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EP-4736855-A2 - TETRAHYDROPYRAN (THP)-SUBSTITUTED BICYCLIC-PYRIMIDINEDIONE COMPOUNDS

EP4736855A2EP 4736855 A2EP4736855 A2EP 4736855A2EP-4736855-A2

Abstract

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

Inventors

  • GRILLO, MARK
  • KANE, BRIAN
  • OSLOB, JOHAN
  • ZHONG, MIN
  • THOMPSON, FABIENNE

Assignees

  • MyoKardia, Inc.

Dates

Publication Date
20260506
Application Date
20191028

Claims (15)

  1. A process for preparing a compound of formula 3, comprising reacting a compound of formula 3G to produce the compound of formula 3:
  2. The process of claim 1, wherein the reaction of the compound of formula 3G takes place in the presence of acetonitrile in a microwave reactor.
  3. The process of claim 1 or claim 2, further comprising reacting a compound of formula 3F with thionyl chloride to produce the compound of formula 3G:
  4. The process of claim 3, wherein the reaction of the compound of formula 3F with thionyl chloride takes place in the presence of ethanol.
  5. The process of claim 3 or claim 4, further comprising reacting a compound of formula 3E with sodium cyanoborohydride to produce the compound of formula 3F:
  6. The process of claim 5, wherein the reaction of the compound of formula 3E with sodium cyanoborohydride takes place in the presence of acetic acid.
  7. The process of claim 5 or claim 6, further comprising reacting a compound of formula 3D with a compound of formula 2-2 in the presence of 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and diisopropyl ethylamine (DIEA) to produce the compound of formula 3E:
  8. The process of claim 7, wherein the reaction of the compound of formula 3D with the compound of formula 2-2 takes place in the presence of dimethyl formamide (DMF).
  9. The process of claim 7 or claim 8, further comprising reacting a compound of formula 3C with sodium hydroxide to produce the compound of formula 3D:
  10. The process of claim 9, wherein the reaction of the compound of formula 3C with sodium hydroxide takes place in the presence of tetrahydrofuran (THF).
  11. The process of claim 9 or claim 10, further comprising reacting a compound of formula 3B with ethyl 2-fluoroacetate in the presence of tetramethylethylenediamine (TMEDA) and lithium hexamethyldisilazane (LiHMDS) to produce the compound of formula 3C:
  12. The process of claim 11, wherein the reaction of the compound of formula 3B with ethyl 2-fluoroacetate takes place in the presence of tetrahydrofuran (THF).
  13. The process of claim 11, further comprising reacting a compound of formula 3A with (R)-2-methylpropane-2-sulfinamide in the presence of cesium carbonate to produce the compound of formula 3B: optionally wherein the reaction of the compound of formula 3A with (R)-2-methylpropane-2-sulfinamide takes place in the presence of dichloromethane (DCM).
  14. A compound selected from the group consisting of: and
  15. Use of a compound selected from the group consisting of: and in the manufacture of the compound of formula 3:

Description

CROSS-REFERENCES TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N. 62/752278, filed October 29, 2018, entitled "Tetrahydropyran (THP)-Substituted Bicyclic-Pyrimidinedione Compounds," which is incorporated herein by reference in its entirety. BACKGROUND OF THE INVENTION Genetic (heritable) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, monogenic, autosomal dominant myocardial diseases. HCM is caused by one or more of over 1,000 known point mutations in any one of the structural protein genes contributing to the functional unit of myocardium, the sarcomere. About 1 in 500 individuals in the general population are found to have left ventricular hypertrophy unexplained by other known causes (e.g., hypertension or valvular disease), and many of these can be shown to have HCM, once other heritable (e.g., lysosomal storage diseases), metabolic, or infiltrative causes have been excluded. Sarcomere gene mutations that cause HCM are highly penetrant, but there is wide variability in clinical severity and clinical course. Some genotypes are associated with a more malignant course, but there is considerable variability between and even within families carrying the same mutation. Sex differences have also been noted, with male patients generally more severely affected than female patients. While many patients with HCM report minimal or no symptoms for extended periods of time, HCM is a progressive disease with a significant cumulative burden of morbidity. Symptoms of effort intolerance predominate, and can be exacerbated by exercise and other maneuvers that increase heart rate and/or decrease preload. As with many other disorders, symptoms tend to worsen with age. By far the most prevalent clinical burden for patients with HCM is exertional dyspnea, which limits their activities of daily living and can be debilitating. Patients with HCM are often symptomatic in the absence of documented hemodynamic abnormalities like left ventricular outflow tract obstruction (with or without mitral regurgitation). Patients' symptoms of exertional dyspnea can rapidly worsen with the onset of atrial fibrillation, a common complication of HCM that can precipitate acute pulmonary edema and increases the risk of systemic arterial thromboembolic disease, including stroke. Other adverse events associated with HCM include intolerance of hypovolemia or hypervolemia, and syncope. Concomitant coronary artery disease may confer a higher risk of acute coronary syndromes than in patients without HCM. Sudden cardiac death (SCD) in patients with HCM is both uncommon and difficult to predict but is a leading cause of non-traumatic death in young adults. For survivors of SCD, ICD placement is standard practice, and in other HCM patients risk profiling, while imprecise, is used to identify those for whom ICD placement for primary prevention is deemed prudent. Medical therapy for HCM is limited to the treatment of symptoms and does not address the fundamental, underlying cause of disease - disruptions in normal sarcomere function. Currently available therapies are variably effective in alleviating symptoms but typically show decreased efficacy with increasing disease duration. Patients are thus empirically managed with beta-blockers, non-dihydropyridine calcium channel blockers, and/or disopyramide. None of these agents carry labeled indications for treating HCM, and essentially no rigorous clinical trial evidence is available to guide their use. Compounding this unfortunate situation is the fact that no new medical therapies for HCM have been identified for many years. For patients with hemodynamically significant outflow tract obstruction (resting gradient >30mmHg), in appropriately selected patients surgical myectomy or alcohol septal ablation is usually required to alleviate the hemodynamic obstruction. The present disclosure provides new therapeutic agents and methods that remedy the long-felt need for improved treatment of HCM and related cardiac disorders and/or diseases. BRIEF SUMMARY OF THE INVENTION In one aspect, provided is a compound having formula (I): or a pharmaceutically acceptable salt thereof, whereinthe subscript n is 1 or 2; each R1 is a member selected from the group consisting of fluoro, chloro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and C2-C4 alkynyl; wherein at least one R1 is fluoro; and one of R2a and R2b is fluoro and the other of R2a and R2b is H. In one aspect, provided is a compound having formula (I): or a pharmaceutically acceptable salt thereof, whereinthe subscript n is 1 or 2; each R1 is a member selected from the group consisting of fluoro, chloro, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 haloalkyl, optionally substituted C1-C4 alkoxy, optionally substituted C1-C4 haloalkoxy, and optionally substituted C2-C4 alkynyl; wherein at least one R1 is fluoro; andone of R2a and R2b