Substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4-diones for treating cardiac diseases

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.

What is claimed is: 
     
         1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         the subscript n is 1 or 2; 
       
       each R 1  is a member selected from the group consisting of fluoro, chloro, optionally substituted C 1 -C 4  alkyl, optionally substituted C 1 -C 4  haloalkyl, optionally substituted C 1 -C 4  alkoxy, optionally substituted C 1 -C 4  haloalkoxy, and optionally substituted C 2 -C 4  alkynyl; wherein at least one R 1  is fluoro; and 
       one of R 2a  and R 2b  is fluoro and the other of R 2a  and R 2b  is H. 
     
     
         2 . The compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         the subscript n is 1 or 2; 
       
       each R 1  is a member selected from the group consisting of fluoro, chloro, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkoxy, and C 2 -C 4  alkynyl; wherein at least one R 1  is fluoro; and 
       one of R 2a  and R 2b  is fluoro and the other of R 2a  and R 2b  is H. 
     
     
         3 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof wherein R 2a  is fluoro and R 2b  is H or wherein R 2a  is H and R 2b  is fluoro. 
     
     
         4 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof wherein R 2a  is fluoro, and n is 1. 
     
     
         5 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof wherein R 2a  is fluoro, and n is 2. 
     
     
         6 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof wherein R 2b  is fluoro, and n is 1. 
     
     
         7 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof wherein R 2b  is fluoro, and n is 2. 
     
     
         8 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof wherein n is 1. 
     
     
         9 . The compound of  claim 1  or  2 , having the formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof, wherein the subscript n is 1; and
 the R 1  is a member independently selected from the group consisting of fluoro, chloro, optionally substituted C 1 -C 4  alkyl, optionally substituted C 1 -C 4  haloalkyl, optionally substituted C 1 -C 4  alkoxy, optionally substituted C 1 -C 4  haloalkoxy, and optionally substituted C 2 -C 4  alkynyl; and 
 one of R 2a  and R 2b  is fluoro and the other of R 2a  and R 2b  is H. 
 
     
     
         10 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof wherein n is 1, and having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The compound of  claim 1  or  2 , or a pharmaceutically acceptable salt thereof where n is 2, one R 1  is fluoro and the other may be selected from the group consisting of fluoro, optionally substituted C 1 -C 4  alkyl, optionally substituted C 1-4  alkoxy and optionally substituted C 2 -C 4  alkynyl. 
     
     
         12 . The compound of  claim 1  or  2 , wherein n is 2, and having the formula: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof. 
     
     
         13 . The compound of  claim 1  or  2  having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 1  may be selected from the group consisting of fluoro, optionally substituted C 1 -C 4  alkyl, optionally substituted C 1 -C 4  alkoxy and optionally substituted C 2 -C 4  alkynyl. 
     
     
         14 . The compound of any one of  claims 1 - 13 , wherein R 1  is hydroxyalkyl (e.g., hydroxymethyl). 
     
     
         15 . The compound of  claim 1  or  2 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt of any of the foregoing. 
     
     
         16 . The compound of  claim 1  or  2 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The compound of  claim 1  or  2 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The compound of  claim 1  or  2 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The compound of  claim 1  or  2 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The compound of  claim 1  or  2 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 20 , or a pharmaceutically acceptable salt thereof optionally, and a pharmaceutically acceptable excipient. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein compound has the formula 1a: 
       
         
           
           
               
               
           
         
       
     
     
         23 . The pharmaceutical composition of  claim 21 , wherein compound has the formula Ib: 
       
         
           
           
               
               
           
         
       
     
     
         24 . The pharmaceutical composition of  claim 21 , wherein compound has the formula 1c: 
       
         
           
           
               
               
           
         
       
     
     
         25 . The pharmaceutical composition of  claim 21 , wherein the compound has the formula Id: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The pharmaceutical composition of  claim 21  wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         27 . A method of treating hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature of HCM, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 20 , or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A method of treating a disease or disorder selected from the group consisting of heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 20 , or a pharmaceutically acceptable salt thereof. 
     
     
         29 . A method of treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload, said disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; in conjunction with therapies aimed at correcting or alleviating the primary cause of volume or pressure overload, including valve repair/replacement or effective antihypertensive therapy, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 20 , or a pharmaceutically acceptable salt thereof. 
     
     
         30 . A method of treating hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature associated with HCM, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 20 , or a pharmaceutically acceptable salt thereof, combined with therapies that retard the progression of heart failure by down-regulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neural endopeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropic agents, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and/or therapies that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (vasodilators of any class, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). 
     
     
         31 . 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:
 a. a powder X-ray diffraction pattern having two or more peaks expressed in degrees 2-theta±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;   b. a DSC thermogram showing endotherms at about 226.05° C., at about 302.47° C., and at about 310.13° C.; or   c. an X-ray crystal structure substantially the same as in  FIG. 4 .   
     
     
         32 . The polymorph of  claim 31 , characterized by a powder X-ray diffraction pattern having three or more peaks expressed in degrees 2-theta±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. 
     
     
         33 . The polymorph of  claim 31 , characterized by a powder X-ray diffraction pattern having four or more peaks expressed in degrees 2-theta±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. 
     
     
         34 . The polymorph of  claim 31 , characterized by a powder X-ray diffraction having peaks expressed in degrees 2-theta±0.2° at each of 11.3, 12.4, and 13.3 degrees. 
     
     
         35 . The polymorph of  claim 43 , characterized by a powder X-ray diffraction having peaks expressed in degrees 2-theta±0.2° at each of 11.3, 12.4, 13.3, 16.5, 17.3, 19.3, 20.4, and 29.5 degrees. 
     
     
         36 . The polymorph of  claim 31 , characterized by melt onsets of about 221.51° C., about 299.53° C., and about 308.81° C. 
     
     
         37 . The polymorph of  claim 31 , wherein the polymorph has a powder X-ray diffraction pattern substantially the same as in  FIG. 1A . 
     
     
         38 . The polymorph of any one of  claims 31 - 37 , wherein the Form 1 polymorph is substantially free of other forms of (6S,7S)-6-fluoro-7-(2-fluoro-5-methylphenyl)-3-(tetrahydro-2H-pyran-4-yl)-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione. 
     
     
         39 . A pharmaceutical composition comprising a polymorph of any one of  claims 31 - 38 , and a pharmaceutically acceptable excipient. 
     
     
         40 . The composition of  claim 39 , wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of other forms is equal to or greater than 80:20. 
     
     
         41 . The composition of  claim 39 , wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of other forms is equal to or greater than 90:10. 
     
     
         42 . The composition of  claim 39 , wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of other forms is equal to or greater than 95:5. 
     
     
         43 . The composition of  claim 39 , wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of other forms is equal to or greater than 97:3. 
     
     
         44 . The composition of  claim 39 , wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of other forms is equal to or greater than 98:2. 
     
     
         45 . The composition of  claim 39 , wherein the ratio of the amount of the Form 1 polymorph to the sum of the amounts of other forms is equal to or greater than 99:1. 
     
     
         46 . A method of treating hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature of HCM, comprising administering to a subject in need thereof an effective amount of a polymorph of any one of  claims 31 - 38 , or a pharmaceutical composition of any one of  claims 39 - 45 . 
     
     
         47 . A method of treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload, said disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; in conjunction with therapies aimed at correcting or alleviating the primary cause of volume or pressure overload, including valve repair/replacement or effective antihypertensive therapy, comprising administering to a subject in need thereof an effective amount of a polymorph of any one of  claims 31 - 38 , or a pharmaceutical composition of any one of  claims 39 - 45 . 
     
     
         48 . A method of treating hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature associated with HCM, comprising administering to a subject in need thereof an effective amount of a polymorph of any one  claims 31 - 38 , or a pharmaceutical composition of any one of  claims 39 - 45 , combined with therapies that retard the progression of heart failure by down-regulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers, aldosterone receptor antagonists, or neural endopeptidase inhibitors); therapies that improve cardiac function by stimulating cardiac contractility (e.g., positive inotropic agents, such as the β-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and/or therapies that reduce cardiac preload (e.g., diuretics, such as furosemide) or afterload (vasodilators of any class, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). 
     
     
         49 . A method of treating a cardiac disease or disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 20 , or a pharmaceutically acceptable salt thereof, pharmaceutical composition of any one of  claims 21 - 26 , polymorph of any one  claims 31 - 38 , or pharmaceutical composition of any one of  claims 39 - 45 , wherein the cardiac disease or disorder is selected from the group consisting of diastolic dysfunction, hypertrophic cardiomyopathy, nHCM, oHCM, heart failure, HFpEF, HFmREF, valvular disease, Aortic Stenosis, left ventricular hypertrophy, restrictive cardiomyopathy, inflammatory cardiomyopathy, Loeffler 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. 
     
     
         50 . The method of  claim 49 , wherein the cardiac disease or disorder is selected from the group consisting of nHCM, oHCM, HFpEF, HFmREF, Aortic Stenosis, Loeffler endocarditis, endomyocardial fibrosis, infiltrative cardiomyopathy, hemochromatosis, Fabry disease, glycogen storage disease, Tetralogy of Fallot, angina pectoris, refractory angina pectoris, and Chagas disease. 
     
     
         51 . The method of any one of  claims 49 - 50 , wherein the compound, or a pharmaceutically acceptable salt thereof, polymorph, or pharmaceutical composition is administered as a monotherapy. 
     
     
         52 . The method of any one of  claims 49 - 50 , wherein the compound, or a pharmaceutically acceptable salt thereof, polymorph, or pharmaceutical composition is administered as a combination therapy, wherein an additional therapeutic agent administered. 
     
     
         53 . The method of  claim 52 , wherein the additional therapeutic agent is selected from the group consisting of beta adrenergic blocking agent (beta-blocker), renin-angiotensin-aldosterone system (RAAS) inhibitor (e.g., an angiotensin converting enzyme (ACE) inhibitor, an angiotensin receptor antagonist, such as an angiotensin II receptor blocker), an angiotensin receptor neprilysin inhibitor (ARNI) (e.g., sacubitril/valsartan), a mineralocorticoid receptor antagonist (MRA) (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, pimobendane, a beta adrenergic receptor agonist such as dobutamine, a phosphodiesterase (PDE)-3 inhibitor such as milrinone, or a calcium-sensitizing agent such as levosimendan), potassium, magnesium, a proprotein convertase subtilisin kexin-type 9 (PCSK9) inhibitor, a vasodilator (e.g., a calcium channel blocker, phosphodiesterase inhibitor, endothelin receptor antagonist, renin inhibitor, or smooth muscle myosin modulator), a diuretic (e.g., furosemide), an arrhythmia medication, an anticoagulant (e.g., warfarin), an antithrombotic agent, an antiplatelet agent, a sodium-glucose cotransporter 2 inhibitor (SGLT2) (e.g., empaglifozin, dapagliflozin, sotagliflozin) or any combination thereof. 
     
     
         54 . The method of  claim 53 , wherein the angiotensin II receptor blocker (ARB) is selected from the group consisting of A-81988, A-81282, BIBR-363, BIBS39, BIBS-222, BMS-180560, BMS-184698, candesartan, candesartan cilexetil, CGP-38560A, CGP-48369, CGP-49870, CGP-63170, CI-996, CV-11194, DA-2079, DE-3489, DMP-811, DuP-167, DuP-532, E-4177, elisartan, EMD-66397, EMD-73495, eprosartan, EXP-063, EXP-929, EXP-3174, EXP-6155, EXP-6803, EXP-7711, EXP-9270, FK-739, GA-0056, HN-65021, HR-720, ICI-D6888, ICI-D7155, ICI-D8731, irbesartan, isoteoline, KRI-1177, KT3-671, KW-3433, losartan, LR-B/057, L-158809, L-158978, L-159282, L-159874, L-161177, L-162154, L-163017, L-159689, L-162234, L-162441, L-163007, LR-B/081, LR B087, LY-285434, LY-302289, LY-315995, LY-235656, LY-301875, ME-3221, olmesartan, PD-150304, PD-123177, PD-123319, RG-13647, RWJ-38970, RWJ-46458, saralasin acetate, S-8307, S-8308, SC-52458, 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. 
     
     
         55 . The method of  claim 53 , wherein the ARNI is selected from the group consisting of sacubitril, valsartan, or a combination of sacubitril and valsartan (sacubitril/valsartan). 
     
     
         56 . The method of  claim 53 , wherein the SGLT2 is selected from the group consisting of empaglifozin, dapagliflozin, and sotagliflozin. 
     
     
         57 . The method of  claim 52 , wherein the additional therapeutic agent improves cardiovascular conditions in the subject. 
     
     
         58 . The method of any one of  claims 52 ,  53 , and  57 , wherein the additional therapeutic agent is selected from the group consisting of a beta blocker, a diuretic, an angiotensin-converting enzyme (ACE) inhibitor, a calcium channel blocker, an angiotensin II receptor blocker, a mineralocorticoid receptor antagonist, an ARNI, a RAAS inhibitor, an arrhythmia medication, and a SGLT2 inhibitor.