Tetrahydropyrane (THP) substituted bicyclic pyrimidinedione compounds

Abstract

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

Description

[0001] This application is a divisional application of Chinese patent application No. 201980071171.4 (application date: October 28, 2019, invention name: bicyclic pyrimidinedione compounds substituted with tetrahydropyran (THP)).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. USSN 62 / 752,278, filed on October 29, 2018, entitled “Tetrahydropyran (THP)-Substituted Bicyclic-pyrimidinedione Compounds”, which is incorporated herein by reference in its entirety. Prior art

[0004] Genetic (inherited) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, monogenic, autosomal dominant heart muscle diseases. HCM is caused by one or more of the more than 1,000 known point mutations in any of the structural protein genes 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 (e.g., hypertension or valvular disease), and many of these individuals may be shown to have HCM once other genetic (e.g., lysosomal storage diseases), metabolic, or infiltrative causes have been ruled out.

[0005] The myometrial 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 a long period of time, HCM is a progressive disease with a significant cumulative burden of morbidity. Symptoms of effort intolerance dominate 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. So far, the most common clinical burden for HCM patients is exercise dyspnea, which limits the patient's daily living activities and can be debilitating.

[0006] 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.

[0007] Medical therapies for HCM are limited to symptomatic treatment and do not address the underlying underlying cause of the disease - the destruction of normal myometrial function. Currently available therapies can variably effectively alleviate symptoms, but typically show that efficacy decreases as the duration of the disease 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 there is essentially no rigorous clinical trial evidence available for guiding its use. The fact that new medical therapies for HCM have not been identified for many years exacerbates this unfortunate situation. For patients with hemodynamically significant outflow tract obstruction (static gradient>30mmHg), surgical myectomy or alcohol septal ablation is usually required in appropriately selected patients to alleviate hemodynamic obstruction. The present application provides a new therapeutic agent and method for remedying the long-term need for the treatment of improving HCM and related cardiac disorders and / or diseases. Summary of the invention

[0008] In one aspect, a compound having formula (I) is provided:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein

[0011] Subscript n is 1 or 2;

[0012] Each R 1 is a member selected from the group consisting of fluorine, chlorine, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C1 -C 4 Haloalkoxy and C 2 -C 4 Alkynyl; wherein at least one R 1 is fluorine; and

[0013] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0014] In one aspect, a compound having formula (I) is provided:

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein

[0017] Subscript n is 1 or 2;

[0018] Each R 1 is a member selected from the group consisting of fluorine, chlorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 Alkoxy, optionally substituted C 1 -C 4 Haloalkoxy and optionally substituted C 2 -C 4 Alkynyl; wherein at least one R 1 is fluorine; and

[0019] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0020] In another aspect, there is provided 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:

[0021] a. having a powder X-ray diffraction pattern having two or more peaks expressed in degrees 2θ ± 0.2° and selected from 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5, 32.9, 34.3, 35.5 and 38.8 degrees;

[0022] b. a DSC thermogram showing endotherms at about 226.05°C, at about 302.47°C, and at about 310.13°C; or

[0023] c. Basically Figure 4 Same X-ray crystal structure.

[0024] In another aspect, the present application provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described herein and optionally a pharmaceutically acceptable excipient.

[0025] 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 to the individual an effective amount of a compound as described herein. In certain 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.

[0026] In certain aspects, the present application provides a method of treating a cardiac disease or disorder, the method 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 disorder is selected from the group consisting of: diastolic dysfunction, hypertrophic cardiomyopathy, nHCM, oHCM, heart failure, HFpEF, HFmREF, valvular disease, aortic stenosis, left ventricular hypertrophy, restrictive cardiomyopathy, inflammatory cardiomyopathy, Loeffler endocarditis, endomyocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, congenital heart disease, tetralogy of Fallot, left ventricular hypertrophy, angina pectoris, refractory angina pectoris, and Chagas' disease. In certain aspects, the cardiac disease or disorder is selected from the group consisting of nHCM, oHCM, HFpEF, HFmREF, aortic stenosis, Loeffler's endocarditis, endomyocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, tetralogy of Fallot, angina pectoris, refractory angina, and Chagas' disease.

[0027] In some aspects, the present application provides a method of treating a cardiac disease or condition, comprising administering to an individual 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.

[0028] In some aspects, the present application provides a method for treating a cardiac disease or condition, the method comprising administering to an individual 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 (ARNI) (e.g., sacubitril / valsartan), mineralocorticoid receptor antagonists (MRA) (e.g., aldosterone inhibitors, such as potassium-sparing diuretics, such as eplerenone, spironolactone (sp 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 (proprotein convertase subtilisin kexin-type 9, PCSK9) inhibitors, vasodilators (e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors or smooth muscle myosin modulators), diuretics (e.g., furosemide), arrhythmic agents, 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, saralasin 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 sogliflozin. In some aspects, the additional therapeutic agent improves the cardiovascular condition 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, arrhythmic drugs and SGLT2 inhibitors.

[0029] 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 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, ejection fraction-preserving heart failure (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.

[0030] 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, the method comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0031] 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.

[0032] In another aspect, the present application provides a method for preventing or treating hypertrophic cardiomyopathy (HCM) or a cardiac disease or its symptoms having pathophysiological features associated with HCM, 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, 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).

[0033] In another aspect, a pharmaceutical composition is provided, comprising the Form 1 polymorph and a pharmaceutically acceptable excipient.

[0034] In another aspect, a method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder 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.

[0035] 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; in combination with a therapy directed to correct or reduce the primary cause of volume or pressure overload, including valve repair / replacement or effective antihypertensive therapy, is provided, the method comprising administering to a subject in need thereof an effective amount of Form 1 polymorph or a pharmaceutical composition comprising Form 1 polymorph.

[0036] 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., 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 inotropic agent, 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 (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). The present 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. Isotope-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 isotope-labeled compounds of formula (I), they can also advantageously modulate biological, pharmacological or pharmacokinetic properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figures 1A to 1C X-ray powder diffraction (XRPD) data for the Form 1 polymorph of the compound of Examples 1-3 (also referred to as Compound 3) are shown.

[0038] Figure 2 Shown is a dynamic scanning calorimetry (DSC) graph of the Form 1 polymorph of the compound of Examples 1-3 (also referred to as Compound 3).

[0039] Figure 3 Thermogravimetric analysis (TGA) of the Form 1 polymorph of the compound of Examples 1-3 (also referred to as Compound 3) is shown.

[0040] Figure 4 Shown is 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. DETAILED DESCRIPTION

[0042] A series of tetrahydropyran (THP) substituted bicyclic pyrimidinedione compounds have been found to reduce excess contractile force in the hypercontractile state 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 binding strongly to actin filaments and releasing 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 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 the risk of CYP induction (such as CYP3A4 induction) is absent or reduced. 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 required time course of the intensity of action in response to the administered drug dose. In addition, the compounds of the present application have a beneficial solubility, such as a micromolar solubility of more than 50, such as more than 70, at pH 7.4. In some cases, the compounds of the present application have a micromolar solubility of more than 80, such as more than 90. The compounds can also be used to treat other cardiac diseases.

[0043] 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. In general, the term "about" provides a deviation of ±0-2°C when referring to temperature.

[0044] 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 includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. In some cases, the alkyl is optionally substituted. In some cases, the alkyl is unsubstituted. In some aspects, the alkyl is substituted. Alkyl substituents include, but are not limited to, any of the substituents described herein that form a stable portion. In some aspects, the substituent may be one or more hydroxyl groups. In some such cases, the alkyl may also be referred to as hydroxyalkyl. The term "hydroxyalkyl" as used herein refers to an alkyl as provided above, wherein at least one hydrogen atom of the hydrocarbon portion is replaced by a hydroxyl group (-OH). Therefore, "hydroxyalkyl" refers to, for example, hydroxymethyl, 2-hydroxyethyl, and 2-hydroxypropyl.

[0045] 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 may 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 may be substituted or unsubstituted.

[0046] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic ring containing 3 or 4 ring atoms or the indicated number of atoms. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl or cyclobutyl. Cycloalkyl may also be partially unsaturated, having one or more double bonds in the ring. Representative partially unsaturated cycloalkyls include cyclobutene. Unless otherwise specified, cycloalkyl is unsubstituted.

[0047] 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).

[0048] The terms "halo" and "halogen" as used herein refer to fluoro, chloro, bromo and iodo.

[0049] 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 fully halogenated 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.

[0050] 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 C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , 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.

[0051] It will be understood that the above-mentioned groups and / or compounds as described herein may be optionally substituted with any number of substituents or functional moieties. That is, any of the above-mentioned groups may be optionally substituted. The term "optionally substituted" as used herein is intended to include unsubstituted variants and / or substituted variants (that is, "optionally substituted" can be used interchangeably with "substituted or unsubstituted"). The term "substituted" as used herein 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 or not preceded by the term "optionally" and the substituents contained in the formula of the present application refers to the replacement of hydrogen groups in a given structure by groups of designated substituents. When more than one position in any given structure may be substituted by more than one substituent selected from a designated group, the substituents at each position may be the same or different. It will be understood that "substituted" also includes substitutions that produce stable compounds, for example, the compound does not spontaneously undergo transformations, such as by rearrangement, cyclization, elimination, etc. In some cases, "substituted" may generally refer to hydrogen being replaced by substituents as described herein. However, "substituted" as used herein does not encompass the replacement and / or change of key functional groups used to identify molecules, for example, so that the "substituted" functional group becomes a different functional group via substitution. For example, "substituted phenyl" must still include a phenyl moiety and cannot be modified by substitution to become, for example, a pyridine ring in this definition. In a broad sense, allowable 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, allowable 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 allowable substituents of organic compounds described herein, which satisfy the valence of heteroatoms. In addition, the application is not intended to be limited in any way by the allowable 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.

[0052] 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, silane, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclic, aromatic or heteroaromatic moiety, -CF3, -CN, aryl, aryloxy, perhaloalkoxy, aralkyloxy, heteroaryl, heteroaryloxy, heteroarylalkyl, heteroaralkyl The invention also includes but is not limited to alkyl, alkylamino, alkylaryl, alkylaminoalkyl, alkyloxy, alkylaminoaryl, alkylaryl, alkylaminoalkyl, alkyloxyaryl, arylamino, arylalkylamino, alkylsulfonyl, -carboxamidoalkylaryl, -carboxamidoaryl, hydroxyalkyl, haloalkyl, alkylaminoalkylcarboxy-, aminocarboxamidoalkyl-, cyano, alkoxyalkyl, perhaloalkyl, arylalkoxyalkyl and the like.

[0053] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications, within the scope of reasonable medical judgment, and are compatible with a reasonable benefit / risk ratio. Pharmaceutically acceptable substances are compatible with the compound of formula (I) and any other ingredients formulated with the compound.

[0054] The term "salt" as used herein refers to an acid salt or base salt of a compound of formula (I). Pharmaceutically acceptable salts may 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.

[0055] 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 acids. In such cases, pharmaceutically acceptable salts may be relatively nontoxic, inorganic and organic acid addition salts of the compounds of the present application. These salts can be prepared on site during the administration of a drug delivery vehicle or a dosage form manufacturing process, or by reacting the purified compounds of the present application in the form of free alkali independently with suitable organic or inorganic acids, and separating the salts thus formed during subsequent purification to prepare. Non-limiting examples of salts include hydrobromate, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthoate (napthylate), mesylate, gluconate, lactobionate and lauryl sulfonate and its analogs. (See, e.g., Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19)

[0056] 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.

[0057] In some cases, the compound of the present application may contain one or more acidic functional groups and thus be able to form a pharmaceutically acceptable salt with a pharmaceutically acceptable base. In such cases, a pharmaceutically acceptable salt may be a relatively nontoxic, 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 making the purified compound in the form of a free acid independently react with a suitable base, such as a pharmaceutically acceptable hydroxide, carbonate or bicarbonate of a metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary or tertiary amine reaction to prepare. 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.

[0058] 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.

[0059] 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.

[0060] Certain compounds of the present application 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 included within the scope of the present application. When a stereochemical drawing is shown, it means that one of the isomers is present and there is substantially no other isomer. "Substantially free" of 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 amount 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 include at least about 99% of the disclosed isomer in the pharmaceutical composition based on the total molar concentration amount of all isomeric forms of the disclosed compound present in the pharmaceutical composition (including the disclosed isomeric form and all other isomeric forms).

[0061] The term "pharmaceutical composition" as used herein 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 resulting directly or indirectly from a combination of specified ingredients in specified amounts.

[0062] As used herein, the term "excipient" refers to a substance that aids in administering an active agent to an individual. Pharmaceutical excipients suitable for use in the present application include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will recognize that other excipients may be suitable for use in the present application.

[0063] As used herein, the term "treat" or "treatment" refers to any mark of success in treating or ameliorating a disease or condition (e.g., a cardiac condition with pathophysiological features of HCM) associated with a morbidity, injury, condition, or symptom, including any objective or subjective parameter, such as elimination; alleviation; reduction of symptoms; making the morbidity, injury, condition, or symptom more tolerable to the patient; or reducing the frequency or duration of the morbidity, injury, condition, or symptom. Treatment or improvement may be based on any objective or subjective parameter; including, for example, the results of a physical examination.

[0064] As used herein, the term "prevent" or "prevention" refers to a preventive treatment of an individual who does not have and does not yet have a morbidity, 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 morbidity, injury, condition, or symptom; or is with a morbidity, injury, condition, or symptom, is not with the morbidity, injury, condition, or symptom, but is at risk of regression of the morbidity, injury, condition, or symptom. In certain aspects, an individual is at a higher risk of developing a morbidity, injury, condition, or symptom, or is at a higher risk of regression of a morbidity, injury, condition, or symptom compared to an average healthy member of a population. In some aspects, prevention refers to preventing the onset of a morbidity, injury, condition, or symptom.

[0065] 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.

[0066] The intended administration "subject" 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.

[0067] Hypertrophic cardiomyopathy (HCM) is clinically identified as unexplained left ventricular (LV) hypertrophy in the absence of a known cause, such as pressure overload, systemic disease, or an infiltrative process. A phenotypic characteristic of HCM is hypercontractility of the myocardium, accompanied by reduced LV compliance, clinically reflected as reduced ventricular cavity size, often an abnormal ejection fraction, increased wall thickness, and diastolic dysfunction. Some of the symptoms and signs experienced by patients with HCM include, but are not limited to, shortness of breath (especially during exercise), chest pain (especially during exercise), fainting (especially during or just after exercise), sensation of rapid, trembling, or pounding heartbeats, and heart murmurs.

[0068] Obstructive HCM (oHCM), also known as hypertrophic obstructive cardiomyopathy (HOCM), refers to HCM with left ventricular outflow tract obstruction (LVOT).

[0069] Non-obstructive HCM (nHCM) refers to HCM without outflow obstruction at rest or after stimulation.

[0070] Heart failure refers to a clinical syndrome in which a patient's heart cannot 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, swollen legs and ankles, prominent neck veins, and edema.

[0071] 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.

[0072] Stable diastolic heart failure refers to an acute exacerbation without symptoms in patients with diastolic heart failure. These patients have impaired diastolic function where symptoms are controlled or stabilized using available therapies.

[0073] 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. Cardiac magnetic resonance 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 pro-BNP) is present at elevated levels in the blood of individuals with diastolic dysfunction.

[0074] Diastolic dysfunction is present or is an important 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 cardiomyopathy (e.g., genetic mutations in one or more sarcomeric proteins), inflammatory cardiomyopathy (e.g., Loefllers and EMF), infiltrative cardiomyopathy (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).

[0075] Class I HCM refers to HCM classified as class I according to the New York Heart Association (NYHA).

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

[0077] Class II-III oHCM refers to oHCM classified as class II or III according to NYHA.

[0078] 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).

[0079] 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).

[0080] NYHA Class III refers to a classification in which a patient or individual has marked limitation in physical activity, is comfortable at rest, and does not provoke fatigue, palpitations, or dyspnea with less than ordinary activity.

[0081] 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 has increased discomfort if any physical activity is initiated.

[0082] As used herein, "Valsalva gradient" refers to the pressure gradient across the LVOT in a subject while the subject performs a Valsalva maneuver.

[0083] III. Compounds

[0084] In one aspect, provided herein is a compound having formula (I):

[0085]

[0086] or a pharmaceutically acceptable salt thereof, wherein

[0087] Subscript n is 1 or 2;

[0088] Each R 1 is a member independently selected from the group consisting of fluorine, chlorine, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy and C 2 -C 4 Alkynyl; wherein at least one R 1 is fluorine; and

[0089] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0090] 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.

[0091] In one aspect, provided herein is a compound having formula (I):

[0092]

[0093] or a pharmaceutically acceptable salt thereof, wherein

[0094] Subscript n is 1 or 2;

[0095] Each R 1 is a member independently selected from the group consisting of fluorine, chlorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 Alkoxy, optionally substituted C 1 -C 4 Haloalkoxy and optionally substituted C 2 -C 4 Alkynyl; wherein at least one R 1 is fluorine; and

[0096] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0097] 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.

[0098] Also provided are pharmaceutically acceptable salts of such compounds of formula (I).

[0099] In certain aspects, the compound of formula (I) may have the following formula:

[0100]

[0101] or a pharmaceutically acceptable salt thereof, wherein the subscript n is 1; and

[0102] R 1 is a member independently selected from the group consisting of fluorine, chlorine, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C4 Alkoxy, C 1 -C 4 Haloalkoxy and C 2 -C 4 an alkynyl group; and

[0103] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0104] In certain aspects, the compound of formula (I) may have the following formula:

[0105]

[0106] or a pharmaceutically acceptable salt thereof, wherein the subscript n is 1; and

[0107] R 1 is a member independently selected from the group consisting of fluorine, chlorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 Alkoxy, optionally substituted C 1 -C 4 Haloalkoxy and optionally substituted C 2 -C 4 alkynyl; and

[0108] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0109] In some cases, n of the compound of formula (I) is 1. The compound of formula (I) may have the following formula:

[0110]

[0111] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0112] Also provided are pharmaceutically acceptable salts of such compounds of formula (Ib).

[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 R1 Can be selected from the group consisting of: fluorine, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy and C 2 -C 4 alkynyl; optionally, fluoro, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH).

[0114] 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 can be selected from the group consisting of: fluorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 Alkoxy and optionally substituted C 2 -C 4 alkynyl; optionally, fluoro, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH).

[0115] The compound of formula (I) may have the following formula:

[0116]

[0117] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other of is H; and

[0118] Each R 1 is a member independently selected from the group consisting of fluorine, chlorine, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy and C 2 -C 4 Alkynyl.

[0119] The compound of formula (I) may have the following formula:

[0120]

[0121] R 2a and R 2b One of them is fluorine and R 2a and R2b The other of is H; and

[0122] Each R 1 is a member independently selected from the group consisting of fluorine, chlorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 Alkoxy, optionally substituted C 1 -C 4 Haloalkoxy and optionally substituted C 2 -C 4 Alkynyl.

[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: fluorine, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy and C 2 -C 4 alkynyl; optionally, fluoro, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH).

[0124] In some cases, for Formula (I), one R 1 is fluorine and the other R 1 can be selected from the group consisting of: fluorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 Alkoxy and optionally substituted C 2 -C 4 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.

[0125] Also provided are pharmaceutically acceptable salts of such compounds of formula (Ic).

[0126] The compound of formula (I) may have the following formula:

[0127]

[0128] R 1 Can be selected from the group consisting of: fluorine, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy and C 2 -C 4 alkynyl; optionally, fluoro, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH); and

[0129] R 2a and R 2b One of them is fluorine and R 2a and R 2b The other one is H.

[0130] The compound of formula (I) may have the following formula:

[0131]

[0132] R 1 can be selected from the group consisting of: fluorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 Alkoxy and optionally substituted C 2 -C 4 alkynyl; optionally, fluoro, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH); and

[0133] 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.

[0134] Also provided are pharmaceutically acceptable salts of such compounds of formula (Id).

[0135] The compound of formula (I) may have the following formula:

[0136]

[0137] In certain aspects, R 2a and R 2b One of them is fluorine and R 2a and R 2bThe other one is H.

[0138] Also provided are pharmaceutically acceptable salts of such compounds of formula (Ie).

[0139] The compound of formula (I) may have the following formula:

[0140]

[0141] 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.

[0142] The compound of formula (I) may have the following formula:

[0143]

[0144] or pharmaceutically acceptable salts thereof.

[0145] The compound may be:

[0146]

[0147] or a pharmaceutically acceptable salt thereof.

[0148] The compound may be: or a pharmaceutically acceptable salt thereof.

[0149] The compounds disclosed above, or pharmaceutically acceptable salts thereof, may be provided (e.g., in pharmaceutical compositions) with substantially no other isomers at carbon atoms bearing benzene rings (i.e., with an absolute configuration different from that disclosed and depicted herein). Alternatively or in addition, compounds or pharmaceutically acceptable salts thereof may be provided with substantially no other isomers at carbon atoms bearing fluorine adjacent to carbon atoms bearing benzene rings. For example, when provided in pharmaceutical compositions, the composition may be substantially free of other isomers at carbon atoms bearing benzene rings. Similarly, alternatively or in addition, the composition may be substantially free of other isomers at carbon atoms bearing fluorine adjacent to carbon atoms bearing benzene rings. In some aspects, substantially free refers to an enantiomeric excess (ee) of ≥95%, ≥98%, ≥99%, or 100% at carbon atoms bearing benzene rings. 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 benzene rings. In some aspects, substantially free refers to > 95%, > 98%, > 99%, or 100% diastereomeric excess (de).

[0150] 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:

[0151] a. having a powder X-ray diffraction pattern having two or more peaks expressed in degrees 2θ ± 0.2° and selected from 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5, 32.9, 34.3, 35.5 and 38.8 degrees;

[0152] b. a DSC thermogram showing endotherms at about 226.05°C, at about 302.47°C, and at about 310.13°C; or

[0153] c. Basically 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 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 powder X-ray diffraction 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 about 221.51°C, about 299.53°C, and about 308.81°C. In some aspects, the Form 1 polymorph has substantially the same Figure 1AIdentical powder X-ray diffraction patterns. 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.

[0154] The compounds of formula (I) may be prepared by any suitable method. The compounds may 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) may 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).

[0155] 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 conditions in humans and other individuals, such as hypertrophic cardiomyopathy. In some aspects, the pharmaceutical composition further comprises 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 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 (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 The invention relates to 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 drug, 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 Alazone, samethacin, 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, an additional drug is administered to the individual for improving the individual's cardiovascular condition. The additional drug may 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.

[0156] In another aspect, provided herein is a pharmaceutical composition comprising a 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 case, 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 cases, 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 some cases, 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 cases, 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.

[0157] 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 modulators). 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 (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 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 The invention relates to 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 drug, 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 Alazone, samethacin, 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, an additional drug is administered to the individual for improving the individual's cardiovascular condition. The additional drug may 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.

[0158] 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 components. 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 the relaxation of the left ventricle during diastole. 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 causing impaired coronary blood flow, thereby improving the latter as an adjunct in angina and / or ischemic heart disease. Alternatively or additionally, the pharmaceutical composition may confer benefit to beneficial left ventricular remodeling in HCM and / or other causes of left ventricular hypertrophy due to chronic volume or pressure overload from, for example, valvular heart disease and / or systemic hypertension.

[0159] 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 making pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants and preservatives to provide 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 making 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 tablet may be uncoated, or it may be enteric-coated or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period of time. For example, time-extending materials such as monostearate or distearate may be used. The tablet may also be coated to form an osmotic therapeutic tablet for controlled release.

[0160] 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.

[0161] 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 are suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersants or wetting agents may be naturally occurring phospholipids, for example, lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecanethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspension 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.

[0162] 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 stated above) and flavoring agents may be added to provide a palatable oral preparation. These compositions may be stored by adding an antioxidant such as ascorbic acid.

[0163] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide a compound of formula (I) or a pharmaceutically acceptable salt or polymorph thereof mixed 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 already mentioned above. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be present.

[0164] 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 of these. Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybeans, lecithin; and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0165] Syrups and elixirs can be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain demulcents, preservatives and flavoring and coloring agents. Oil solutions can be prepared in combination with, for example, cyclodextrins, PEG and surfactants.

[0166] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension. This suspension may be formulated using those suitable dispersants or wetting agents and suspending agents 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 are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils are conventionally used as solvents or suspension 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.

[0167] 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 via the eye with the aid of a solution or an ointment. Further, the transdermal delivery of the subject compound can be achieved with the aid of an iontophoresis patch and the like. For topical use, an ointment, ointment, jelly, solution or suspension containing the compound provided herein or its pharmaceutically acceptable salt is used. Topical application as used herein also means including the use of a mouthwash and a gargle.

[0168] The compound of formula (I) provided herein or its pharmaceutically acceptable salt or polymorph can also be coupled to a carrier, which is a suitable polymer for a targetable drug carrier. Such polymers may include polyvinyl pyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-asparagine-phenol or polyethylene oxide-polylysine substituted with palmitoyl residues. 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 drugs, 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 form shaped articles, such as valves, stents, pipes, prostheses and the like.

[0169] 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 of 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 sarcomeric 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.

[0170] 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.

[0171] The present application also provides a method for treating hypertrophic cardiomyopathy (HCM) or heart disease. 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 (6S, 7S)-6-fluoro-7-(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, 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.

[0172] 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 cardiomyopathy (e.g., genetic mutations in one or more sarcomeric proteins), inflammatory cardiomyopathy (e.g., Loeffler's disease and EMF), infiltrative cardiomyopathy (e.g., amyloid, sarcoid, and XRT), storage disease (e.g., hemochromatosis, Fabry disease, and glycogen storage disease), 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).

[0173] The present application provides a method of treating a cardiac disease or disorder in a subject in need thereof, the method 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 feature of and / or is associated with a cardiac disease or disorder. For example, the cardiac disease or disorder can be a cardiomyopathy (e.g., hypertrophic cardiomyopathy), heart failure (e.g., heart failure with preserved ejection fraction, heart failure with mid-range ejection fraction), a valvular disease (e.g., valvular aortic stenosis), a 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, a moderate 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 may have a moderate ejection fraction and diastolic dysfunction. For example, an individual in need of treatment for a cardiac disease or condition (e.g., ejection fraction mid-range heart failure) may have diastolic dysfunction and an ejection fraction between about 40% and about 50%.

[0174] 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, an individual in need of treatment for diastolic dysfunction may suffer 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 amyloid degeneration, 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., 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.

[0175] 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 Form 1 polymorph of (6S, 7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. Non-limiting examples of cardiomyopathy 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, the hypertrophic cardiomyopathy is nHCM. The method may include administering 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 to an individual in need of treatment for nHCM. The individual in need of treatment for nHCM may have NYHA Class II, III, or IV heart failure. In other cases, the hypertrophic cardiomyopathy is oHCM. The method may include administering to an individual 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 individual in need of treatment for oHCM may have NYHA Class II, III or IV heart failure.

[0176] 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, 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 include administering to an individual 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.

[0177] 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, an individual in need of treatment for HFpEF may have normal or elevated contractility (e.g., as measured by echocardiography). In some cases, an individual in need of treatment for HFpEF may have abnormal global longitudinal strain (e.g., less than -15%). In certain aspects, an individual in need of treatment for HFpEF may suffer from diabetes (type I, type II) and / or valvular disease (e.g., aortic stenosis). In some cases, an individual in need of treatment for HFpEF may have a prosthetic valve (e.g., aortic valve) due to valvular disease (e.g., aortic stenosis). A method of treating HFpEF (e.g., diabetic HFpEF) in an individual in need thereof may comprise 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 heart failure is HFmrEF. The method may include administering 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 to an individual in need of treatment for HFmrEF. An individual in need of treatment for HFmrEF may have NYHA Class II, III or IV heart failure.

[0178] In some aspects, a method of treating left ventricular hypertrophy 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. In some aspects, an individual in need of treatment for left ventricular hypertrophy has abnormal left ventricular wall thickness. The left ventricular wall thickness of the individual may be greater than normal, but less than the diagnostic criteria for hypertrophic cardiomyopathy. For example, an individual 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 some 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.

[0179] 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.

[0180] 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.

[0181] In some aspects, the individual in need thereof is from a patient population suffering from HFpEF.

[0182] The present application also provides a method for treating a disease or condition selected from the group consisting of diastolic heart failure (e.g., ejection fraction preserved heart failure), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, 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, or a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0183] The compounds of formula (I) can be administered as monotherapy or 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 individual cardiac conditions or other therapies suitable for treating related diseases or conditions. The additional therapeutic agent can be administered by a route and amount normally used for that agent or in a reduced amount, and can be administered simultaneously, sequentially or concurrently with the compounds of formula (I).

[0184] In certain aspects, the compound of formula (I) is administered in addition to a condition of diastolic dysfunction, such as SOC for diastolic heart failure. In other aspects, in addition to the compound of formula (I), another therapeutic agent is administered to the subject, 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 The invention relates to 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 drug, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent, or any combination thereof.

[0185] 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-6 155, 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 Alaquintin, samexin, 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 a specific aspect, 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, an additional drug is administered to an individual for improving the individual's cardiovascular condition. The additional drug may 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 particular aspect, the additional drug is an ANRI, such as sacubitril / valsartan; or an SGLT2 inhibitor. In yet another aspect, an individual 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.

[0186] The present application also provides a method for treating a disease or condition selected from the group consisting of diastolic heart failure (e.g., ejection fraction preserved heart failure), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, 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 selected from the group consisting of diastolic heart failure (e.g., ejection fraction preserved heart failure), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, 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.

[0187] 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 a 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 may be administered by a route and in an amount typically used for that agent, or in a reduced amount, and may 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, another therapeutic agent is administered to the subject, 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), 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 type 9 (PCSK9) inhibitors, vasodilators (e.g., calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators), diuretics (e.g., furosemide), arrhythmic agents, anticoagulants (e.g., warfarin), antithrombotic agents, antiplatelet agents, or any combination thereof.Suitable ARBs are provided herein (see above). In particular 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 the administration of Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, 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.

[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 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 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. 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 effective antihypertensive therapy, the method comprising administering to an individual in need thereof an effective amount of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0189] The present application also provides a method of 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 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 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 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 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.

[0190] The present application also provides a method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease with pathophysiological features associated with HCM), the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in combination with 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).

[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), 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, 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).

[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), 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, 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), 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).

[0193] 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), 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, in combination with the following therapies: (1) delaying the progression of heart failure and attempting to prevent heart recurrence by downregulating cardiac neurohormonal stimulation; (1) 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 modulators).

[0194] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used as a medicament. The present application also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used as a medicament. The present application also provides 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, which is used 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, which is used as a medicament.

[0195] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease with pathophysiological characteristics of HCM). The present application also provides a pharmaceutically acceptable salt thereof for use in treating hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease with pathophysiological characteristics of HCM). The present application also provides 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 for use in treating hypertrophic cardiomyopathy or cardiac disease (e.g., cardiac disease with pathophysiological characteristics 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 disease (e.g., a cardiac disease having pathophysiological features of HCM).

[0196] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used to treat 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 compound of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used to treat 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., ejection fraction preserved heart failure), 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, which is used to treat a disease or condition selected from the group consisting of diastolic heart failure (e.g., ejection fraction preserved heart failure), ischemic heart disease, angina pectoris and restrictive cardiomyopathy.

[0197] The present application also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is used to treat 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, which is used to treat 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 being 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 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.

[0198] 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 disease (e.g., a cardiac disease 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 disease (e.g., a cardiac disease 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).

[0199] 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 the following therapies: a therapy that delays the progression of heart failure and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart 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 modulators).

[0200] 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 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 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.

[0201] 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 hypertrophic cardiomyopathy or a cardiac disease (e.g., a cardiac disease with pathophysiological characteristics of HCM). 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 or a cardiac disease (e.g., a cardiac disease with pathophysiological characteristics of HCM). The present application also provides a use of 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 for the manufacture of a medicament for treating hypertrophic cardiomyopathy or a cardiac disease (e.g., a cardiac disease with pathophysiological characteristics 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 disease (e.g., a cardiac disease having pathophysiological features of HCM).

[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 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 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., ejection fraction preserved heart failure), 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., ejection fraction preserved heart failure), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy.

[0203] 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 the treatment of 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 effective antihypertensive therapy. The present application also provides a use of a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of 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 effective antihypertensive therapy. 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 left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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 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 left ventricular hypertrophy (e.g., due to volume or pressure overload), the disease or condition being 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.

[0204] 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 hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease with pathophysiological features associated with HCM), in combination with the following therapies: 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); a therapy that improves cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a 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). 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 disease (e.g., a cardiac disease with pathophysiological features associated with HCM), in combination with the following therapies: 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); a therapy that improves cardiac function by stimulating cardiac contractility (e.g., positive inotropes, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and / or a 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).

[0205] 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 modulators). 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 and attempts to prevent cardiac remodeling by downregulating neurohormonal stimulation of the heart 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 modulators).

[0206] The compounds of formula (I) or pharmaceutically acceptable salts thereof may alter the natural history of HCM and other diseases rather than merely alleviating symptoms. The Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione may alter the natural history of HCM and other diseases rather than merely alleviating symptoms. The mechanism of clinical benefit imparted to HCM patients may extend to patients with other forms of heart disease that share similar pathophysiology with or without demonstrable genetic influences. For example, effective treatment of HCM by improving ventricular relaxation during diastole may also be effective in a broader population characterized by diastolic dysfunction. The compounds of formula (I) or pharmaceutically acceptable salts thereof may specifically target the underlying cause of the condition or act on other downstream pathways. 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 used to specifically target the underlying cause of the condition or act on other downstream pathways. Therefore, the compound of formula (I) or a pharmaceutically acceptable salt thereof can also confer benefits to patients suffering from heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris or restrictive cardiomyopathy. Thus, the Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione may also confer benefit to patients suffering from heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris or restrictive cardiomyopathy. The compounds of formula (I) or pharmaceutically acceptable salts thereof may also promote beneficial ventricular remodeling in 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 reducing 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; in combination with therapy aimed at correcting or reducing the primary cause of volume or pressure overload (valve repair / replacement, effective antihypertensive therapy). By reducing left ventricular filling pressures, the compounds 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 with it the risk of arterial thromboembolic complications, including but not limited to the concomitant 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 concomitant risks of its 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 repeated ICD discharges) and / or the need for potentially toxic antiarrhythmic drugs. 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 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. The compound of formula (I) or a pharmaceutically acceptable salt thereof can be valuable in reducing or eliminating the need for concomitant medications and their attendant potential toxicity, drug-drug interactions and / or side effects. 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 valuable in reducing or eliminating the need for co-administration and its associated potential toxicity, drug-drug interactions and / or side effects. The compound of formula (I) or a pharmaceutically acceptable salt thereof can reduce interstitial myocardial fibrosis and / or slow the progression of left ventricular hypertrophy, inhibit or reverse left ventricular hypertrophy. Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione can reduce interstitial myocardial fibrosis and / or slow down the progression of left ventricular hypertrophy, and inhibit or reverse left ventricular hypertrophy.

[0207] Depending on the disease to be treated and the condition of the individual, the compound of formula (I) or its pharmaceutically acceptable salt provided herein can be administered by oral, parenteral (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, nasal, vaginal, rectal, sublingual or topical administration, and can be formulated separately or together into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each administration route.

[0208] 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 by oral, parenteral (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, nasal, vaginal, rectal, sublingual or topical administration routes and can be formulated separately or together into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each administration route.

[0209] 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 a day, preferably once or twice a day. 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 or a pharmaceutical composition comprising the Form 1 polymorph of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione can be administered on a regimen of 1 to 4 times a day, preferably once or twice a day.

[0210] 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 its pharmaceutically acceptable salt, the age, weight, genetic characteristics, general health, sex and diet of the individual, as well as the mode and time of administration, rate of excretion, drug combination and the severity of the particular condition of the individual undergoing therapy.

[0211] The compounds of formula (I) provided herein, the pharmaceutically acceptable salts of the compounds of formula (I) and / or the pharmaceutical compositions can be used in combination with other drugs, and the other drugs are used to treat, prevent, inhibit or improve the diseases or conditions to 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 and / or the pharmaceutical compositions provided herein can be used in combination with other drugs, and the other drugs are used to treat, prevent, inhibit or improve the diseases or conditions to 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 neuropeptidase 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.

[0212] Where the compounds of the present application are 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 one or more therapeutic agents. Where the compounds of the present application are 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 one or more therapeutic agents. Example

[0213] Abbreviations: ACN: acetonitrile; aq: aqueous solution; Ar: argon; CH 2 Cl 2 : Dichloromethane; CH 3 CN: acetonitrile; CH 3 OH: methanol; Cs 2 CO 3 : cesium carbonate; DCM: dichloromethane; DIEA: diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; equiv.: equivalent; Et 2 O: 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-methylmethylammonium hexafluorophosphate N-oxide; HCl: hydrogen chloride; H 2 O: water; IPA: isopropyl alcohol; iPr 2 O: diisopropyl ether; K 2 CO 3 : potassium carbonate; LiHMDS: lithium hexamethyldisilazane; MeOH: methanol; MgSO 4 : magnesium sulfate; min: minute; mL: milliliter; MW or μW: microwave (the reaction was completed in a microwave reactor); NaBH 4 :Sodium borohydride; NaBH 3 CN: sodium cyanoborohydride; NaCl: sodium chloride; NaBH 3CN : sodium cyanoborohydride; NaH: sodium hydride; NaHCO 3 : sodium bicarbonate; NaOH: sodium hydroxide; NaOMe: sodium methoxide; Na 2 SO 4 :Sodium sulfate; n-BuOH:n-butanol; NH 4 Cl: ammonium chloride; pH: -log[H + ]; RT: room temperature; SOCl 2 : 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.

[0214] Example 1: Synthesis

[0215] Intermediate Example 1: Preparation of (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4)

[0216] Process I-1

[0217]

[0218] Step 1. Synthesis of (S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfenamide (1-2). In a 1000-mL round-bottom flask under argon atmosphere, 3-fluorobenzaldehyde (50 g, 0.40 mol), (S)-2-methylpropane-2-sulfenamide (50 g, 0.41 mol), Cs 2 CO 3 (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). Subsequently, the mixture was 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 (300 MHz, CDCl 3 ): 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).

[0219] Step 2. Synthesis of ethyl (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoate (1-3). To a suspension of Zn (38 g, 0.58 mmol) in tetrahydrofuran (600 mL) was added 1-2 (53.5 g, 0.24 mol) and ethyl 2-bromo-2,2-difluoroacetate (120 g, 0.59 mol) in tetrahydrofuran (250 mL) under argon atmosphere 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 washed with anhydrous Na 2 SO 4 The solvent was removed and the residue was dried in vacuo to give 1-3 (50 g, 60%) as a yellow oil. LC-MS (ES, m / z): 352 [M+H] + .

[0220] 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 1 N NaOH aqueous solution (350 mL) at room temperature under argon atmosphere. After stirring at room temperature for 30 minutes, the pH value of the reaction mixture was adjusted to 5 with 1 N citric acid aqueous solution. The resulting mixture was extracted with ethyl acetate (1000 mL x 3). The combined organic extracts were then washed with brine (500 mL) and dried over anhydrous Na 2 SO 4 The solvent was removed and the product was purified by flash preparative HPLC (column: C18 silica gel; mobile phase: CH 3 CN / H 2 O = 10 / 90 (v / v) to CH 3 CN / H 2 O=95 / 5 (v / v); detector: UV 254 nm) to purify the residue to give 1-4 (30 g, 41%) as a white solid. LC-MS (ES, m / z): 324 [M+H] + ; 1 H-NMR (400MHz, 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).

[0221] Intermediate Example 2: Preparation of 1-(tetrahydro-2H-pyran-4-yl)piperidine-2,4,6-trione (2-3)

[0222] Process I-2

[0223]

[0224] Step A-1. Synthesis of 1-(tetrahydro-2H-pyran-4-yl)urea (2-2) (Method A). To a solution of 2-1 (24 g, 0.24 mol) in DCM (3000 mL) was added isocyanatotrimethylsilane (30 g, 0.26 mol) at 0 ° C under an 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 ether (50 mL). Subsequently, the suspension was filtered and the solid was washed with ether (500 mL x 3) and dried in vacuo to give 2-2 (34 g, 68%) as a white solid. 1 H NMR (300MHz, d6 -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).

[0225] 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).

[0226] Step B-1. Synthesis of phenyl carbamate (2-5). A solution of 2-4 (30 g) in DCM (45 mL) was added to a mixture of saturated aqueous ammonia solution (50 mL) and DCM (50 mL) at 0°C. 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 (400MHz, 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).

[0227] 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 (400MHz, 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).

[0228] Intermediate Example 3: Preparation of (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (3-3)

[0229] Process I-3

[0230]

[0231] Step 1. Synthesis of (R,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfenamide (4-1). 1-1 (5.0 g, 40.3 mmol), (R)-2-methylpropane-2-sulfenamide (5.1 g, 42.2 mmol) and Cs 2 CO 3 A mixture of (15.7 g, 48.25 mol) in DCM (60 mL) was stirred at room temperature overnight. Subsequently, the reaction mixture was diluted with ether (200 mL) and then filtered. The filtrate was concentrated and the residue was dried in vacuo to give a crude material 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 (300MHz, 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).

[0232] 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 atmosphere at -78 °C over 30 min. After stirring at -78 °C for 1 h, 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 purified by anhydrous Na 2 SO 4 The solvent was removed and the residue was dried in vacuo to give crude 3-2 (4.6 g) as an off-white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 334 [M+H] + .

[0233] 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 NaOH aqueous 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 the resulting mixture was extracted with EtOAc (200 mL x 3). Then, the combined organic extracts were washed with brine (100 mL) and washed with anhydrous Na 2 SO 4 The solvent was removed and the residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 19 x 250 mm, 5 um; mobile phase: water (0.05% TFA (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 (400MHz, 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).

[0234] 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)

[0235] Process C-1

[0236]

[0237] 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 mixture was heated to 40°C with saturated NaHCO 3 The reaction mixture was diluted with aqueous 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 washed with anhydrous Na 2 SO 4 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] + .

[0238] 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. Then, the reaction mixture was diluted with ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic extracts were washed with brine and washed with anhydrous Na 2 SO 4 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] + .

[0239] 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] + .

[0240] 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). The crude material CC (800 mg) in a sealed vial was stirred in CH 3 The mixture in CN (10 mL) was stirred at 120 °C for 20 min. Then, 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 washed with anhydrous Na 2 SO 4 The solvent was removed and the column 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 3CN = 11.0% (v / v) to 30.0% (v / v) in 8 minutes; detector: UV 254 nm) The residue was purified to give C-1 (197 mg, 27%, three steps from CA) as a white solid. LC-MS (ES, m / z): 382 [M+H] + ; 1 H NMR (400MHz, 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).

[0241] 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)

[0242] Process 1

[0243]

[0244] 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 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 (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 (300MHz, 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 (376MHz,d 6 -DMSO):δ-113.18,-192.36.

[0245] 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)

[0246] Process 2

[0247]

[0248] 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] + .

[0249] 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 (2S,3S)-3-(((S)-tert-butylsulfinyl)amino)-2-fluoro-3-(3-fluorophenyl)propanoic acid (2B) was used to replace (S)-3-(((S)-tert-butylsulfinyl)amino)-2,2-difluoro-3-(3-fluorophenyl)propanoic acid (1-4) to obtain 2 as a white solid. LC-MS (ES, m / z): 364 [M+H] + ; 1 H NMR (300MHz, d6 -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 (376MHz, d 6 -DMSO):δ-112.59,-175.93.

[0250] 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).

[0251] Process 3

[0252]

[0253] Step 1. Synthesis of (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfenamide (3B). Under argon atmosphere, 2-fluoro-5-methylbenzaldehyde (3A) (5 g, 36.2 mmol), Cs 2 CO 3 A mixture of (R)-2-methylpropane-2-sulfinamide (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. The reaction mixture was filtered and the filtrate was diluted with ether (150 mL). Subsequently, the resulting suspension was filtered. The filtrate was concentrated and the residue was dried in vacuo to give 3B (8.7 g, 97%) as a yellow oil. LC-MS (ES, m / z): 242 [M+H] + ; 1 H NMR (400MHz, 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).

[0254] Step 2. Synthesis of ethyl (2R,3S)-3-(((R)-tert-butylsulfinyl)amino)-2-fluoro-3-(2-fluoro-5-methylphenyl)propanoate (3C). To a solution of 3B (4 g, 16.6 mmol), ethyl 2-fluoroacetate (2.6 g, 24.6 mmol) and TMEDA (4.8 mL) in anhydrous THF (40 mL) was added LiHMDS (1 M in THF, 24.6 mL, 24.6 mmol) dropwise over 30 min at -78 °C under argon atmosphere. 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 < -20 °C. Subsequently, the mixture was concentrated to remove most of the organic solvent and then extracted with EtOAc (100 mL x 3). The combined organic extracts were washed with brine (100 mL) and purified by anhydrous Na 2 SO 4 The solvent was removed and the residue was dried in vacuo to give crude 3C (6.0 g) as a yellow oil, which was used in the next step without further purification. LC-MS (ES, m / z): 348 [M+H] + .

[0255] 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 NaOH aqueous 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 washed with anhydrous Na 2 SO 4 The solvent was removed and the residue was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 19 x 250 mm, 5 um; mobile phase: water (0.05% TFA) and ACN (28.0% ACN to 36.0% in 10 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 (400MHz, 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).

[0256] 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 x 3). The combined organic extracts were washed with brine (50 mL x 2) and purified by anhydrous Na 2 SO 4 The solvent was removed and the residue was dried in vacuo to give crude 3E (1.3 g) as a white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 514 [M+H] + ; 1 H NMR (400MHz, 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).

[0257] 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 purified by anhydrous Na 2 SO 4 The solvent was removed and the residue was dried in vacuo to give crude 3F (1.3 g) as a white solid, which was used in the next step without further purification. LC-MS (ES, m / z): 500 [M+H] + ; 1 H NMR (400MHz, 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).

[0258] 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] + .

[0259] 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). The crude material 3G (1.0 g, 2.53 mmol) was dissolved in CH 3CN (15mL) 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) increased to CH3CN:H2O=80:20 (v / v) in 40 minutes; detector: UV 254nm) to give compound 3 (302mg, 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 (376MHz,d 6 -DMSO): δ-123.51(t,J=86.5Hz),-191.57(d,J=129.34Hz).

[0260] 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)

[0261] Process 4

[0262]

[0263] 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, d6 -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 (376MHz, d 6 -DMSO):δ-124.08,-175.61.

[0264] 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)

[0265] Process 5

[0266]

[0267] 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 replacing (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfenamide (4B) with (S,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfenamide (3B) afforded 5 as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 1 H NMR (300MHz, 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); 19F NMR (376MHz, d 6 -DMSO):δ-123.49,-191.34.

[0268] 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)

[0269] Process 6

[0270]

[0271] 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 replacing (S,E)-N-(3-fluorobenzylidene)-2-methylpropane-2-sulfenamide (1-2) with (R,E)-N-(2-fluoro-5-methylbenzylidene)-2-methylpropane-2-sulfenamide (3B) gave 6 as a white solid. LC-MS (ES, m / z): 378 [M+H] + ; 1 H NMR (300MHz, 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 (376MHz,d 6 -DMSO):δ-124.36,-175.43.

[0272] Additional compounds were prepared using methods analogous to those provided above.

[0273] Characterization data of compounds

[0274] Table 1A

[0275]

[0276]

[0277]

[0278]

[0279]

[0280] Example 2

[0281] Single Crystal X-ray Analysis - Form 1

[0282] The monochromated Cu Kα spectra were obtained using a sealed tube on an Agilent Technologies (Dual Source) SuperNova diffractometer. SXRD analysis was performed using 100 nm irradiation. The diffractometer was equipped with an Oxford Cryosystems cryogenic device capable of data collection 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).

[0283] By direct method (SHELXS97) 1 The structure was solved and the F 2 (SHELXL97) 1 Developed for full least squares refinement (see Figure 4 ). Via OLEX2 2 The resulting image was collected, analyzed and crystallized in the orthorhombic space group P2 1 2 1 2 1 And use PLATON 4 ADDSYMM 3The routine refined in a search for higher metric symmetries, but failed to reveal any higher order symmetries. All non-hydrogen atoms were located in the Fourier map and their positions were refined, and then all non-hydrogen atoms were described anisotropically thermally shifted. 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, the Flack parameter can be calculated to be -0.0657 with an esd of 0.7497 (calculated from 1477 Bijovet pairs at 97.6% completeness). Attempts to refine the structure using TWIN and BASF commands did not yield further improvement. A riding model with fixed Uiso was used to refine the structure for all CH, CH 2 and 1.2 times that of NH groups and for all CH 3 The highest residual Fourier peak was found to be from C(16) approximation And found that the deepest Fourier hole is from O(2) approximation

[0284] Crystal Data - Form 1

[0285] C 19 H 21 F 2 N 3 O 3 (M = 377.39 g / mol): orthorhombic system, space group P2 1 2 1 2 1 (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 wR 2 is 0.3889 (all data).

[0286] 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 middle.

[0287] Biological Examples

[0288] 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.

[0289] Compounds with reduced half-lives are selected to enable potentially more rapid dose adjustments because shorter half-lives allow for a faster time to steady-state exposure. Removal or minimization of the dependence of the metabolic clearance of drug candidates on polymorphic cytochrome P450 (CYP) enzymes, such as CYP2C19, provides the potential advantage of reduced human PK variability that may occur, for example, between poor and rapid drug metabolizers. Removal or minimization of the potent CYP enzyme inducing properties of new drug candidates provides the potential advantage of avoiding drug-drug interactions. Increased selectivity of drug candidates for cardiac myosin versus skeletal myosin has the benefit of desired human pharmacokinetics related to myosin modulator drug distribution. Myosin modulator candidate drugs 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 performed to optimize the 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.

[0290] KS Solubility Analysis

[0291] The kinetic solubility of small molecule agents in PBS (pH 7.4) was evaluated 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 20 mM DMSO stock solution of the compound was added to the wells in the 96-well plate, followed by 198 μL PBS at room temperature. After shaking for 1.5 hours at room temperature, the mixture was filtered under vacuum through a 96-well filter plate, which was pre-washed with 100 μL 70% ethanol per well. Subsequently, 70 μL of filtrate was added to the wells in the 96-well reading plate, which was pre-loaded with 70 μL DMSO per well. Compared with the standard curve of each compound established in DMSO, the concentration of the sample in the well was determined based on the integration on the LC under UV detection.

[0292] Myosin inhibition assay (bcMF pCa 6IC 50 (μM)

[0293] The ability of small molecule agents to inhibit the enzymatic activity of bovine cardiac myosin was evaluated 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 monitoring 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 is from bovine heart in the form of skinned myofibrils. Prior to testing small molecule agents, the calcium responsiveness of bovine myofibrils was evaluated, 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 (PM12 buffer) containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)), 2 mM magnesium chloride (pH 6.8). The final assay conditions were 1 mg / mL bovine heart myofibrils, 0.4 mM PK / LDH, 50 uM ATP, 0.1 mg / mL BSA (bovine serum albumin), 10 ppm antifoam, 2 mM BME, 0.5 mM NADH and 1.5 mM PEP at the desired free calcium concentration required to achieve 50% activation of myofibrils.

[0294] A dilution series of compounds is created in DMSO so that the final desired concentration of the compound will be achieved in a 30 μL volume at a fixed DMSO concentration of 3.3% (v / v). 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 at ambient temperature in a PerkinElmer Envision plate reader. The plate reader is configured to read the absorbance at 340nm 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 for the slope on the plate containing DMSO. This normalized rate is then plotted as a function of small molecule concentration, and the data is 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).

[0295] Myosin inhibition assay (bcMF serum pCa 6IC 50 (μM)

[0296] 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)) but with the addition of 10% human serum.

[0297] Myosin inhibition assay (rbskMF pCa 6IC 50 (μM)

[0298] 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 replacing bovine cardiac myofibrils with rabbit skeletal myofibrils. 50 (μM)) are the same.

[0299] Pharmacokinetic / pharmacodynamic (PK / PD) relationships

[0300] The ability of small molecules to modulate systolic cardiac performance in a dose-dependent manner was assessed non-invasively in isoflurane-anesthetized SD rats using echocardiography. First, cardiac function / geometry was studied continuously before and during (approximately every 3 minutes) an intravenous infusion (2.0 mg / kg / h IV, n=4) lasting 30-60 minutes. Subsequently, a group of conscious rats were 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 independent 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, 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 (Vevo2100, 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 volumes (LVV = 7 x [2.4 + LVid]) were derived using the Teichholz model. - 1 xV 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.

[0301] Cardiomyocyte contractility analysis

[0302] The contractility of adult rat ventricular myocytes was determined by edge detection using the IonOptix contractility system. Myocytes were in Tyrode buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl 2 , 1.5 mM CaCl 2Aliquots of 10 μM 10 μg / mL of 10 μg / mL of 4 mM HEPES (4 mM HEPES, 11 mM glucose) were placed in a perfusion chamber (20RC-27NE series; Warner Instruments), allowed to adhere to the coverslip, and then perfused with 37°C Tyrode's buffer. Myocytes were stimulated by magnetic field at 1 Hz and 10 V. Only myocytes with distinct striations, dormant before pacing, with a cell length of 120-180 μm, a basal fractional shortening equal to 3-8% of the cell length, and a contraction velocity greater than 100 μm / sec were used for contractility experiments. To determine the response to compounds (0.3 μM concentration), myocytes were first perfused with Tyrode's buffer for 60 seconds, followed by perfusion with compounds for 5 minutes and washout with Tyrode's buffer for 140 seconds. Data were recorded continuously using IonOptix software. Contractility data were analyzed using Ionwizard software (IonOptix). For each cell, 10-20 contractility transients were averaged and compared under basal conditions (no compound) and compound-treated conditions. Compound activity was measured by the effect on fractional shortening (FS), which is the ratio of the peak length of the cell at the time of contraction divided by the basal cell length normalized to 100% of untreated cells. % inhibition measurements were calculated by subtracting the FS value from 100%.

[0303] Reactive metabolite identification

[0304] Reactive metabolite formation of small molecules was determined in vitro by detecting glutathione adducts formed in incubation with human liver microsomes fortified with NADPH and glutathione.

[0305] Methods: The metabolism of small molecules (30 μM) was assessed for glutathione adduct formation in a 1-hour incubation (200 μL volume, n=3 incubations / treatment, 60 min incubation time) with liver microsomes from humans (1 mg / mL protein) in potassium phosphate buffer (0.1 M, pH 7.4) at 37°C in a 96-well plate (2 mL well volume) in the absence of NADPH (used as a negative control) and in the presence of NADPH (1 mM) and glutathione (GSH, 10 mM). Incubations with liver microsomes were performed in a shaking water bath incubator under slow horizontal shaking (30 rpm). To obtain 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 the incubation is started by adding 40 μL NADPH solution (5mM, dissolved in potassium phosphate buffer). The incubation without NADPH is supplemented with 40 μL potassium phosphate buffer. After incubation, the reaction is terminated by adding an equal volume of acetonitrile containing 20nM carbamazepine (carbamazepine) internal standard and 3% formic acid. Then the quenched sample is 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 a volume equivalent of HPLC grade water, then heat-sealed with aluminum foil before analysis by liquid chromatography / mass spectrometry (LC-MS / MS).

[0306] 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 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 using LC / UV absorbance under the 280nm peak area ratio obtained between the GSH-adduct detected by the cultivation extract strengthened by using Xcalibur software (version 2.1.0) and the corresponding LC / UV peak area of ​​the parent compound from the cultivation extract without NADPH. The LC-MS / MS analysis using online LC-UV detection at 280nm determined the degree of GSH-adduct formation by dividing the LC / UV peak area of ​​the corresponding parent HCM-1NG analogue determined by the analysis of the extract from the control (-NAPDH, -GSH) cultivation extract with glutathione-adduct LC / UV peak area.

[0307] 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 chromatography grade.

[0308] 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, and 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. Full scan (m / z 100 to m / z 1000) LC-MS analysis in positive ion mode was performed with a scan time of 0.73 seconds and a source collision energy of 10 V. The tandem MS / MS conditions used were 2 mTorr collision helium and 35 eV collision potential. Xcalibur software (version 2.1.0, Thermo Fisher Scientific, Waltham, MA) was used to acquire all data.

[0309] Capillary temperature (℃): 325

[0310] Source heater temperature (°C): 345

[0311] Sheath gas flow rate (mL / min): 50

[0312] Auxiliary gas flow rate (mL / min): 12

[0313] Purge gas flow rate (mL / min): 5

[0314] Source voltage(kV):5.01

[0315] Source current (μA): 2.6

[0316] S-lens RF level: 50

[0317] Data dependent scanning was used which collected MS / MS spectra of the most abundant masses in a full scan mass spectrum of the Orbitrap (15,000 resolving power).

[0318] 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 100x 2.1mm reverse phase column. Chromatographic separation was achieved by eluting into an ESI source with a reverse phase gradient at a flow rate of 0.3 mL / min over 30 minutes, and wherein 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 keeping constant at 0% solvent-A for 1 minute. Finally, before further analysis, the gradient was linearly increased to 95% solvent-A over 0.5 minutes, then balanced at 95% solvent-A for 5 minutes.

[0319] Column: Phenomenex 2.6μm,C18, 100x 2.1mm reverse phase column Column oven temperature: 30℃

[0320] Flow rate: 0.3mL / 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 min 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 disk with a Kapton or Mylar polymer film to support the sample. The porous disk was then placed in a diffractometer and the Cu K radiation ( α 1 :α 2 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] About 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 kept 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 flushing gas with a flow rate of 50 cm 3 / min. Modulated DSC was performed with amplitude = 0.32°C and frequency = 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, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy and C 2 -C 4 Alkynyl; wherein at least one R 1 is 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 1is a member selected from the group consisting of fluorine, chlorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 Alkoxy, optionally substituted C 1 -C 4 Haloalkoxy and optionally substituted C 2 -C 4 Alkynyl; wherein at least one R 1 is 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. A compound according to item 1 or a pharmaceutically acceptable salt thereof, wherein R 2b For fluorine.

[0358] 4. A 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. A 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 the subscript n is 1; and

[0366] R 1is a member independently selected from the group consisting of fluorine, chlorine, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy and C 2 -C 4 alkynyl; 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] R 1 is a member independently selected from the group consisting of fluorine, chlorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 haloalkyl, optionally substituted C 1 -C 4 Alkoxy, optionally substituted C 1 -C 4 Haloalkoxy and optionally substituted C 2 -C 4 alkynyl; and

[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 Selected from fluorine, C 1 -C 4 Alkyl, C 2 -C 4 Alkoxy and C 2 -C 4alkynyl; 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 Selected from fluorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 2 -C 4 Alkoxy and optionally substituted C 2 -C 4 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. A 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 1 Selected from the group consisting of: fluorine, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy and C 2 -C 4 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 is selected from the group consisting of fluorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 Alkoxy and optionally substituted C 2 -C 4 alkynyl; optionally, fluoro, hydroxymethyl, methoxy and ethynyl (-C≡CH); optionally, methyl, methoxy and ethynyl (-C≡CH).

[0381] 14. A compound according to 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 Selected from the group consisting of: fluorine, C 1 -C 4 Alkyl, C 1 -C 4 Alkoxy and C 2 -C 4 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 fluorine, optionally substituted C 1 -C 4 Alkyl, optionally substituted C 1 -C 4 Alkoxy and optionally substituted C 2 -C 4 alkynyl; optionally, fluoro, methyl, methoxy and ethynyl (-C≡CH); optionally, methyl, hydroxymethyl, methoxy and ethynyl (-C≡CH).

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

[0387] or a pharmaceutically acceptable salt thereof.

[0388] 17. The compound according to item 1, wherein the compound is:

[0389]

[0390] or a pharmaceutically acceptable salt of any one of the foregoing.

[0391] 18. The compound according to item 1, wherein the compound is:

[0392] or a pharmaceutically acceptable salt of any one of the foregoing.

[0393] 19. A compound according to item 1, which has the following formula:

[0394] or a pharmaceutically acceptable salt thereof.

[0395] 20. The compound according to item 1, which has the following formula:

[0396]

[0397] or a pharmaceutically acceptable salt thereof.

[0398] 21. The compound according to item 1, which has the following formula:

[0399]

[0400] or a pharmaceutically acceptable salt thereof.

[0401] 22. A compound according to item 1, which has the following formula:

[0402]

[0403] or a pharmaceutically acceptable salt thereof.

[0404] 23. A compound according to item 1, which has the following formula:

[0405]

[0406] or a pharmaceutically acceptable salt thereof.

[0407] 24. A compound according to item 1, which has the following formula:

[0408]

[0409] or a pharmaceutically acceptable salt thereof.

[0410] 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.

[0411] 26. The pharmaceutical composition of clause 25, wherein the composition is substantially free of other isomers at the carbon atom bearing the benzene ring.

[0412] 27. A pharmaceutical composition according to clause 25 or 26, wherein the composition is substantially free of other isomers at the carbon atom bearing fluorine adjacent to the carbon atom bearing the benzene ring.

[0413] 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.

[0414] 29. A method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disease (e.g., a cardiac disease with pathophysiological features of HCM), the method comprising administering to an individual 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.

[0415] 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 an individual 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.

[0416] 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), the disease or condition being selected from the group consisting of chronic mitral valve regurgitation, chronic aortic stenosis, and chronic systemic hypertension; in combination with therapy directed 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 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.

[0417] 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 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, 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, 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 modulators).

[0418] 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.

[0419] 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 (eg, a cardiac disorder having pathophysiological features of HCM).

[0420] 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.

[0421] 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 alleviating the primary cause of volume or pressure overload, including valve repair / replacement or effective antihypertensive therapy.

[0422] 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 the treatment of 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 (any type of vasodilator, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators).

[0423] 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.

[0424] 39. Use 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, for the manufacture of a medicament for treating hypertrophic cardiomyopathy or a cardiac disease (e.g., a cardiac disease with pathophysiological features of HCM).

[0425] 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., ejection fraction preserved heart failure), ischemic heart disease, angina pectoris, and restrictive cardiomyopathy.

[0426] 41. Use of a compound as claimed in any one of clauses 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in 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), 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.

[0427] 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 (AR blockers) 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).

[0428] 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:

[0429] a. having a powder X-ray diffraction pattern having two or more peaks expressed in degrees 2θ ± 0.2° and selected from 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5, 32.9, 34.3, 35.5 and 38.8 degrees;

[0430] b. a DSC thermogram showing endotherms at about 226.05°C, at about 302.47°C, and at about 310.13°C; or

[0431] c. Basically Figure 4 Same X-ray crystal structure.

[0432] 44. A polymorph as described in item 43, wherein the powder X-ray diffraction pattern has three or more peaks expressed in degrees 2θ±0.2° and selected from 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5, 32.9, 34.3, 35.5 and 38.8 degrees.

[0433] 45. A polymorph as described in item 43, wherein the powder X-ray diffraction pattern has four or more peaks expressed in degrees 2θ±0.2° and selected from 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, 21.2, 22.5, 23.2, 25.5, 26.4, 28.2, 29.5, 31.5, 32.9, 34.3, 35.5 and 38.8 degrees.

[0434] 46. ​​The polymorph of clause 43, wherein powder X-ray diffraction has peaks at each of 11.3, 12.4 and 13.3 degrees expressed in degrees 2θ±0.2°.

[0435] 47. The polymorph of clause 43, wherein powder X-ray diffraction has 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°.

[0436] 48. The polymorph of clause 43, wherein the melting onsets are about 221.51°C, about 299.53°C, and about 308.81°C.

[0437] 49. A polymorph according to clause 43, wherein the polymorph has substantially the same Figure 1A Same powder X-ray diffraction pattern.

[0438] 50. A polymorph as in 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.

[0439] 51. A pharmaceutical composition comprising a polymorph as described in any one of clauses 43 to 50, and a pharmaceutically acceptable excipient.

[0440] 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.

[0441] 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.

[0442] 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.

[0443] 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.

[0444] 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.

[0445] 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.

[0446] 58. A method for 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 described in any one of clauses 43 to 50, or a pharmaceutical composition as described in any one of clauses 51 to 57.

[0447] 59. A method for 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 valve regurgitation, chronic aortic stenosis and chronic systemic hypertension; in combination with a therapy directed to correct or reduce 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 polymorph as described in any one of clauses 43 to 50, or a pharmaceutical composition as described in any one of clauses 51 to 57.

[0448] 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 as described in any one of clauses 43 to 50, or a pharmaceutical composition as described in any one of clauses 51 to 57, 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), 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).

[0449] 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.

[0450] Although the above disclosure has been described in considerable detail by way of illustration and example for the purpose of clear understanding, it will be appreciated by those skilled in the art 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 the references 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, 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 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 or 2, which has 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, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 haloalkoxy, and optionally substituted C2-C4 alkynyl; and R 2a and R 2b One of 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.

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