer for 140 seconds. IonOptix software was used to record data continuously. Ionwizard software (IonOptix) was used to analyze contractility data. For each cell, 10-20 contractility transient mean values ​​were taken and compared under basal conditions (no compound) and compound-treated conditions. Compound activity was measured by the impact of fractional shortening (FS), where fractional shortening is the ratio of the peak length of cells when contracting divided by the normalized basal cell length for 100% of untreated cells. % inhibition measurements were calculated by deducting FS values ​​from 100%.

[0302] Reactive metabolite identification

[0303] Reactive metabolite formation of small molecules was determined in vitro by detecting glutathione adducts formed in vitro during incubation with human liver microsomes fortified with NADPH and glutathione.

[0304] Methods: The metabolism of small molecules (30 μM) was assessed for glutathione adduct formation in a 1-hour incubation with human liver microsomes (1 mg / mL protein) in potassium phosphate buffer (0.1 M, pH 7.4) in a 96-well plate (2 mL well volume) at 37°C (200 μL volume, n = 3 incubations / treatment, 60-minute 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 waterbath incubator with slow horizontal shaking (30 rpm). To achieve a 30 μM compound incubation concentration, a 3 mM substrate stock solution in DMSO was used. The final incubation mixture contains 148 μL potassium phosphate buffer, 10 μL liver microsome solution (20 mg protein / mL), 2 μL 3mM matrix solution, and wherein by adding 40 μL NADPH solution (5mM, dissolved in potassium phosphate buffer) initial cultivation. Cultivation without NADPH is supplemented with 40 μL potassium phosphate buffer. After cultivation, the reaction is terminated by adding an equal volume of acetonitrile containing 20nM carbamazepine (carbamazepine) internal standard and 3% formic acid. The quenched sample is then centrifuged (4,600rpm, 4 ° C, 10 minutes), after which the supernatant is transferred to a 96-well LC-MS sample analysis plate and diluted with one volume equivalent of HPLC grade water, then heat-sealed with aluminum foil before analysis by liquid chromatography / mass spectrometry (LC-MS / MS).

[0305] Analyte identification: LC-MS / MS detection of test compounds and potential GSH-adducts (using online UV detection at 280 nm) was focused on the protonated molecular ion MH of the parent compound up to 4 decimal places using Xcalibur software (version 2.1.0, Thermo Fisher Scientific, Waltham, MA). + m / z and the corresponding protonated molecular ions (m / z MH +The relative GSH-adduct abundance in the in vitro liver microsomal extract was assessed by LC / UV absorbance using Xcalibur software (version 2.1.0) at 280 nm peak area ratios obtained between the GSH-adducts detected from the incubation extracts fortified with NADPH and GSH and the corresponding LC / UV peak areas of the parent compound from the incubation extracts without NADPH. The degree of GSH-adduct formation was determined by LC-MS / MS analysis using online LC-UV detection at 280 nm, divided by the LC / UV peak area of ​​the corresponding parent HCM-1NG analogue determined from the analysis of the control (-NAPDH, -GSH) incubation extracts.

[0306] Materials: Pooled male human (HLM, 50 donors) liver microsomes were obtained from Bioreclamation IVT (Baltimore, MD). Glutathione (GSH) and NADPH were purchased from Sigma Chemical Co. (St. Louis, MO). All solvents used for liquid chromatography-tandem mass spectrometry (LC-MS / MS) analysis were chromatographic grade.

[0307] LC-MS Conditions: Extracts from incubation with liver microsomes and hepatocytes were characterized by LC-MS and LC-MS / MS on a ThermoElectron LTQ Orbitrap XL mass spectrometer coupled to a Dionex UltiMate 3000 UHPLC with online secondary array detection and an OAS-3300TXRS autosampler (40 μL injection volume). Electrospray ionization (ESI) was employed in positive ion mode with a needle potential maintained at 5.01 kV, a sheath flow rate of 35.02, an auxiliary flow rate of 9.99, a current of 2.6 uA, a capillary temperature of 325°C, and a capillary voltage of 15.99. The vacuum conditions used were 2.33 × 10 -5 The ion gauge pressure used was 0.000 Torr and the convection gauge pressure was 0.90 Torr. LC-MS analysis was performed in positive ion mode (m / z 100 to m / z 1000) with a scan time of 0.73 seconds and a source collision energy of 10 V. Tandem MS / MS conditions used were 2 mTorr collision helium gas and a collision potential of 35 eV. Xcalibur software (version 2.1.0, Thermo Fisher Scientific, Waltham, MA) was used to acquire all data.

[0308] Capillary temperature (℃): 325

[0309] Source heater temperature (°C): 345

[0310] Sheath gas flow rate (mL / min): 50

[0311] Auxiliary gas flow rate (mL / min): 12

[0312] Purge gas flow rate (mL / min): 5

[0313] Source voltage (kV): 5.01

[0314] Source current (μA): 2.6

[0315] S-lens RF level: 50

[0316] Data-dependent scanning was used, which collected MS / MS spectra of the most abundant masses in an Orbitrap (15,000 resolving power) full scan mass spectrum.

[0317] HPLC conditions: Phenomenex with 30°C column oven temperature for chromatographic separation of HCM-1NG compounds and corresponding glutathione adducts. 2.6μm,C18, The incubation extract was chromatographed on a 100 x 2.1 mm reverse phase column. Chromatographic separation was achieved by eluting into an ESI source over 30 minutes at a flow rate of 0.3 mL / min using a reverse phase gradient elution. The gradient aqueous mobile phase (Solvent-A) consisted of water containing 0.1% formic acid (v / v) and the organic mobile phase (Solvent-B) contained acetonitrile containing 0.1% formic acid (v / v). Elution was achieved by linearly decreasing the initial aqueous Solvent-A mobile phase from 95% to 50% Solvent-A over 20 minutes, then linearly decreasing to 0% Solvent-A over 3.5 minutes, and holding constant at 0% Solvent-A for 1 minute. Finally, prior to further analysis, the gradient was linearly increased to 95% Solvent-A over 0.5 minutes, followed by a 5-minute equilibration at 95% Solvent-A.

[0318] Column: Phenomenex 2.6μm,C18, 100x 2.1mm reverse phase columns

[0319] Column oven temperature: 30°C

[0320] Flow rate: 0.3 mL / min

[0321] Mobile phase solvent-A: water containing 0.1% formic acid (v / v)

[0322] Mobile phase solvent-B: acetonitrile containing 0.1% formic acid (v / v)

[0323] Elution gradient:

[0324] 0 minutes 95% A

[0325] 0 to 20 minutes 50% A; linear

[0326] 20 to 23.5 minutes 0% A; linear

[0327] 23.5 to 24.5 minutes 0% A

[0328] 24.5 to 25.0 minutes 95% A; linear

[0329] 25.0 to 30.0 minutes 95% A

[0330] Biology Evaluation Form

[0331] Table 5

[0332]

[0333]

[0334] In Table 1B, in the column headed "% Inhibition of 0.3 μM FS", + indicates less than 33% inhibition of fractional shortening, ++ indicates 33% to 66% inhibition of fractional shortening, and +++ indicates greater than 66% inhibition of fractional shortening (i.e., maximum inhibition is +++).

[0335] Table 6

[0336]

[0337]

[0338] Table 1C represents data from a single experiment.

[0339] As demonstrated above, these compounds show minimal or no appearance of reactive metabolites.

[0340] X-ray powder diffraction (XRPD)

[0341] XRPD analysis was performed on a PANalytical X'pert pro scanning the sample between 3° and 35° 2θ. The material was gently ground to release any agglomerates and loaded onto a porous plate with Kapton or Mylar polymer film to support the sample. The porous plate was then placed in the diffractometer and the sample was analyzed using Cu K radiation ( α1:α2 ratio = 0.5) were analyzed using a 40 kV / 40 mA generator setting.

[0342] Thermogravimetric analysis (TGA)

[0343] About 5 mg of material was weighed into an open aluminum pan and loaded into a simultaneous thermogravimetric / differential thermal analyzer (TG / DTA) and kept at room temperature. The sample was then heated from 20°C to 400°C at a rate of 10°C / min, during which the sample weight change and any differential thermal events (DTA) were recorded. Nitrogen was used as a flushing gas with a flow rate of 300 cm 3 / min.

[0344] Differential Scanning Calorimetry (DSC)

[0345] Approximately 5 mg of material was weighed into a DSC aluminum pan and sealed non-hermetically with a perforated aluminum lid. The sample pan was then loaded into a Seiko DSC6200 (equipped with a cooler), cooled, and maintained at 20°C. Once a stable heat flow response was obtained, the sample and reference were heated to a maximum of 330°C at a scan rate of 10°C / min, and the resulting heat flow response was monitored. Nitrogen was used as a purge gas at a flow rate of 50 cm 3 Modulated DSC was performed with an amplitude of 0.32°C and a frequency of 0.017 Hz.

[0346] This application also includes the following terms:

[0347] 1. A compound having the formula:

[0348]

[0349] or a pharmaceutically acceptable salt thereof, wherein

[0350] Subscript n is 1 or 2;

[0351] Each R 1 is a member selected from the group consisting of fluorine, chlorine, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl; wherein at least one R 1 is fluorine; and

[0352] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other of is H; or optionally,

[0353] Where subscript n is 1 or 2;

[0354] 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, and optionally substituted C2-C4 alkynyl; wherein at least one R 1is fluorine; and

[0355] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0356] 2. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 2a For fluorine.

[0357] 3. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 2b For fluorine.

[0358] 4. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 2a is fluorine, and n is 1.

[0359] 5. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 2a is fluorine, and n is 2.

[0360] 6. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 2b is fluorine, and n is 1.

[0361] 7. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 2b is fluorine, and n is 2.

[0362] 8. The compound according to any one of clauses 1 to 3, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0363] 9. The compound according to item 1, which has the following formula:

[0364]

[0365] or a pharmaceutically acceptable salt thereof, wherein subscript n is 1; and

[0366] 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

[0367] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other of is H; or optionally,

[0368] Where n is 1; and

[0369] R1 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, and optionally substituted C2-C4 alkynyl; and

[0370] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0371] 10. The compound according to item 8, which has the following formula:

[0372]

[0373] or a pharmaceutically acceptable salt thereof.

[0374] 11. The compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein n is 2; optionally, one R 1 is fluorine and the other R 1 is selected from the group consisting of fluorine, C1-C4 alkyl, C2-C4 alkoxy and C2-C4 alkynyl; optionally, one R 1 is fluorine and the other R 1 is selected from the group consisting of fluoro, methyl, methoxy and ethynyl; or optionally,

[0375] wherein n is 2; optionally, one R 1 is fluorine and the other R 1 is selected from the group consisting of fluorine, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkoxy and optionally substituted C2-C4 alkynyl; optionally, one R 1 is fluorine and the other R 1 Selected from the group consisting of fluorine, hydroxymethyl, methyl, methoxy and ethynyl.

[0376] 12. The compound according to any one of clauses 1 to 3, or a pharmaceutically acceptable salt thereof, wherein n is 2, optionally having the formula:

[0377]

[0378] or a pharmaceutically acceptable salt thereof.

[0379] 13. The compound according to item 12 or a pharmaceutically acceptable salt thereof, wherein one R 1 is fluorine and the other R 1is selected from the group consisting of fluorine, C1-C4 alkyl, C1-C4 alkoxy and C2-C4 alkynyl; optionally, fluorine, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH); or optionally,

[0380] One of the R 1 is fluorine and the other R 1 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, hydroxymethyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH).

[0381] 14. The compound of any one of clauses 1 to 3, which has the following formula:

[0382]

[0383] or a pharmaceutically acceptable salt thereof.

[0384] 15. The compound according to item 14 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of fluorine, C1-C4 alkyl, C1-C4 alkoxy and C2-C4 alkynyl; optionally, fluorine, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH); or optionally,

[0385] where R 1 is 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, hydroxymethyl, methoxy, and ethynyl (—C≡CH).

[0386] 16. The compound according to item 1, which has the following formula:

[0387]

[0388] or a pharmaceutically acceptable salt thereof.

[0389] 17. The compound according to item 1, wherein the compound is:

[0390]

[0391] or a pharmaceutically acceptable salt of any one of the foregoing.

[0392] 18. The compound according to item 1, wherein the compound is:

[0393]

[0394] or a pharmaceutically acceptable salt of any one of the foregoing.

[0395] 19. The compound according to item 1, which has the following formula:

[0396]

[0397] or a pharmaceutically acceptable salt thereof.

[0398] 20. The compound according to item 1, which has the following formula:

[0399]

[0400] or a pharmaceutically acceptable salt thereof.

[0401] 21. The compound according to item 1, which has the following formula:

[0402]

[0403] or a pharmaceutically acceptable salt thereof.

[0404] 22. The compound according to item 1, which has the following formula:

[0405]

[0406] or a pharmaceutically acceptable salt thereof.

[0407] 23. The compound according to item 1, which has the following formula:

[0408]

[0409] or a pharmaceutically acceptable salt thereof.

[0410] 24. The compound according to item 1, which has the following formula:

[0411]

[0412] or a pharmaceutically acceptable salt thereof.

[0413] 25. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, optionally further comprising a pharmaceutically acceptable excipient.

[0414] 26. The pharmaceutical composition of clause 25, wherein the composition is substantially free of other isomers at carbon atoms bearing a phenyl ring.

[0415] 27. The pharmaceutical composition of clause 25 or 26, wherein the composition is substantially free of other isomers at carbon atoms bearing fluorine adjacent to carbon atoms bearing a benzene ring.

[0416] 28. A method of treatment, comprising administering to a subject in need thereof an effective amount of a compound according to any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27.

[0417] 29. A method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features of HCM), the method comprising administering to a subject in need thereof an effective amount of a compound as described in any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in any one of clauses 25 to 27.

[0418] 30. A method for treating a disease or condition selected from the group consisting of diastolic heart failure (e.g., heart failure with preserved ejection fraction), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, the method comprising administering to a subject in need thereof 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.

[0419] 31. A method for treating a disease or condition characterized by left ventricular hypertrophy (e.g., left ventricular hypertrophy due to volume or pressure overload) selected from the group consisting of chronic mitral valve regurgitation, chronic aortic stenosis, and chronic systemic hypertension; in combination with a therapy aimed at correcting or reducing the primary cause of volume or pressure overload, including valve repair / replacement or effective antihypertensive therapy, the method comprising administering to a subject in need thereof an effective amount of a compound as described in any one of items 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in any one of items 25 to 27.

[0420] 32. A method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), the method comprising administering to a subject in need thereof an effective amount of a compound of any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of clauses 25 to 27, in combination with a therapy that delays the progression of heart failure by downregulating neurohormonal stimulation of the heart and attempts to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers,

[0013] Therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0421] 33. A compound according to any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for use as a medicament.

[0422] 34. A compound according to any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for use in treating hypertrophic cardiomyopathy or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features of HCM).

[0423] 35. A compound according to any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for use in treating a disease or condition 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.

[0424] 36. A compound according to any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for use in the treatment of a disease or condition characterized by left ventricular hypertrophy (e.g., left ventricular hypertrophy due to volume or pressure overload) 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 reducing the primary cause of volume or pressure overload, including valve repair / replacement or effective antihypertensive therapy.

[0425] 37. A compound according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for use in treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), wherein the compound is used in combination with a therapy that delays the progression of heart failure by downregulating neurohormonal stimulation of the heart and attempts to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs) , beta-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (vasodilators of any kind, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0426] 38. A compound according to any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for use in the manufacture of a medicament.

[0427] 39. Use of a compound according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for the manufacture of a medicament for treating hypertrophic cardiomyopathy or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features of HCM).

[0428] 40. Use of a compound according to any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for the manufacture of a medicament for treating a disease or condition 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.

[0429] 41. Use of a compound according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for the manufacture of a medicament for the treatment of a disease or condition characterized by left ventricular hypertrophy (e.g. due to volume or pressure overload), 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 reducing the primary cause of volume or pressure overload, including valve repair / replacement or effective antihypertensive therapy.

[0430] 42. Use of a compound according to any one of clauses 1 to 24, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of clauses 25 to 27, for the manufacture of a medicament for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder (e.g., a cardiac disorder with pathophysiological features associated with HCM), in combination with a therapy that delays the progression of heart failure by downregulating neurohormonal stimulation of the heart and attempts to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), B), beta-blockers, aldosterone receptor antagonists or neuropeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropes such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators).

[0431] 43. A Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione characterized by at least one of the following:

[0432] a. a powder X-ray diffraction pattern having two or more peaks expressed in degrees 2θ ± 0.2° 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;

[0433] b. a DSC thermogram showing endotherms at about 226.05 ° C, at about 302.47 ° C, and at about 310.13 ° C; or

[0434] c. X-ray crystal structure essentially the same as that in FIG4 .

[0435] 44. The polymorph of clause 43, wherein the powder X-ray diffraction pattern has three or more peaks expressed in degrees 2θ±0.2° selected from the group consisting of 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.

[0436] 45. The polymorph of clause 43, wherein the powder X-ray diffraction pattern has four or more peaks expressed in degrees 2θ±0.2° selected from the group consisting of 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.

[0437] 46. ​​The polymorph of clause 43, wherein powder X-ray diffraction has peaks expressed in degrees 2θ±0.2° at each of 11.3, 12.4, and 13.3 degrees.

[0438] 47. The polymorph of clause 43, wherein powder X-ray diffraction has peaks expressed in degrees 2θ±0.2° at each of 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, and 29.5 degrees.

[0439] 48. The polymorph of item 43, wherein the melting onsets are about 221.51°C, about 299.53°C, and about 308.81°C.

[0440] 49. The polymorph of clause 43, wherein the polymorph has a powder X-ray diffraction pattern substantially the same as that of Figure 1A.

[0441] 50. The polymorph of any one of clauses 43 to 49, wherein the Form 1 polymorph is substantially free of other forms of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

[0442] 51. A pharmaceutical composition comprising the polymorph of any one of clauses 43 to 50, and a pharmaceutically acceptable excipient.

[0443] 52. The composition of clause 51, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 80:20.

[0444] 53. The composition of clause 51, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 90:10.

[0445] 54. The composition of clause 51, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 95:5.

[0446] 55. The composition of clause 51, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 97:3.

[0447] 56. The composition of clause 51, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 98:2.

[0448] 57. The composition of clause 51, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 99:1.

[0449] 58. A method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder with pathophysiological features of HCM, the method comprising administering to a subject in need thereof an effective amount of a polymorph as defined in any one of clauses 43 to 50, or a pharmaceutical composition as defined in any one of clauses 51 to 57.

[0450] 59. A method of treating a disease or condition characterized by left ventricular hypertrophy due to volume or pressure overload, the disease or condition being selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; in combination with a therapy directed to correcting or alleviating the primary cause of volume or pressure overload, including valve repair / replacement or an effective antihypertensive therapy, the method comprising administering to a subject in need thereof an effective amount of a polymorph as defined in any one of clauses 43 to 50, or a pharmaceutical composition as defined in any one of clauses 51 to 57.

[0451] 60. A method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder with pathophysiological features associated with HCM, the method comprising administering to a subject in need thereof an effective amount of a polymorph of any one of clauses 43 to 50, or a pharmaceutical composition of any one of clauses 51 to 57, in combination with: a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuropeptidase inhibitors); a therapy that improves cardiac function by stimulating cardiac contractility (e.g., a positive inotrope, such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a therapy that reduces cardiac preload (e.g., a diuretic, such as furosemide) or afterload (a vasodilator of any kind, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin regulators).

[0452] The recitation of a list of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups.

[0453] Although the above disclosure has been described in considerable detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will appreciate that certain variations and modifications may be implemented within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and a reference provided herein, the present application shall prevail.

Claims

1. A compound having the formula: or a pharmaceutically acceptable salt thereof, wherein Subscript n is 1 or 2; Each R 1 is a member selected from the group consisting of fluorine, chlorine, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl optionally substituted with hydroxy; wherein at least one R 1 is fluorine; and R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

2. The compound of claim 1, which has the formula: or a pharmaceutically acceptable salt thereof, wherein Subscript n is 1 or 2; Each R 1 is a member selected from the group consisting of fluorine, chlorine, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy and C2-C4 alkynyl; wherein at least one R 1 is fluorine; and R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 2a is fluorine and R 2b is H, or R 2a H and R 2b For fluorine.

4. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 2a is fluorine, and n is 1.

5. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 2a is fluorine, and n is 2.

6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 2b is fluorine, and n is 1.

7. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2b is fluorine, and n is 2.

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

9. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt thereof, 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 optionally substituted with hydroxy; and R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

10. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein n is 1 and has the following formula: or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 2, one R 1 is fluorine and the other R 1 can be selected from the group consisting of fluorine, C1-C4 alkyl optionally substituted with hydroxyl, C 1-4 Alkoxy and C2-C4 alkynyl.

12. The compound of claim 1 or 2, wherein n is 2 and has the formula: or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 having the formula: or a pharmaceutically acceptable salt thereof, wherein R 1 It may be selected from the group consisting of fluorine, C1-C4 alkyl optionally substituted with hydroxy, C1-C4 alkoxy and C2-C4 alkynyl.

14. The compound according to any one of claims 1, 9, 11 and 13, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a hydroxyalkyl group.

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 1 It is hydroxymethyl.

16. A compound selected from the group consisting of: or a pharmaceutically acceptable salt of any one of the foregoing.

17. A compound having the formula: or a pharmaceutically acceptable salt thereof.

18. A compound having the formula: or a pharmaceutically acceptable salt thereof.

19. A compound having the formula:

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A pharmaceutical composition comprising the compound of claim 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. A pharmaceutical composition comprising the compound of claim 19 and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition of claim 20, wherein the compound has Formula 1a: Where subscript n is 1.

24. The pharmaceutical composition of claim 20, wherein the compound has Formula 1b:

25. The pharmaceutical composition of claim 20, wherein the compound has Formula 1c:

26. The pharmaceutical composition of claim 20, wherein the compound has Formula Id:

27. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or a compound according to claim 19 for the preparation of a medicament for the treatment of hypertrophic cardiomyopathy (HCM) or a cardiac disorder with pathophysiological features of HCM.

28. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof or a compound according to claim 19 in the preparation of a medicament for treating a disease or condition selected from the group consisting of heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris and restrictive cardiomyopathy.

29. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a compound according to claim 19, for the preparation of a medicament for the treatment of a disease or condition characterized by left ventricular hypertrophy due to volume or pressure overload, 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, including valve repair / replacement or effective antihypertensive therapy.

30. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a compound according to claim 19, for the preparation of a medicament for the treatment of hypertrophic cardiomyopathy (HCM) or a cardiac disorder with pathophysiological features associated with HCM, in combination with a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart; a therapy that improves cardiac function by stimulating cardiac contractility; and / or a therapy that reduces cardiac preload or afterload.

31. The use of claim 30, wherein the therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart is selected from ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists or neuropeptidomase inhibitors.

32. The use according to claim 30, wherein the therapy for improving cardiac function by stimulating cardiac contractility is a positive inotropic agent.

33. The use according to claim 32, wherein the positive inotropic agent is the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone.

34. The use of claim 30, wherein the therapy for reducing cardiac preload is a diuretic.

35. The use according to claim 34, wherein the diuretic is furosemide.

36. The use according to claim 30, wherein the therapy for reducing cardiac afterload is any kind of vasodilator.

37. The method of claim 36, wherein the vasodilator of any kind is selected from calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators.

38. A polymorphic form 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 in that A powder X-ray diffraction pattern having two or more peaks expressed in degrees 2θ±0.2° 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.

39. The polymorph of claim 38, characterized in that DSC thermogram showing endotherms at 226.05°C±2°C, at 302.47°C±2°C, and at 310.13°C±2°C.

40. The polymorph of claim 38 or 39, wherein the powder X-ray diffraction pattern has three or more peaks expressed in degrees 2θ±0.2° selected from the group consisting of 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.

41. The polymorph of claim 38 or 39, wherein the powder X-ray diffraction pattern has four or more peaks expressed in degrees 2θ±0.2° selected from the group consisting of 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.

42. The polymorph of claim 38 or 39, wherein powder X-ray diffraction has peaks expressed in degrees 2θ ± 0.2° at each of 11.3, 12.4 and 13.3 degrees.

43. The polymorph of claim 42, wherein powder X-ray diffraction has peaks expressed in degrees 2θ ± 0.2° at each of 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4 and 29.5 degrees.

44. The polymorph of claim 38 or 39, wherein the melting onsets are 221.51°C ± 2°C, 299.53°C ± 2°C, and 308.81°C ± 2°C.

45. The polymorph of any one of claims 38 to 44, 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.

46. ​​A pharmaceutical composition comprising the polymorph according to any one of claims 38 to 45, and a pharmaceutically acceptable excipient.

47. The composition of claim 46, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 80:

20.

48. The composition of claim 46, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 90:

10.

49. The composition of claim 46, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 95:

5.

50. The composition of claim 46, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 97:

3.

51. The composition of claim 46, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 98:

2.

52. The composition of claim 46, wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of the other forms is greater than or equal to 99:

1.

53. Use of a polymorph according to any one of claims 38 to 45 or a pharmaceutical composition according to any one of claims 46 to 52 in the preparation of a medicament for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having pathophysiological features of HCM in a subject in need thereof.

54. Use of a polymorph according to any one of claims 38 to 45 or a pharmaceutical composition according to any one of claims 46 to 52 in the preparation of a medicament for treating a disease or condition characterized by left ventricular hypertrophy due to volume or pressure overload in a subject in need thereof, the disease or condition being selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis and chronic systemic hypertension; wherein the medicament is used in combination with a therapy aimed at correcting or reducing the primary cause of volume or pressure overload, including valve repair / replacement or an effective antihypertensive therapy.

55. Use of a polymorph according to any one of claims 38 to 45 or a pharmaceutical composition according to any one of claims 46 to 52 in the preparation of a medicament for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder with pathophysiological features associated with HCM in an individual in need thereof, wherein the medicament is used in combination with a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart; a therapy that improves cardiac function by stimulating cardiac contractility; and / or a therapy that reduces cardiac preload or afterload.

56. The method of claim 55, wherein the therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart is selected from ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists or neuropeptidase inhibitors.

57. The use of claim 55, wherein the therapy for improving cardiac function by stimulating cardiac contractility is a positive inotropic agent.

58. The use according to claim 57, wherein the positive inotropic agent is the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone.

59. The method of claim 55, wherein the therapy for reducing cardiac preload is a diuretic.

60. The use of claim 59, wherein the diuretic is furosemide.

61. The use of claim 55, wherein the therapy for reducing cardiac afterload is any type of vasodilator.

62. The method of claim 61, wherein the vasodilator of any kind is selected from calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin regulators.

63. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a compound according to claim 19, in the preparation of a medicament for treating a cardiac disease or disorder in a subject in need thereof, wherein the cardiac disease or disorder is selected from the group consisting of: diastolic dysfunction, hypertrophic cardiomyopathy, nHCM, oHCM, heart failure, HFpEF, HFmREF, valvular disease, aortic stenosis, left ventricular hypertrophy, restrictive cardiomyopathy, inflammatory cardiomyopathy, Loeffler endocarditis, endomyocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, Tetralogy of Fallot, left ventricular hypertrophy, angina pectoris, refractory angina pectoris, and Chagas disease.

64. The use of claim 63, wherein the cardiac disease or disorder is selected from the group consisting of nHCM, oHCM, HFpEF, HFmREF, aortic stenosis, Loeffler's endocarditis, endomyocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, tetralogy of Fallot, angina pectoris, refractory angina and Chagas' disease.

65. The use of any one of claims 63 to 64, wherein the compound or a pharmaceutically acceptable salt thereof is administered as a monotherapy.

66. The use of any one of claims 63 to 64, wherein the compound or a pharmaceutically acceptable salt thereof is administered as a combination therapy, wherein an additional therapeutic agent is administered.

67. The use of claim 66, wherein the additional therapeutic agent is selected from the group consisting of: beta adrenergic blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, angiotensin receptor neprilysin inhibitors (ARNI), mineralocorticoid receptor antagonists (MRA), cholesterol-lowering drugs, neutral endopeptidase inhibitors (NEPi), positive inotropes, potassium, magnesium, proprotein convertase subtilisinkexin-type 9 (PCSK9) inhibitors, vasodilators, diuretics, arrhythmic drugs, anticoagulants, antithrombotic agents, antiplatelet agents, sodium-glucose co-transporter 2 inhibitors (SGLT2) or any combination thereof.

68. The method of claim 67, wherein the renin-angiotensin-aldosterone system (RAAS) inhibitor is an angiotensin converting enzyme (ACE) inhibitor or an angiotensin receptor antagonist.

69. The method of claim 68, wherein the angiotensin receptor antagonist is an angiotensin II receptor blocker.

70. The method of claim 67, wherein the angiotensin receptor neprilysin inhibitor (ARNI) is sacubitril / valsartan.

71. The method of claim 67, wherein the mineralocorticoid receptor antagonist (MRA) is an aldosterone inhibitor.

72. The method of claim 71, wherein the aldosterone inhibitor is a potassium sparing diuretic.

73. The use of claim 72, wherein the potassium-sparing diuretic is eplerenone, spironolactone or canrenone.

74. The method of claim 67, wherein the cholesterol-lowering drug is a statin.

75. The method of claim 67, wherein the positive inotropic agent is digoxin, pimobendan, a beta adrenergic receptor agonist, a phosphodiesterase (PDE)-3 inhibitor, or a calcium sensitizer.

76. The method of claim 75, wherein the beta adrenergic receptor agonist is dobutamine.

77. The method of claim 75, wherein the phosphodiesterase (PDE)-3 inhibitor is milrinone.

78. The method of claim 75, wherein the calcium sensitizer is levosimendan.

79. The method of claim 67, wherein the vasodilator is a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor or a smooth muscle myosin regulator.

80. The use of claim 67, wherein the diuretic is furosemide.

81. The method of claim 67, wherein the anticoagulant is warfarin.

82. The method of claim 67, wherein the sodium-glucose co-transporter 2 inhibitor (SGLT2) is empaglifozin, dapagliflozin or sotagliflozin.

83. The method of claim 69, wherein the angiotensin II receptor blocker (ARB) is selected from the group consisting of A-81988, A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, candesartan, candesartan cilexetil, 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-0 056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan, isoteoline, KRI-1177, KT3-671, KW-3433, losartan, LR-B / 057, L-158809, L-158978, L-159282, L-159874, L-161177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B / 081, LR B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin acetate acetate), S-8307, S-8308, SC-52458, saprisartan, saralasin, sarmesin, SL-91.0102, tasosartan, telmisartan, UP-269-6, U-96849, U-97018, UP-275-22, WAY-126227, WK-1492.2K, YM-31472, WK-1360, X-6803, valsartan, XH-148, XR-510, YM-358, ZD-6888, ZD-7155, ZD-8731 and zolasartan.

84. The use of any one of claims 67-82, wherein the ARNI is selected from the group consisting of sacubitril, valsartan, or a combination of sacubitril and valsartan.

85. The use of claim 84, wherein the SGLT2 is selected from the group consisting of empagliflozin, dapagliflozin and sogliflozin.

86. The use of claim 66, wherein the additional therapeutic agent improves a cardiovascular condition in the individual.

87. The use of any one of claims 66-82 and 86, 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 blockers, mineralocorticoid receptor antagonists, ARNI, RAAS inhibitors, arrhythmic drugs and SGLT2 inhibitors.

88. Use of a compound according to claim 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating hypertrophic cardiomyopathy (HCM).

89. The use according to claim 88, wherein the HCM is obstructive hypertrophic cardiomyopathy (oHCM).

90. The use of claim 88, wherein the HCM is non-obstructive hypertrophic cardiomyopathy (nHCM).

91. Use of a compound as claimed in claim 19 in the preparation of a medicament for the treatment of hypertrophic cardiomyopathy (HCM).

92. The use of claim 91, wherein the HCM is obstructive hypertrophic cardiomyopathy (oHCM).

93. The use of claim 91, wherein the HCM is non-obstructive hypertrophic cardiomyopathy (nHCM).

94. Use of a compound according to claim 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating heart failure with preserved ejection fraction (HFpEF).

95. Use of a compound as claimed in claim 19 for the preparation of a medicament for the treatment of heart failure with preserved ejection fraction (HFpEF).

96. Use of a compound as claimed in claim 18 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating left ventricular hypertrophy.

97. Use of a compound as claimed in claim 19 in the preparation of a medicament for the treatment of left ventricular hypertrophy.

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