Pyrimidinedione compounds against cardiac conditions

Abstract

To provide novel therapeutic agents and methods for improved treatment of hypertrophic cardiomyopathy (HCM) and related cardiac disorders.SOLUTION: Provided are novel pyrimidine dione compounds and pharmaceutically acceptable salts thereof that are useful for the treatment of hypertrophic cardiomyopathy (HCM) and conditions associated with left ventricular hypertrophy or diastolic dysfunction. The synthesis and characterization of the compounds and pharmaceutically acceptable salts thereof are described, as well as methods for treating HCM and other forms of heart disease.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 61 / 838,088, filed June 21, 2013, U.S. Provisional Application No. 61 / 939,655, filed February 13, 2014, and U.S. Provisional Application No. 61 / 981,366, filed April 18, 2014, each of which is incorporated herein by reference in its entirety.

[0002] STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER U.S. GOVERNMENT-SPONSORED RESEARCH OR DEVELOPMENT Not applicable. [Background technology]

[0003] Genetic (inherited) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, monogenic, autosomal dominant cardiomyopathies. HCM is caused by one or more of over 1,000 known point mutations in any one of the structural protein genes that contribute to the functional unit of cardiac muscle, the sarcomere. Approximately 1 in 500 individuals in the general population are found to have left ventricular hypertrophy that is not explained by other known causes (e.g., hypertension or valvular disease), and many of these can be shown to have HCM once other genetic (e.g., lysosomal storage disorders), metabolic, or infiltrative causes are excluded.

[0004] Sarcomeric gene mutations that cause HCM are highly penetrant but show wide variability in clinical severity and course. Some genotypes are associated with a more aggressive course, but there is considerable variability between and even within families carrying the same mutation. Gender differences have also been noted, with male patients generally being more severely affected than female patients. While many patients with HCM report few or no long-term symptoms, HCM is a progressive disease with a significant cumulative burden of morbidity. Symptoms of exertion intolerance predominate and are exacerbated by exercise and other procedures that increase heart rate and / or reduce preload. As with many other disorders, symptoms tend to worsen with age. By far the most common clinical burden for patients with HCM is exertional dyspnea, which limits and debilitates patients' activities of daily living.

[0005] Patients with HCM often present with symptoms in the absence of documented hemodynamic abnormalities such as left ventricular outflow tract obstruction (with or without mitral regurgitation). Their symptoms of exertional dyspnea can rapidly worsen with the onset of atrial fibrillation, a common complication of HCM that can induce acute pulmonary edema, increasing the risk of systemic arterial thromboembolic disease, including stroke. Other adverse events associated with HCM include hypovolemia or hypervolemia intolerance and syncope. Concomitant coronary artery disease confers a higher risk of acute coronary syndromes than patients without HCM. Sudden cardiac death (SCD) in patients with HCM, although rare and difficult to predict, is a leading cause of non-traumatic death in young adults. For survivors of SCD, ICD replacement is standard practice; for other HCM patients, risk profiling, although uncertain, is used to identify those for whom ICD replacement for primary prevention is prudent.

[0006] Medical therapies for HCM are limited to treating symptoms and do not address the underlying underlying cause of the disease—the disruption of normal sarcomere function. Currently available treatments are variably effective in alleviating symptoms but typically demonstrate diminishing efficacy with increasing disease duration. Patients are therefore empirically managed with beta-blockers, non-dihydropyridine calcium channel blockers, and / or disopyramide. None of these medications have a labeled indication for treating HCM, and essentially no rigorous clinical trial evidence is available to guide their use. Compounding this unfortunate situation is the fact that no new medical therapies for HCM have been identified for many years. Surgical myectomy or alcohol septal ablation for patients with hemodynamically significant outflow tract obstruction (resting gradient >30 mmHg) in appropriately selected patients is usually required to relieve the hemodynamic obstruction. Provided are new therapeutic agents and methods that alleviate the long-felt need for improved treatment of HCM and related cardiac disorders. Summary of the Invention [Means for solving the problem]

[0007] In one embodiment, provided is a compound of the formula:

[0008] [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, 1 is a member selected from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C4 alkyl, 4- to 7-membered heterocycloalkyl, phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-C1-C4 alkyl, where each R 1 may contain 1 to 3 R a is substituted by R 2is a member selected from phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-C1-C4 alkyl, where each R 2 may contain 1 to 5 R b is substituted by R 3 is a member selected from C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7-membered heterocycloalkyl, where each R 3 may contain 1 to 3 R c is substituted by R 4 is H; X is selected from H and halo, and in some embodiments, X is selected from H and F. Each R a when present, is selected from halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenyl, phenyl-C1-C4 alkyl, phenyl-C1-C4 alkoxy, phenoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , and -CONR a1 R a2 where each R a1 and R a2 are independently selected from H, C1-C4 alkyl and phenyl, or optionally R a1 and R a2 When attached to a nitrogen atom, they combine to form a 4- to 6-membered ring. Similarly, each R b When present, it is selected from halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenoxy, phenyl-C1-C4 alkoxy, methylenedioxy, difluoromethylenedioxy, -COR b1 , -CO2R b1 , -SO2R b1 , -SO2NR b1 R b2 , -CONR b1 R b2 , N.R. b1 R b2, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted by oxo, wherein each R b1 and R b2 are independently selected from H and C1-C4 alkyl, or optionally R b1 and R b2 when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; each R c when present, is independently selected from halo, hydroxyl and C1-C2 alkoxy.

[0009] In another aspect, provided is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

[0010] In another aspect, provided is a method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having one or more pathophysiological characteristics associated with HCM, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt described herein. [Brief explanation of the drawings]

[0011] [Figure 1] 1A-1B show schematic routes for the synthesis of compounds or pharmaceutically acceptable salts described herein (FIG. 1A) and routes for the preparation of chiral amines (FIG. 1B). DETAILED DESCRIPTION OF THE INVENTION

[0012] I. Overview A series of pyrimidinedione compounds and their pharmaceutically acceptable salts have been found to strongly bind actin filaments, release phosphate, and thus reduce excessive contractility in hypercontractile states and / or promote cardiac relaxation in hearts with diastolic dysfunction by stabilizing the conformation of beta cardiac myosin after ATP hydrolysis, except before the proportion of myosin molecules that can participate in the "power stroke" portion of the muscle contraction cycle is reduced. As such, the compounds improve cardiac elasticity, reduce dynamic and / or static left ventricular outflow tract obstruction, improve diastolic left ventricular relaxation, reduce left ventricular diastolic (filling) pressure, reduce functional mitral regurgitation, and / or reduce left atrial and pulmonary capillary wedge pressure in patients with HCM, helping to overcome the debilitating exertional dyspnea and / or symptoms often associated with left ventricular outflow tract obstruction (near-syncope or syncope). The compounds can also be used to treat other cardiac disorders.

[0013] II. Definition As used herein, the term "alkyl" refers to a straight or branched, saturated, aliphatic group having the number of carbon atoms indicated. Alkyl can have any number of carbons, including C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 and C 5~6 For example, C 1~6Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl can refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, and the like. Unless otherwise specified, alkyl groups are unsubstituted. "Substituted alkyl" groups are substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

[0014] The term "cycloalkyl" as used herein refers to a saturated or partially unsaturated monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, including C 3~6 , C 4~6 , C 5~6 , C 3~8 , C 4~8 , C 5~8 , and C 6~8

[0033] Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. Unless otherwise specified, cycloalkyl groups are unsubstituted. "Substituted cycloalkyl" groups are substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

[0015] As used herein, the term "heterocycloalkyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 heteroatoms selected from N, O, and S. Additional heteroatoms can also be present in a heterocycloalkyl group, including, but not limited to, B, Al, Si, and P. The heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)-. Heterocycloalkyl groups can contain any number of ring atoms, for example, 3 to 6, 4 to 6, 5 to 6, or 4 to 7 ring members. Any suitable number of heteroatoms can be included in a heterocycloalkyl group, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Examples of heterocycloalkyl groups include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups are unsubstituted, but in some embodiments are described as substituted. "Substituted heterocycloalkyl" groups are substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

[0016] As used herein, the term "heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, of which 1 to 5 ring atoms are heteroatoms such as N, O, or S. Additional heteroatoms, including but not limited to, B, Al, Si, and P, can also be present in a heteroaryl group. These heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)-. A heteroaryl group can contain any number of ring atoms, for example, 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ring members. Any suitable number of heteroatoms can be included in a heteroaryl group, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Examples of heteroaryl groups include, but are not limited to, pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups are unsubstituted, but in some embodiments are described as substituted. "Substituted heteroaryl" groups are substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

[0017] As used herein, the term "alkoxy" refers to an alkyl group having an oxygen atom attached to the alkyl group at the point of attachment: i.e., alkyl-O-. With respect to the alkyl moiety, the alkoxy group is C 1~6 or C 1~4Alkoxy groups can have any suitable number of carbon atoms, such as . Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. Alkoxy groups are unsubstituted, but in some embodiments are described as substituted. "Substituted alkoxy" groups are substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

[0018] As used herein, the terms "halo" and "halogen" refer to fluorine, chlorine, bromine and iodine.

[0019] As used herein, the term "pharmaceutically acceptable" refers to a material that is compatible with the compounds or salts described herein, as well as with any other ingredients with which the compound is formulated. Moreover, a pharmaceutically acceptable material is not toxic to the recipient of the material.

[0020] The term "salt" as used herein refers to an acid or base salt of the compounds described herein. Pharmaceutically acceptable salts are obtained, for example, from mineral acids (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like), organic acids (acetic acid, propionic acid, glutamic acid, citric acid, and the like), and quaternary ammonium ions. It is understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Easton, PA, Mack Publishing Company, 1985, incorporated herein by reference. 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.

[0021] As used herein, the term "pharmaceutical composition" refers to a product that contains a compound or pharmaceutically acceptable salt thereof described herein, an excipient as defined herein, and other optional ingredients in specified amounts, as well as any product that results directly or indirectly from the combination of specified ingredients in specified amounts.

[0022] The term "additive" as used herein refers to a substance that helps administer active agent to a subject. Pharmaceutical additives include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents and coloring agents. Those skilled in the art will recognize that other additives are useful.

[0023] As used herein, the terms "treat," "treating," and "treatment" refer to any objective or subjective parameter, such as relief; remission; reduction of symptoms; making the condition, injury, condition, or symptom more tolerable to the patient; reducing the frequency or persistence of the condition, injury, condition, or symptom; or, in some cases, preventing the onset of the condition, injury, condition, or symptom, or any indication of successful treatment or amelioration of the condition, injury, condition, or symptom associated with hypertrophic cardiomyopathy. Treatment or amelioration is based on any objective or subjective parameter, including, for example, the results of a physical examination.

[0024] III. Compounds and Pharmaceutically Acceptable Salts Thereof In one embodiment, provided is a compound of the formula: [ka] or a pharmaceutically acceptable salt thereof.

[0025] In the above equation, R 1is a member selected from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C4 alkyl, 4- to 7-membered heterocycloalkyl, phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-C1-C4 alkyl, where each R 1 may contain 1 to 3 R a is substituted by R 2 is a member selected from phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-C1-C4 alkyl, where each R 2 may contain 1 to 5 R b is substituted by R 3 is a member selected from C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7-membered heterocycloalkyl, where each R 3 may contain 1 to 3 R c is substituted by R 4 is H; X is a member selected from H and halo, and in selected embodiments, is selected from H and F. Each R a when present, is selected from halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenyl, phenyl-C1-C4 alkyl, phenyl-C1-C4 alkoxy, phenoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , and -CONR a1 R a2 where each R a1 and R a2 are independently selected from H, C1-C4 alkyl and phenyl, or optionally R a1 and R a2 When attached to a nitrogen atom, they combine to form a 4- to 6-membered ring. Similarly, each R bWhen present, it is selected from halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenoxy, phenyl-C1-C4 alkoxy, methylenedioxy, difluoromethylenedioxy, -COR b1 , -CO2R b1 , -SO2R b1 , -SO2NR b1 R b2 , -CONR b1 R b2 , N.R. b1 R b2 , 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted by oxo, wherein each R b1 and R b2 are independently selected from H and C1-C4 alkyl, or optionally R b1 and R b2 when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; each R c when present, is independently selected from halo, hydroxyl and C1-C2 alkoxy.

[0026] In some embodiments, R 1 is selected from C1-C8 alkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each R 1 may contain 1 to 3 R a is replaced by R 2 may contain 1 to 5 R b R is phenyl substituted by 3 is selected from C1-C4 alkyl, C3-C4 cycloalkyl, or 4- to 7-membered heterocycloalkyl, wherein each R 3 may contain 1 or 2 R c is replaced by R 4 is H and X is H or F. In some embodiments, each R a when present, independently represents halo, CN, C1-C4 alkyl, C1-C4 alkoxy, -COR a1, -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , or -CONR a1 R a2 where each R a1 and R a2 are independently H or C1-C4 alkyl. Alternatively, R a1 and R a2 When attached to a nitrogen atom, they are optionally combined to form a 4- to 6-membered ring. b when present, independently represents halo, CN, C1-C4 alkyl, C1-C4 alkoxy, -COR b1 , -CO2R b1 , -SO2R b1 , -SO2NR b1 R b2 , -CONR b1 R b2 , N.R. b1 R b2 , 5- to 6-membered heteroaryl, or 5- to 6-membered heterocyclyl optionally substituted by oxo, wherein each R b1 and R b2 are independently H or C1-C4 alkyl. Alternatively, R b1 and R b2 When attached to a nitrogen atom, they may optionally combine to form a 4- to 6-membered ring. c When present, is independently halo or C1-C2 alkoxy.

[0027] In some embodiments, X is H.

[0028] In some embodiments, R 1 is C-C alkyl, C-C cycloalkyl, or 4- to 6-membered heterocycloalkyl, where each R 1 may contain 1 or 2 R a is replaced by

[0029] In some embodiments, R 1is phenyl or 5- to 6-membered heteroaryl, where each R 1 may contain 1 to 3 R a is replaced by

[0030] In some embodiments, R 1 is C3-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycloalkyl.

[0031] In some embodiments, R 1 is C1-C4 alkyl, C1-C4 alkoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , and -CONR a1 R a2 (where each R a1 and R a2 are independently H or C1-C4 alkyl) a and 4 to 6 membered heterocycloalkyl optionally substituted by:

[0032] In some embodiments, R 1 is cyclobutyl, isopropyl, isobutyl, 1-methoxypropan-2-yl, cyclopentyl, cyclohexyl, 4-tetrahydropyranyl, 1-(methylsulfonyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 4,4-difluorocyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, or 1-methyl-3-pyrazolyl.

[0033] In some embodiments, R 2 is one to two R b is optionally replaced by

[0034] In some embodiments, R 2is phenyl, 3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3-(3-oxazolidin-2-onyl)phenyl, 3-(2-methyl-1-imidazyl)phenyl, 3-(1-pyrazolyl)phenyl, or 3-(1,2,4-triazol-1-yl)phenyl.

[0035] In some embodiments, R 3 is C1-C4 alkyl, C1-C4 alkoxyalkyl, or C3-C4 cycloalkyl.

[0036] In some embodiments, R 3 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl or 2-methoxymethyl.

[0037] In some embodiments, R 3 is methyl.

[0038] The compounds or pharmaceutically acceptable salts described herein may be any of the R groups listed above. 1 , R 2 , R 3 , R 4 , R a , R a1 , R a2 , R b , R b1 , R b2 , R c and X groups. 2 Selected embodiments listed for, for example, R 1 can be combined with any of the selected embodiments listed for R 3 10. The above-mentioned embodiments may be combined with any of the selected embodiments listed above.

[0039] In some embodiments, for example, R 1 is a C3-C8 alkyl; R3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is phenyl. In other embodiments, R 1 is C1-C4 alkyl, -CO2R a1 , -SO2NR a1 R a2 , or -SO2R a1 R is a 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is phenyl. In still other embodiments, R 1 is C3-C8 cycloalkyl or phenyl, and R 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is phenyl.

[0040] In other embodiments, R 1 is a C3-C8 alkyl; R 3 is C1-C4 alkyl; R 2 is phenyl. In still other embodiments, R 1 is C1-C4 alkyl, -CO2R a1 , or -SO2R a1 R is a 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with 3 is C1-C4 alkyl; R 2 is phenyl. In still other embodiments, R 1 is C3-C8 cycloalkyl or phenyl; R 3 is C1-C4 alkyl; R 2 is phenyl.

[0041] In some embodiments, R 1 is a C3-C8 alkyl; R 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R2 is phenyl substituted with 1 to 2 C1-C4 alkoxy or halo. 1 is C1-C4 alkyl, -CO2R a1 , or -SO2R a1 R is a 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is phenyl substituted with 1 to 2 C1-C4 alkoxy or halo. In yet another embodiment, R 1 is C3-C8 cycloalkyl or phenyl; R 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is phenyl substituted with 1 to 2 C1-C4 alkoxy or halo.

[0042] In some embodiments, R 1 is a C3-C8 alkyl; R 3 is C1-C4 alkyl; R 2 is phenyl substituted with 1 to 2 C1-C4 alkoxy or halo. 1 is C1-C4 alkyl, -CO2R a1 , or -SO2R a1 R is a 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with 3 is C1-C4 alkyl; R 2 is phenyl substituted with 1 to 2 C1-C4 alkoxy or halo. 1 is C3-C8 cycloalkyl or phenyl; R 3 is C1-C4 alkyl; R 2 is phenyl substituted with 1 to 2 C1-C4 alkoxy or halo.

[0043] In some embodiments, R 1 is a C3-C8 alkyl; R 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is phenyl substituted with 5- to 6-membered heteroaryl optionally substituted with oxo or 5- to 6-membered heterocyclyl. 1 is C1-C4 alkyl, -CO2R a1 , or -SO2R a1 R is a 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is phenyl substituted with 5- to 6-membered heteroaryl optionally substituted with oxo or 5- to 6-membered heterocyclyl. 1 is C3-C8 cycloalkyl or phenyl, and R 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is phenyl substituted by 5- to 6-membered heteroaryl optionally substituted by oxo or 5- to 6-membered heterocyclyl.

[0044] In some embodiments, R 1 is a C3-C8 alkyl; R 3 is C1-C4 alkyl; R 2 is phenyl substituted with 5- to 6-membered heteroaryl optionally substituted with oxo or 5- to 6-membered heterocyclyl. 1 is C1-C4 alkyl, -CO2R a1 , or -SO2R a1 R is a 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with 3 is C1-C4 alkyl; R 2is phenyl substituted with 5- to 6-membered heteroaryl optionally substituted with oxo or 5- to 6-membered heterocyclyl. 1 is C3-C8 cycloalkyl or phenyl; R 3 is C1-C4 alkyl; R 2 is phenyl substituted by 5- to 6-membered heteroaryl optionally substituted by oxo or 5- to 6-membered heterocyclyl.

[0045] In some embodiments, R 1 is a C3-C8 alkyl; R 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is CN, C1-C4 alkyl, -COR b1 , -CO2R b1 , -SO2R b1 , -SO2NR b1 R b2 ,CONR b1 R b2 , or NR b1 R b2 In another embodiment, R 1 is C1-C4 alkyl, -CO2R a1 , or -SO2R a1 R is a 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with 3 is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is CN, C1-C4 alkyl, -COR b1 , -CO2R b1 , -SO2R b1 ,CONR b1 R b2 , or NR b1 R b2 In another embodiment, R 1 is C3-C8 cycloalkyl or phenyl; R 3is a C-C cycloalkyl or a 4- to 7-membered heterocycloalkyl; R 2 is CN, C1-C4 alkyl, -COR b1 , -CO2R b1 , -SO2R b1 ,CONR b1 R b2 , or NR b1 R b2 is phenyl substituted by

[0046] In some embodiments, R 1 is a C3-C8 alkyl; R 3 is C1-C4 alkyl; R 2 is CN, C1-C4 alkyl, -COR b1 , -CO2R b1 , -SO2R b1 ,CONR b1 R b2 , or NR b1 R b2 In another embodiment, R 1 is C1-C4 alkyl, -CO2R a1 , or -SO2R a1 R is a 4- to 7-membered heterocycloalkyl or a 5- to 6-membered heteroaryl optionally substituted with 3 is C1-C4 alkyl; R 2 is CN, C1-C4 alkyl, -COR b1 , -CO2R b1 , -SO2R b1 ,CONR b1 R b2 , or NR b1 R b2 In another embodiment, R 1 is C3-C8 cycloalkyl or phenyl; R 3 is C1-C4 alkyl; R 2 is CN, C1-C4 alkyl, -COR b1 , -CO2R b1 , -SO2R b1 ,CONR b1 R b2, N.R. b1 R b2 or -CONR a1 R a2 is phenyl substituted by

[0047] In some embodiments, R 1 is isopropyl; R 2 is one to two R b optionally substituted by R 3 is methyl.

[0048] In some embodiments, R 1 is C1-C4 alkyl, C1-C4 alkoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , and -CONR a1 R a2 (where each R a1 and R a2 are independently H or C1-C4 alkyl) a R is a 4- to 6-membered heterocycloalkyl optionally substituted with 2 is one to two R b optionally substituted by R 3 is methyl.

[0049] In some embodiments, R 1 is phenyl or 5- to 6-membered heteroaryl, where each R 1 is one to three R a optionally substituted by R 2 is one to two R b optionally substituted by R 3 is methyl.

[0050] X can be H in any of the embodiments set forth above. In other embodiments, X can be F in any of the embodiments set forth above. Still further, it will be understood by those of skill in the art that compounds provided herein with the identified stereochemistry (shown as R or S, or having a dashed or wedge bond designation) are substantially free of other isomers (e.g., at least 80%, 90%, 95% up to 100% free of other isomers).

[0051] In some embodiments, the compound is (S)-3-Isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-5-fluoro-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-5-bromo-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3,5-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((cyclopropyl(3-methoxyphenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-methoxyphenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione; 6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione; (S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; Methyl (S)-4-(2,6-dioxo-4-((1-phenylethyl)amino)-3,6-dihydropyrimidin-1(2H)-yl)piperidine-1-carboxylate; 3-((R)-sec-butyl)-6-(((S)-1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-phenylethyl)amino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione; (S)-3-(isoxazol-3-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-(1H-pyrazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;

[0052] (S)-3-Isopropyl-6-((1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(2-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-5-methyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(2-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(4-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-5-fluoro-3-isopropyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-5-fluoro-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-5-fluoro-3-isopropyl-6-((1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(2,5-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-bromophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-3-ethyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Cyclopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-phenylethyl)amino)-3-(pyridin-2-yl)pyrimidine-2,4(1H,3H)-dione; (S)-3-(1-methyl-1H-pyrazol-3-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;

[0053] (S)-3-(isoxazol-5-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-(1H-1,2,4-triazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(3-(2-methyl-1H-imidazol-1-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(3-(2-oxooxazolidin-3-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Cyclohexyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-phenyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-ethyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-methyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione; (S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (R)-3-Isopropyl-6-((2,2,2-trifluoro-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; 3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; 3-((R)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-2-(1-((1-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)amino)ethyl)benzonitrile

[0054] (S)-3-benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(2,6-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(4-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-3-(6-methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(2,2-difluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(o-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-(1H-imidazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-phenylethyl)amino)-3-(pyridazin-4-yl)pyrimidine-2,4(1H,3H)-dione;

[0055] (S)-4-((1-phenylethyl)amino)-2H-[1,5'-bipyrimidine]-2,6(3H)-dione; (S)-6-((1-phenylethyl)amino)-3-(pyrazin-2-yl)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(pyridin-3-yl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(1-methyl-1H-pyrazol-4-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-phenylbutyl)amino)pyrimidine-2,4(1H,3H)-dione; 6-(((S)-1-phenylethyl)amino)-3-((R)-tetrahydro-2H-pyran-3-yl)pyrimidine-2,4(1H,3H)-dione; (S)-3-Cyclopentyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((2-methyl-1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(4,4-difluorocyclohexyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(pentan-3-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(1-benzoylpiperidin-4-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((4-phenylbutan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione; Methyl (S)-2-(2,6-dioxo-4-((1-phenylethyl)amino)-3,6-dihydropyrimidin-1(2H)-yl)acetate (S)-3-Isopropyl-6-((1-phenylpropan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione; 3-((S)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; 3-((S)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (R)-6-((2-hydroxy-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;

[0056] 6-(((S)-1-phenylethyl)amino)-3-((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4(1H,3H)-dione; 6-(((S)-1-phenylethyl)amino)-3-((S)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4(1H,3H)-dione; 6-(((S)-1-phenylethyl)amino)-3-(4,4,4-trifluorobutan-2-yl)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-phenylethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione; (S)-3-(tert-butyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(2-methoxyethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; 6-(((S)-1-phenylpropyl)amino)-3-((S)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4(1H,3H)-dione; 3-((R)-1-cyclopropylethyl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; 3-((S)-1-cyclopropylethyl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((cyclobutyl(phenyl)methyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-phenylpropyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione; (S)-3-(cyclopropylmethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione; (S)-6-((cyclobutyl(phenyl)methyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione; (S)-3-(1,3-dihydroxypropan-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;

[0057] 6-(((S)-1-(4-fluorophenyl)propan-2-yl)amino)-3-((S)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; 6-((1-(2-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-phenylethyl)amino)-3-(1-(trifluoromethyl)cyclopropyl)pyrimidine-2,4(1H,3H)-dione; (S)-3-(3,5-difluorophenyl)-6-((1-(4-fluorophenyl)propan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(2-chlorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-3-Isopropyl-6-((1-(4-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione; (S)-3-ethyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(cyclopropylmethyl)-6-((1-(3-fluorophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-(cyclopropylmethyl)-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-(cyclopropylmethyl)pyrimidine-2,4(1H,3H)-dione; (S)-5-chloro-6-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;

[0058] (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione; (S)-3-Propyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-3-cyclobutyl-6-((1-(4-fluorophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(2-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(3,4-difluorophenyl)ethyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione; 3-((S)-sec-butyl)-6-(((S)-1-(4-fluorophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione; (S)-6-((1-(4-fluorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione; and (S)-3-(6-fluoropyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt of any of the above.

[0059] In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0060] The compounds or pharmaceutically acceptable salts (I) described herein can be prepared by any suitable method. The compounds can be prepared, for example, by the route outlined in Figure 1. As shown in Figure 1A, pyrimidinetrione v can be synthesized by condensation of urea iii with malonate iv. The urea iii is prepared by reaction of amine i with an appropriate cyanate ii. The pyrimidinetrione v is derivatized with a suitable leaving group (Lg) to provide intermediate vi. The leaving group can be a halogen, such as, but not limited to, chloride or iodide. The halogenated intermediate vi can be prepared from the pyrimidinetrione by methods such as those described by Brown (The Chemistry of Heterocyclic Compounds, The Pyrimidines, John Wiley & Sons, 2009). Intermediate vi can be converted to a compound of Formula I by reaction with amine vii. Certain chiral amines can be prepared from ketones or aldehydes ix as shown in Figure 1B; sulfinyl imines xii derived from ketones or aldehydes can be reacted with Grignard reagents to provide chiral amines vii. Those skilled in the art will appreciate that the compounds described herein can also be prepared by other methods, such as those described by LaRock (Comprehensive Organic Transformations: A Guide to Functional Group Preparations, Wiley, 1999).

[0061] IV. Composition Also provided are pharmaceutical compositions comprising a compound or a pharmaceutically acceptable salt thereof described herein and a pharmaceutically acceptable excipient, which compositions are useful for treating hypertrophic cardiomyopathy in humans and other subjects.

[0062] Pharmaceutical compositions for administering the compounds or pharmaceutically acceptable salts described herein can be conveniently provided in unit dosage form and prepared by any method known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with a carrier containing one or more accessory ingredients. Generally, the pharmaceutical compositions are prepared by uniformly and intimately combining the active ingredient with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired formulation. The active agent in the pharmaceutical composition is generally included in an amount sufficient to produce the desired effect on myocardial contractility (i.e., to reduce systolic contractile force, which is often excessive in HCM) and to improve left ventricular relaxation during diastole. Such improved relaxation can alleviate symptoms in hypertrophic cardiomyopathy and other causes of diastolic dysfunction. It can also be used as an adjunct in angina pectoris and ischemic heart disease to ameliorate the effects of diastolic dysfunction, which causes coronary blood flow dysfunction. It may also confer benefit against beneficial left ventricular remodeling in HCM and other causes of left ventricular hypertrophy due to chronic volume or pressure overload, such as from valvular heart disease or systemic hypertension.

[0063] Pharmaceutical compositions containing the active ingredient are in a form suitable for oral use, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gels, chewing gums, chewable tablets, effervescent powders, and effervescent tablets. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, antioxidants, and preservatives to provide pharmaceutically elegant and palatable formulations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These additives can be, for example, inert fillers such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as PVP, cellulose, PEG, starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets can be uncoated, or they can be enteric or otherwise coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period of time. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used. They can also be coated to form osmotic therapeutic tablets for controlled release.

[0064] Formulations for oral use can also be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid excipient, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.In addition, emulsions can be prepared with non-water-miscible ingredients such as oils, and stabilized with surfactants such as mono- and diglycerides, PEG esters, and the like.

[0065] Aqueous suspensions contain the active substance in admixture with excipients suitable for the manufacture of aqueous suspensions, such as suspending agents, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, and dispersing or wetting agents, such as naturally occurring phosphatides, for example, lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearic acid esters, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides, for example, polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, ethyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0066] Oily suspensions can be formulated by suspending active ingredients in vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.These oily suspensions can contain thickening agents, such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and flavoring agents, such as those listed above, can be added to provide a palatable oral preparation.These compositions are maintained by adding antioxidants, such as ascorbic acid.

[0067] Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water provide the active ingredient in a mixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional additives, such as sweeteners, flavorings, and coloring agents, can also be present.

[0068] The pharmaceutical compositions described herein can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers can be naturally occurring gums, such as acacia gum or tragacanth gum, naturally occurring phosphatides, such as soybean 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 emulsions can also contain sweeteners and flavoring agents.

[0069] Syrups and elixirs are formulated with sweeteners such as glycerin, propylene glycol, sorbitol or sucrose.Such preparations can also contain demulcents, preservatives, and flavoring and coloring agents.Oral liquid preparations can be prepared, for example, with cyclodextrin, PEG and surfactants.

[0070] The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension is formulated according to known techniques using suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable excipient or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and physiological saline solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid are found to be used in the preparation of injectables.

[0071] The compounds or pharmaceutically acceptable salts described herein can also be administered in the form of suppositories for rectal administration of drugs.These compositions are prepared by mixing the drug with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug.Such materials include cocoa butter and polyethylene glycol.In addition, the compounds or pharmaceutically acceptable salts can be administered by visible delivery through liquid or ointment.Furthermore, transdermal delivery of the subject compounds or pharmaceutically acceptable salts can be achieved using iontophoretic patches and the like.For topical use, creams, ointments, jellies, solutions or suspensions containing the compounds or pharmaceutically acceptable salts described herein can be used.Topical application as used herein also means the use of mouthwashes and gargles.

[0072] The compounds or pharmaceutically acceptable salts described herein may also be linked to carriers, which are suitable polymers for targetable drug delivery. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds or pharmaceutically acceptable salts described herein may be linked to carriers, which are biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, polyε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles such as valves, stents, vascular structures, prostheses, and the like.

[0073] V. Methods of Treating Heart Disorders Mutations that lead to HCM cause significant perturbations in myosin structure. These mutations affect them through unique mechanisms depending on their location in the myosin gene. The well-studied HCM mutations, R403Q and R453C, map to different sections of the motor domain and cause unique mechanical perturbations that result in the common outcome of increased force generation. While not wishing to be bound by any particular theory, it is believed that the compounds or pharmaceutically acceptable salts described herein can bind directly to mutant sarcomeric proteins in cis (by affecting the same specific function) or in trans (by altering a complementary function) and correct their abnormal function. As such, they can provide therapeutic benefit to HCM patients by correcting the hypercontractility and / or impaired relaxation associated with the disease.

[0074] Also provided is a method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having one or more pathophysiological characteristics associated with HCM, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt described herein.

[0075] The compounds of the present invention or their pharmaceutically acceptable salts can alter the natural course of HCM and other diseases rather than simply alleviating their symptoms. The mechanisms that provide clinical benefit to HCM patients can be extended to patients with other forms of heart disease that share similar pathophysiology, with or without demonstrable genetic influence. For example, an effective treatment for HCM by improving ventricular relaxation during diastole would also be effective in a broader population characterized by diastolic dysfunction. The compounds of the present invention or their pharmaceutically acceptable salts can specifically target the underlying cause of the condition or act on other downstream pathways. Thus, the compounds of the present invention or their pharmaceutically acceptable salts can also benefit patients suffering from diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, or restrictive cardiomyopathy. The compounds of the present invention or their pharmaceutically acceptable salts can also promote beneficial left ventricular remodeling in left ventricular hypertrophy caused by volume or pressure overload, such as chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension, in conjunction with treatments aimed at correcting or alleviating the underlying cause of volume or pressure overload (valve repair / replacement, effective antihypertensive therapy). By reducing left ventricular filling pressure, the compounds can reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and / or reducing left atrial pressure can reduce the risk of paroxysmal or persistent atrial fibrillation, along with the associated risk of arterial thromboembolic complications, including, but not limited to, cerebral arterial embolic stroke. Reducing or eliminating either dynamic and / or static left ventricular outflow tract obstruction can reduce the likelihood of requiring surgical or subcutaneous septal reduction therapy, with its associated risks of short-term and long-term complications. The compounds, or pharmaceutically acceptable salts thereof, can reduce the severity of the chronic ischemic condition associated with HCM, thereby reducing the risk of sudden cardiac death (SCD) or its equivalent in patients with implantable cardioverter-defibrillators (frequent and / or repeated ICD discharges) and / or the need for potentially toxic antiarrhythmic drug therapy.The compounds or pharmaceutically acceptable salts thereof serve to reduce or eliminate the need for concomitant drug treatments with their associated potential toxicities, drug-drug interactions, and / or side effects. The compounds or pharmaceutically acceptable salts thereof can reduce and / or slow the progression of interstitial myocardial fibrosis and prevent or reverse left ventricular hypertrophy.

[0076] Depending on the disease being treated and the condition of the subject, the compounds or pharmaceutically acceptable salts described herein may be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection, or implantation), by implantation (e.g., when the compound or pharmaceutically acceptable salt is linked to a stent device), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration, either alone or together formulated in suitable dosage unit formulations containing carriers, adjuvants, and vehicles appropriate for each conventional, non-toxic, pharmaceutically acceptable route of administration.

[0077] For the treatment or prevention of conditions requiring improved ventricular relaxation during diastole, an appropriate dosage level is generally about 0.001 to 100 mg / kg of patient body weight per day, administered in single or multiple doses. In some embodiments, the dosage level is about 0.01 to about 25 mg / kg per day; in some embodiments, about 0.05 to about 10 mg / kg per day. Suitable dosage levels are about 0.01 to 25 mg / kg per day, about 0.05 to 10 mg / kg per day, or about 0.1 to 5 mg / kg per day. Within this range, the dosage can be 0.005 to 0.05, 0.05 to 0.5, or 0.5 to 5.0 mg / kg per day. In some embodiments, for oral administration, the composition is provided in the form of a tablet containing 1.0 to 1000 milligrams of active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of active ingredient, for symptomatic adjustment of dosage to the patient to be treated. The compound or pharmaceutically acceptable salt is administered on a regimen of 1 to 4 times per day, and in some embodiments, once or twice per day.

[0078] It will be understood, however, that the specific dose level and frequency of administration for any particular patient will vary and will depend upon a variety of factors, including the activity of the particular compound or pharmaceutically acceptable salt used, the metabolic stability and length of action of the compound or pharmaceutically acceptable salt, the subject's age, weight, genetic characteristics, general health, sex, and diet, as well as the manner and time of administration, rate of excretion, drug combination, and the severity of the particular condition being treated.

[0079] The compounds and compositions provided herein can be used in combination with other drugs used in the treatment, prevention, suppression, or amelioration of diseases or conditions for which the compounds and compositions provided herein are useful. Such other drugs are administered by routes and in amounts commonly used, and thus can be administered simultaneously or sequentially with the compounds or compositions provided herein. 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. Thus, pharmaceutical compositions provided herein include those that also contain 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, therapies that attempt to slow the progression of heart failure and prevent cardiac remodeling by downregulating cardiac neurohormonal stimulation (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, aldosterone receptor antagonists, or neuroendopeptidase inhibitors); therapies that improve cardiac function by stimulating myocardial contractility (e.g., positive inotropic agents such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and therapies that reduce cardiac preload (e.g., diuretics such as furosemide) or afterload (any class of vasodilators, including but not limited to calcium channel blockers, phosphodiesterase inhibitors, endothelin receptor antagonists, renin inhibitors, or smooth muscle myosin modulators). The weight ratio of the compound provided herein to the second active ingredient will vary and will depend on the effective amount of each ingredient. Generally, an effective amount of each is used.

[0080] VI. Working Examples Abbreviation: aq: aqueous BBr3: Boron tribromide CH2Cl2: Dichloromethane CH3CN:Acetonitrile CH3OH:methanol DIAD: Diisopropyl azodicarboxylate DIEA: Diisopropylethylamine DMF: dimethylformamide DMSO: dimethyl sulfoxide equiv.: equivalent Et3N: Triethylamine Et2O: Diethyl ether EtOH: ethanol FeSO4: Ferrous sulfate h: time HCl: Hydrogen chloride H2O: Water K2CO3: Potassium carbonate KHSO4: Potassium hydrogen sulfate KNCO: Potassium isocyanate LiBr: Lithium bromide MgSO4: Magnesium sulfate mL: milliliter MW: Microwave (reactions carried out in a microwave reactor) NaCl: Sodium chloride NaH: sodium hydride NaHCO3: Sodium bicarbonate NaOEt: sodium ethoxide NaOH: Sodium hydroxide NaOMe: sodium methoxide Na2SO4: Sodium sulfate NH4Cl: Ammonium chloride NMP: n-methylpyrrolidinone pH:-log[H + ] POCl3: Phosphoryl trichloride PPTS: Pyridinium p-toluenesulfonate RP-HPLC: reversed-phase high-pressure liquid chromatography RT: room temperature SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride TEBAC: Triethylbenzylammonium chloride TFA: Trifluoroacetic acid THF: tetrahydrofuran TLC: Thin Layer Chromatography

[0081] Example 1 Preparation of (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0082] [ka]

[0083] Compound 1.1. Isopropylurea. To a stirred solution of isopropylamine (15.3 g, 0.258 mol, 1.0 equiv.) in CHCl (200 mL) under argon at 0 °C, trimethylsilyl isocyanate (30 g, 0.26 mol, 1.0 equiv.) was added dropwise. The resulting mixture was allowed to reach ambient temperature and stirred overnight. After cooling to 0 °C, CHOH (100 mL) was added dropwise. The resulting solution was stirred at room temperature for 2 hours (h) and then concentrated under reduced pressure. The crude residue was recrystallized from CHOH:EtO (1:20) to yield 15.4 g (58%) of the title compound as a white solid. LC / MS: m / z (ES+) 103 (M+H). + .

[0084] [ka]

[0085] Compound 1.2. 1-Isopropyl barbiturate. To a stirred solution of 1.1 (14.4 g, 0.14 mol, 1.00 equiv.) in CHOH (500 mL) was added dimethyl malonate (19.55 g, 0.148 mol, 1.05 equiv.) and sodium methoxide (18.9 g, 0.35 mol, 2.50 equiv.). The resulting mixture was stirred at 65 °C overnight. After cooling to ambient temperature and then to 0 °C, the pH was carefully adjusted to 3 with concentrated aqueous HCl. The resulting mixture was concentrated under reduced pressure. The residue was taken up in EtOH (200 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using CHCl / CHOH (20:1) as eluent to yield 16.8 g (50%) of the title compound as a white solid. LC / MS: m / z(ES+)171 (M+H) +1 . 1 H-NMR (300MHz, d6-DMSO): δ11.19(s,1H),4.83(m,1H),3.58(s,2H),1.32(d,J=6.0Hz,6H).

[0086] [ka]

[0087] Compound 1.3. 6-Chloro-3-isopropylpyrimidine-2,4-(1H,3H)-dione. To a 100 mL round-bottom flask under argon containing compound 1.2 (11.4 g, 66.99 mmol, 1.00 equiv.) was added triethylbenzylammonium chloride (21.3 g, 93.51 mmol, 1.40 equiv.) and POCl3 (30 mL). The resulting mixture was stirred at 50 °C overnight. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was dissolved in CHCl (150 mL), followed by the slow addition of HO (100 mL). The phases were separated, and the organic layer was washed with HO (100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1:1) to give 5.12 g (40%) of the title compound as a pale yellow solid. 1 H-NMR (300MHz, d6-DMSO): δ12.22(s,1H),5.88(s,1H),4.95(m,1H),1.34(d,J=6.0Hz,6H).

[0088] [ka]

[0089] Compound 1. (S)-3-Isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 1.0 g, 5.31 mmol) in 1,4-dioxane (20 mL) was added (S)-α-methylbenzylamine (Sigma-Aldrich, 1.43 g, 11.7 mmol, 2.2 equiv.). The reaction mixture was stirred at 80 °C for 24 h. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was taken up in EtOAc (70 mL) and washed with 1 N aqueous HCl (2 × 50 mL) and brine (40 mL). The organic layer was dried over anhydrous NaSO and then concentrated to half its original volume under reduced pressure to produce a precipitate. Hexane (20 mL) was added and the mixture was stirred at room temperature. The resulting solid was collected by filtration, washed with hexane (20 mL), and dried to give 1.0 g (69%) of the title compound as a white solid. LC / MS: m / z (ES+) 274 (M+H). + . 1 H-NMR(400MHz,d6-DMSO):δ9.77(s,1H),7.32(m,4H),7.24(m,1H),6.50(d,J=6.8H z,1H),4.87(m,1H),4.52(m,1H),4.31(d,J=6.8Hz,1H),1.37(m,3H),1.24(m,6H). 1 H NMR(400MHz,CD3OD)δppm 7.39-7.20(m,5H),5.01(m,1H),4.48(m,1H),1.49(d,J=6.7Hz,3H),1.36(m,6H).

[0090] Example 2 Preparation of (S)-5-fluoro-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (2). [ka]

[0091] To a solution of 1 (80 mg, 0.293 mmol) in acetic acid (2.0 mL) was added Selectfluor (104 mg, 0.293 mmol, 1.0 equiv). The mixture was stirred at room temperature for 2 h. It was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with 0-50% EtOAc in hexane to give 6 mg (7%) of the title compound as a white solid. LC / MS: m / z (ES+) 292 (M+H). + . 1 H NMR(400MHz,CD3OD):δppm 7.36-7.24(m,5H),5.04-4.97(m,1H),4.94-4.88(m,1H),1.54(d,J=8.0Hz,3H),1.39(m,6H).

[0092] Example 3 Preparation of (S)-5-bromo-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (3). [ka] To a solution of 1 (55 mg, 0.201 mmol) in acetic acid (1.0 mL) was added N-bromosuccinamide (35 mg, 0.196 mmol). The mixture was stirred at room temperature for 1 h. It was then concentrated under reduced pressure. The residue was purified on a silica gel column eluted with 0-40% EtOAc in hexane to give 52 mg (74%) of the title compound as a white solid. LC / MS: m / z (ES+) 352, 354 (M+H, bromine pattern). + . 1 H-NMR(400MHz,CDCl3)δppm 8.96(br s,1H),7.43-7.28(m,5H),5.28(d,J=7.4Hz,1H),5.14(m,1H),4.87(m,1H),1.62(d,J=6.7Hz,3H),1.45-1.39(m,6H).

[0093] Example 4 Preparation of (S)-6-((1-(3-chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0094] [ka]

[0095] Compound 4.1. 5-Fluoro-1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione). To a 100 mL round-bottom flask containing a solution of 1.1 (1.31 g, 0.013 mol, 1.00 equiv.) in CHOH (15 mL) was added diethyl fluoromalonate (2.41 g, 0.014 mol, 1.05 equiv.) and sodium methoxide (1.74 g, 0.032 mol, 2.50 equiv.). The reaction flask was equipped with a reflux condenser and stirred in an oil bath heated to 85 °C for 4 h. The reaction was cooled to 0 °C and quenched by careful addition of concentrated HCl, adjusting the pH to 2 by addition of excess concentrated HCl. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dried under high vacuum for 18 h to provide 2.65 g of the title compound (98%). 1 H-NMR (400MHz, CDCl3): δppm 5.53(d,J=24.0Hz,1H),4.91(m,2H),1.46(m,6H).

[0096] [ka]

[0097] Compound 4.2. 6-Chloro-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione. To a 100 mL round-bottom flask equipped with a reflux condenser containing 4.1 (2.65 g, 0.014 mmol, 1.00 equiv.) was added triethylbenzylammonium chloride (4.50 g, 0.019 mmol, 1.40 equiv.) and POCl3 (25 mL). The reaction mixture was stirred at 50 °C for 4 h and then cooled to room temperature. The mixture was concentrated under reduced pressure, and the resulting residue was dissolved in CHCl (50 mL). Water (50 mL) was added slowly, and the layers were separated. The organic layer was washed twice with H2O (100 mL), dried over anhydrous MgSO4, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 30% EtOAc in hexanes) to give 2.67 g (93%) of the title compound as a white solid. 1 H-NMR (400MHz, CDCl3): δppm 5.19-5.05(m,2H),1.48(d,J=7.04Hz,6H).

[0098] [ka]

[0099] Compound 4. (S)-6-((1-(3-chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione. To a solution of 4.2 (150 mg, 0.70 mmol, 1 equiv) in DMF (2 mL) in a heavy-walled pressure vessel was added (S)-3-chloro-α-methylbenzylamine (150 mg, 0.70 mmol, 1.0 equiv) and proton sponge (190 mg, 0.90 mol, 1.25 equiv). The pressure vessel was sealed, and the reaction mixture was heated to 95° C. for 3 h behind an explosion shield. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative RP-HPLC using a Shimadzu Prominence LC-20AP system equipped with a Phenomenex Gemini-NX C18 column (eluting with 10-90% CH3CN / H2O, both containing 0.1% TFA, at 20 mL / min for 30 min). Fractions containing the pure compound were combined and lyophilized to provide 30 mg (13%) of the title compound as a white solid. LC / MS: m / z (ES+) 326 (M+H). +1 H-NMR(400MHz,CDCl3)δppm 9.47(br s,1H),7.35-7.27(m,3H),7.22-7.16(m,1H),5.12(m,1H),4.89(m,1H),4.69(d,J=5.9Hz,1H),1.59(d,J=6.7Hz,3H),1.43(m,6H).

[0100] Example 5 Preparation of (S)-6-((1-(3,5-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0101] [ka]

[0102] Compound 5.1. ((R,E)-N-(3,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide. To a solution of 3,5-difluorobenzaldehyde (1.00 g, 7.04 mmol, 1.00 equiv.) in CHCl (20 mL) was added pyridinium p-toluenesulfonate (0.089 g, 0.35 mmol, 0.05 equiv.), (R)-(+)-2-methylpropane-2-sulfinamide (0.852 g, 7 To the resulting mixture was added MgSO (4.2 g, 35.00 mmol, 5.00 equiv.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 20% EtOAc in petroleum ether) to provide 500 mg (29%) of the title compound as a yellow oil.

[0103] [ka]

[0104] Compound 5.2. (R)-N-((S)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide. Methylmagnesium bromide (5.17 mL, 3 M, 2.00 equiv.) was added dropwise to a solution of 5.1 (1.9 g, 7.75 mmol, 1.00 equiv.) in CHCl (50 mL) under argon at −48 °C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was carefully quenched with saturated aqueous NHCl (20 mL). The phases were separated, and the aqueous layer was further extracted with CHCl (3 × 50 mL). The combined organic layers were dried over anhydrous MgSO and concentrated under reduced pressure to provide 1.3 g (64%) of the title compound as a yellow oil. 1 H NMR (300MHz, CDCl3): δppm 6.92-6.81(m,2H),6.75-6.65(m,1H),4.65-4.55,(m,1H),3.46-3.42(m,1H),1.53-1.44(m,3H),1.26-1.22(m,9H).

[0105] [ka]

[0106] Compound 5.3. (S)-1-(3,5-Difluorophenyl)ethan-1-amine hydrochloride. To a solution of 5.2 (1.3 g, 4.97 mmol, 1.00 equiv) in CHOH (10 mL) was added 4 N HCl in 1,4-dioxane (2.67 mL, 2.00 equiv). The reaction mixture was stirred at room temperature for 0.5 h and then concentrated under reduced pressure. The resulting residue was dissolved in CHOH (3 mL) and EtO (300 mL) was added. The resulting precipitate was isolated by filtration to provide 0.80 g (83%) of the title compound. 1 H NMR(300MHz,D2O):δppm 6.98-6.83(m,3H),4.45-4.38(m,1H),1.51-1.48(d,J=6.9Hz,3H).

[0107] [ka]

[0108] Compound 5. (S)-6-((1-(3,5-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione. Compound 5.3 (50 mg, 0.32 mmol, 1.00 equiv) was dissolved in 1 N NaOH (10 mL), and the resulting mixture was stirred at 25 °C. After 1 h, the mixture was extracted with EtOAc (5 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue and compound 1.3 (35.6 mg, 0.19 mmol, 0.60 equiv) were mixed. The mixture was stirred at 100 °C for 18 h, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative RP-HPLC to provide 28 mg (29%) of the title compound as an off-white solid. LC / MS: m / z (ES+) 310 (M+H) +1H-NMR (300MHz, DMSO-d6): δppm 9.83(s,1H),7.06-7.12(m,3H),6.54(d,J=6.6Hz,1H),4.91-4.82(m,1H),4 .54-4.46(m,1H),4.30(m,1H),1.34(d,J=6.6Hz,3H),1.22(d,J=6.9Hz,6H).

[0109] Example 6 Preparation of (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0110] [ka]

[0111] Compound 6.1. (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide. The title compound was prepared in the same manner as 5.1, except that benzaldehyde (5.0 g, 47.12 mmol, 1.00 equiv.) was used instead of 3,5-difluorobenzaldehyde to provide 2.8 g (28%) of the title compound. 1 H NMR (300MHz, d6-DMSO): δppm 8.62 (s, 1H), 7.89-7.87 (m, 2H), 7.55-7.49 (m, 3H), 1.31 (s, 9H).

[0112] [ka]

[0113] Compound 6.2. (S)—N-((S)-cyclopropyl(phenyl)methyl)-2-methylpropane-2-sulfinamide. The title compound was prepared using a similar protocol to that used for the preparation of 5.2, except that 6.1 (1.0 g, 4.78 mmol, 1.00 equiv.) and cyclopropylmagnesium bromide (9.6 mL, 1 M, 2.00 equiv.) were used instead of 5.1 and methylmagnesium bromide to provide 0.5 g (35%) of the title compound as a yellow oil. 1 H NMR (300MHz, DMSO-d6): δppm 7.36-7.23(m,5H),3.67-3.51(m,2H),1.31(m,10H),0.85-0.15(m,4H).

[0114] [ka]

[0115] Compound 6.3. (S)-Cyclopropyl(phenyl)methanamine hydrochloride. The title compound was prepared using a protocol similar to that used for the preparation of 5.3, except that 6.2 (500 mg, 1.69 mmol, 1.00 equiv) was used instead of 5.2 to provide 220 mg (88%) of the title compound as a yellow oil. 1 H NMR(300MHz,d6-DMSO):δppm 7.37-7.31(m,5H),3.53(d,J=10.0Hz,1H),1.37-1.25(m,1H),0.75-0.55(m,1H),0.53-0.31(m,2H),0.25-0.15(m,1H).

[0116] [ka]

[0117] Compound 6. (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione. The title compound was prepared using a procedure similar to that used for the preparation of 5, except that 6.3 (200 mg, 1.36 mmol, 1.00 equiv.) was used instead of 5.3, and 1,4-dioxane was utilized as the solvent. After concentration under reduced pressure, the eluate was purified by chiral HPLC (Phenomenex Lux 5μ Cellulose-4, 2.12) with an isocratic mixture of EtOH:hexane (1:4) as the eluent. * Purification by HPLC (HPLC, 5 μm column) provided 22 mg (5%) of the title compound as a white solid. LC / MS: m / z (ES+) 300 (M+H) + . 1 H-NMR(300MHz,DMSO-d6)δppm 9.82(s,1H),7.39-7.25(m,5H),7.25-7.32(m,1H),6.72(m,1H),4.90(m,1H),4.2 2(s,1H),3.78(m,1H),1.27(m,6H),1.57(m,1H),0.60(m,1H),0.56-0.32(m,2H).

[0118] Example 7 Preparation of (S)-6-((cyclopropyl(3-methoxyphenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione. [ka] A solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 50 mg, 0.265 mmol), (S)-cyclopropyl-(3-methoxyphenyl)methylamine (Sigma-Aldrich, 104 mg, 0.587 mmol), and proton sponge (85 mg, 0.397 mmol) in NMP (0.5 mL) was stirred at 130 °C for 2 h. After cooling to room temperature, the mixture was purified by preparative RP-HPLC (Shimadzu, Prominence LC-20AP system equipped with a Phenomenex Gemini-NX C18 column) eluting with 20–90% CH3CN in HO (both containing 0.1% TFA). Fractions containing the pure compound were combined and lyophilized to give 10 mg (11%) of the title compound as a white solid. LC / MS: m / z (ES+) 330 (M+H). + . 1 H-NMR(400MHz,CD3OD):δppm 7.26(t,J=7.8Hz,H),6.92-6.79(m,3H),5.00(m,1H),3.79(s,3H),3.74(d,J=8.6Hz,1H),1.36(d,J=7.0 Hz,6H),1.23-1.13(m,1H),0.68-0.60(m,1H),0.58-0.50(m,1H),0.50-0.42(m,1H),0.41-0.34(m,1H).

[0119] Example 8 Preparation of (S)-6-((cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0120] [ka]

[0121] Compound 8.1. (S,E)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide. To a solution of cyclobutanecarbaldehyde (1.0 g, 11.89 mmol, 1.00 equiv) in CHCl (10 mL) was added pyridinium p-toluenesulfonate (0.143 g, 0.57 mmol, 0.05 equiv), (S)-(−)-2-methylpropane-2-sulfinamide (1.22 g, 10.07 mmol, 0.85 equiv), and magnesium sulfate (7.14 g, 59.32 mmol, 5.00 equiv). The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 30% EtOAc in petroleum ether) to provide 2.0 g (90%) of the title compound as a white solid. 1 H NMR(400MHz,CDCl3)δppm 8.08(d,J=10.8Hz,1H),3.36-3.32(m,1H),2.25-2.16(m,4H),2.03-1.90(m,2H),1.15(s,9H).

[0122] [ka]

[0123] Compound 8.2. (S)-N-((S)-Cyclobutyl(phenyl)methyl)-2-methylpropane-2-sulfinamide. Phenylmagnesium bromide (3 M in EtO, 15.3 mL, 2.00 equiv.) was added dropwise to a solution of 8.1 (4.3 g, 22.96 mmol, 1.00 equiv.) in THF (40 mL). The reaction mixture was heated at 65 °C for 3 h. It was then cooled to room temperature and carefully quenched with saturated aqueous NH Cl (30 mL). The resulting mixture was extracted with EtOAc (3 × 30 mL), and the combined organic layers were dried over anhydrous Na SO and concentrated under reduced pressure to provide 5.8 g (95%) of the title compound as a white solid. 1H-NMR (300MHz, CDCl3) δ7.30-7.21(m,5H),4.23(d,J=9.6Hz,1H),2.73-2.68(m,1H),1.95-1.60(m,6H),1.14(s,9H).

[0124] [ka]

[0125] Compound 8.3. (S)-Cyclobutyl(phenyl)methanamine hydrochloride. The title compound was prepared using a procedure similar to that used for the preparation of 5.3, except that 8.2 (5.8 g, 0.022 mol, 1.00 equiv.) was used instead of 5.2, to provide 3.20 g (91%) of the title compound as a white solid. 1 H NMR(300MHz,D2O):δppm 7.36-7.28(m,5H),4.18(m,1H),2.87-2.73(m,1H),2.11-2.01(m,1H),1.90-1.69(m,5H).

[0126] [ka]

[0127] Compound 8. (S)-6-((cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione. Compound 8.3 (0.200 g, 1.24 mmol, 1.00 equiv) was dissolved in 1 N NaOH (10 mL) and stirred at 25 °C for 1 h. The reaction mixture was extracted with EtOAc (5 × 10 mL). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in NMP, mixed with 1.3 and proton sponge, and heated as described for the preparation of 7. The title compound (35 mg, 9%) was isolated as a white solid. LC / MS: m / z (ES+) 314 (M+H). + . 1H NMR(300MHz,CD3OD):δppm 7.38-7.26(m,5H),5.08-4.97(m,1H),4.25(d,J=6.9Hz,1H),2.68-2.58(m,1H),2.19-2.13(m,1H),1.98-1.83(m,5H),1.36(d,J=6.9Hz,6H).

[0128] Example 9 Preparation of (S)-6-((1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione

[0129] [ka]

[0130] Compound 9.1. 1-(tetrahydro-2H-pyran-4-yl)urea. Tetrahydro-2H-pyran-4-amine (5.0 g, 49.4 mmol, 1.0 equiv) and potassium isocyanate (4.0 g, 49.5 mmol, 1.0 equiv) were refluxed overnight in HO (50 mL). The reaction was cooled to room temperature, and excess NaCl was added to help saturate the aqueous layer. The precipitate was isolated by filtration to provide the desired product (1.28 g, 8.88 mmol). The aqueous layer was washed with EtOAc (3 × 15 mL), then concentrated and azeotroped with toluene (3 × 100 mL). The resulting solid was suspended in 1:4 CHOH:EtOAc (100 mL) and filtered a total of four times. The combined organics were concentrated under reduced pressure, and the isolated precipitate was combined to provide 5.01 g (70%) of the title compound. LC / MS: m / z (ES+) 145 (M+H) + . 1 H-NMR(400MHz,DMSO-d6):δ6.14(d,J=7.5Hz,1H),5.47(s,2H),3.85(dt,J=11.6,3.6Hz,2 H),3.65-3.52(m,1H),3.38(td,J=11.4,2.2Hz,2H),1.80-1.72(m,2H),1.42-1.27(m,2H).

[0131] [ka]

[0132] Compound 9.2. 1-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione. Compound 9.1 (2.8 g, 19.4 mmol) was dissolved in EtOH (30 mL), and diethyl malonate (2.45 mL, 21.4 mmol, 1.1 equiv.) and NaOEt (7.55 mL, 23.3 mmol, 1.2 equiv.) were added. The reaction was stirred at 85 °C overnight and then cooled to room temperature. The reaction mixture was diluted with HO (5 mL), and excess KHSO was added to saturate the aqueous layer. The reaction mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over anhydrous MgSO, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 0-25% CHOH in CHCl) to provide 1.57 g of a mixture containing the title compound, which was used without further purification. LC / MS: m / z (ES-) 211 (MH). - .

[0133] [ka]

[0134] Compound 9.3. 6-Chloro-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione. To a solution of 9.2 (1.57 g, 7.4 mmol, 1 equiv) in CHCN (15 mL) was added POCl (0.551 mL, 5.9 mmol, 0.8 equiv). The reaction mixture was stirred at 80 °C overnight. An additional aliquot of POCl (0.4 equiv) was added, and the reaction mixture was stirred at 80 °C for 3 h. Additional aliquots of POCl (0.4 equiv) were added after 3 h and 5 h of stirring at 80 °C. The reaction mixture was then stirred at 90 °C for 1 h. The reaction was cooled to room temperature, concentrated, spun with EtO (15 mL), and decanted. The resulting residue was rinsed with EtO (15 mL) and decanted until the EtO was clear. The resulting residue was carefully suspended in CHOH (10 mL) and filtered. The filtrate was concentrated to give a mixture of starting material and the title compound (approximately 85% purity, 1.6 g). LC / MS: m / z (ES-) 229 (MH). - .

[0135] [ka]

[0136] Compound 9. (S)-6-((1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione. A mixture of 9.3 (0.15 g, 0.65 mmol, 1 equiv.) and (S)-(-)-α-methylbenzylamine (470 mg, 3.88 mmol, 6.0 equiv.) was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature, and the resulting residue was purified by preparative RP-HPLC (0-40% CHCN in HO in 30 min), followed by a second purification on a preparative TLC plate (2000 μm) (7% CHOH in CHCl) to provide 23 mg (11%) of the title compound. LC / MS: m / z (ES+) 316 (M+H). + . 1H NMR(400MHz,DMSO-d6):δppm 10.23(s,1H),7.40-7.32(m,4H),7.31-7.17(m,1H),6.93(s,1H),4.84-4.71(m,1H),4.56-4.43(m,1H),4.35( s,1H),3.93-3.78(m,2H),3.28(t,J=12.1Hz,2H),2.63-2.39(m,2H),1.40(d,J=6.7Hz,3H),1.35-1.16(m,2H).

[0137] Example 10 Preparation of (S)-6-((1-(3-methoxyphenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione (10). [ka] To a solution of 9.3 (0.58 g, 0.25 mmol) in a mixture of 2-propanol and HO (4:1, 1 mL) was added (S)-1-(3-methoxyphenyl)-ethylamine (0.113 g, 0.75 mmol, 3.0 equiv.). The reaction mixture was heated to 120 °C for 2 h. After cooling, the reaction mixture was concentrated under reduced pressure, dissolved in CHOH, and filtered. The filtrate was purified by preparative RP-HPLC (20-100% CHCN in HO in 40 min at 25 mL / min) to provide 18 mg (21%) of the title compound as an off-white solid. LC / MS: m / z (ES+) 346 (M+H). + . 1 H NMR (400MHz, acetone-d6) δ8.90(s,1H),7.15(dd,J=8.3,8.1Hz,1H),6.88(s,1H),6.86(d,J=8.3Hz,1H),6.68(d,J=8 .1Hz,1H),6.15(s,1H),4.74(m,1H),4.48(m,1H),4.35(s,1H),3.82(m,2H),3.68(s,3H),3.2(m,2H),2.55(m,2H) 1.44(d,J=6.6Hz,3H),1.15(m,2H).

[0138] Example 11 Preparation of 6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione

[0139] [ka]

[0140] Compound 11.1. 6-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione. To a mixture of 6-chlorouracil (3.0 g, 20.47 mmol, 1 equiv) and LiBr (1.78 g, 20.5 mmol, 1.0 equiv) in NMP (70 mL) at 0 °C was added NaH (60% dispersion in mineral oil, 0.82 g, 20.5 mmol, 1.0 equiv). The reaction mixture was stirred at 0 °C for 10 min, and 2-(trimethylsilyl)ethoxymethyl chloride (3.75 g, 22.5 mmol, 1.1 equiv) was added slowly via addition funnel. The reaction mixture was stirred at room temperature overnight and then diluted with EtOAc (150 mL). The mixture was washed with saturated aqueous NH4Cl (50 mL), saturated aqueous NaHCO3 (50 mL), and brine (50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide 3.2 g (57%) of the title compound as a white solid. LC / MS: m / z (ES+) 299 (M+Na). + . 1 H NMR (400MHz, CDCl3): δppm 9.00-8.80(br-s,1H),5.95(s,1H),5.45(s,2H)),3.63(t,J=7.0Hz,2H),1.48(t,J=7.0Hz,2H),0.01(s,9H).

[0141] [ka]

[0142] Compound 11.2. 6-Chloro-3-(tetrahydrofuran-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione. To a solution of 11.1 (277 mg, 1.0 mmol, 1 equiv.), 3-hydroxytetrahydrofuran (106 mg, 1.2 mmol, 1.2 equiv.), and triphenylphosphine (320 mg, 1.2 mmol, 1.2 equiv.) in THF (7.5 mL) at 0 °C was added diisopropyl azodicarboxylate (0.240 g, 1.2 mmol, 1.2 equiv.) dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative RP-HPLC (20-100% CHCN in H2O containing 0.1% formic acid buffer at 25 mL / min for 40 min) to provide 102 mg (29%) of the title compound. LC / MS: m / z (ES+) 347 (M+H). + . 1 H NMR(400MHz,CDCl3)δ5.92(s,1H),5.58(m,1H),5.41(s,2H),4.20(m,1H),4.00-3.85(m,3 H),3.65(t,J=7.0Hz,2H),2.35-2.20(m,1H),2.20-2.08(m,1H),0.95(t,2H),0.01(s,9H); 13 C NMR(CDCl3)δ160.7,150.7,145.6,102.0,74.8,68.7,67.9,67.5,51.9,28.7,18.0,0.0.

[0143] [ka]

[0144] Compound 11.3. 6-Chloro-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione. Compound 11.2 (0.50 g, 1.4 mmol, 1.0 equiv) was dissolved in trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The resulting residue was purified by preparative RP-HPLC (10% CHCN in HO at 25 mL / min for 40 min) to provide 300 mg (96%) of the title compound as a white solid. LC / MS: m / z (ES+) 217 ​​(M+H). + . 1 H NMR (400MHz, DMSO-d6): δppm 5.90(s,1H),5.35(m,1H),4.00(m,1H),3.85-3.68(m,3H),2.20(m,1H),2.01(m,1H).

[0145] [ka]

[0146] Compound 11. 6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione. The title compound was prepared using a procedure similar to that used for the preparation of 9, except that 11.3 (22 mg, 0.10 mmol, 1.00 equiv.) was used instead of 9.3 to provide 15 mg (50%) of the title compound as a white solid. LC / MS: m / z (ES+) 302 (M+H). + . 1 H NMR(400MHz,CDCl3):δppm 10.50(1H),7.50-7.20(m,5H),5.90(m,1H),5.60(m,1H),4.78(m,1H),4.45(s,1H),4.20 (m,1H),4.05-3.90(m,2H),3.90-3.80(m,1H),2.45-2.10(m,2H),1.55(d,J=6.7Hz,3H).

[0147] Example 12 Preparation of (S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-(1-phenylethylamino)pyrimidine-2,4(1H,3H)-dione.

[0148] [ka]

[0149] Compound 12.1. tert-Butyl 4-(3-benzoylureido)piperidine-1-carboxylate. To a solution of benzoyl isocyanate (4.8 g, 32.6 mmol) in CHCl (180 mL) at 0 °C was added 4-amino-1-N-boc-piperidine (6.0 g, 30 mmol). The reaction mixture was stirred at room temperature for 4 h and concentrated. The residue was treated with EtO (100 mL). The precipitate was filtered and washed with EtO to give 5.70 g (55%) of the title compound as a white solid. LC / MS: m / z (ES+) 337 (M+H). + .

[0150] [ka]

[0151] Compound 12.2. tert-Butyl 4-ureidopiperidine-1-carboxylate. To a mixture of 12.1 (5.60 g, 16.1 mmol) in CHOH (70 mL) and HO (70 mL) was added sodium hydroxide (11.6 g, 290 mmol) in portions. The reaction mixture was stirred at room temperature overnight and then refluxed for 1 h. The mixture was cooled to room temperature and concentrated under reduced pressure to remove CHOH. The precipitate was filtered, washed with HO, and dried to give 3.2 g (82%) of the title compound as a white solid. LC / MS: m / z (ES+) 266 (M+Na). + .

[0152] [ka]

[0153] Compound 12.3. tert-Butyl 4-(2,4,6-trioxo-tetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate. To a mixture of 12.2 (3.63 g, 14.9 mmol), diethyl malonate (2.6 mL, 16.5 mmol, 1.1 equiv.), and absolute ethanol (60 mL) was added NaOEt (21% in EtOH, 6.6 mL, 17.7 mmol, 1.2 equiv.). The mixture was refluxed for 14 h and concentrated. The residue was taken up in HO (15 mL) and washed with EtOAc (2 × 30 mL). The aqueous layer was separated and adjusted to pH = 5 with concentrated HCl. The precipitate was filtered, washed with HO, and dried to give 3.70 g (80%) of the title compound as an off-white solid. LC / MS: m / z (ES+) 334 (M+Na) + .

[0154] [ka]

[0155] Compound 12.4. 6-Chloro-3-(piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione. To a mixture of 12.3 (2.55 g, 8.19 mmol) and POCl (10 mL, 100.65 mmol), HO (0.41 mL, 22.78 mmol) was added dropwise. The mixture was stirred at 120 °C for 30 min and then concentrated. The residue was carefully taken up in ice water (20 g). To the mixture, KCO (approximately 8.0 g) was added portionwise until the pH was approximately 7. The precipitate was filtered and washed with HO (20 mL) and EtOAc (50 mL). The resulting material was dried to give the title compound as an off-white solid, 1.45 g (77%). LC / MS: m / z (ES+) 230 (M+H). - .

[0156] [ka]

[0157] Compound 12.5. 6-Chloro-3-(1-(methylsulfonyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione. To a mixture of 12.4 (380 mg, 1.65 mmol, 1.0 equiv) and CHCl (8 mL), EtN (0.70 mL, 4.95 mmol, 3 equiv) and methanesulfonyl chloride (0.23 mL, 2.5 mmol, 1.5 equiv) were added. The mixture was stirred at room temperature for 2 h and then quenched with HO (3 mL) to give a precipitate. The precipitate was filtered and washed with CHCl (3 × 3 mL). The filtrate was concentrated to approximately 1.5 mL. Filtration of the second precipitate was followed by washing with HO (2 × 1 mL) and CHCl (3 × 2 mL). The precipitates were combined to provide 320 mg (63%) of the title compound as an off-white solid. LC / MS: m / z (ES+) 308 (M+H). + .

[0158] [ka]

[0159] Compound 12. (S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-(1-phenylethylamino)pyrimidine-2,4(1H,3H)-dione. A mixture of 12.5 (20 mg, 0.065 mmol) and (S)-α-methylbenzylamine (180 mg, 1.5 mmol, 23 equiv.) was stirred at 125 °C for 1 h. The mixture was concentrated under reduced pressure, dissolved in CHOH, and filtered. The filtrate was purified using preparative RP-HPLC eluting with a linear gradient of 20% to 100% CHCN in HO (0.1% formic acid buffer) over 40 min to give 16 mg (63%) of the title compound as an off-white solid. LC / MS: m / z (ES+) 393 (M+H). + . 1H-NMR(400MHz,DMSO-d6):δppm 9.40(br s,1H),7.35-7.25(m,4H),7.15(m,1H),6.55(s,1H),4.58(m,1H),4.42(m,1H),4.30(s,1H),3.52(m ,2H),2.79(s,3H),2.70-2.62(m,2H),2.50-2.48(m,2H),1.48-1.38(m,2H),1.32(d,J=6.8Hz,3H).

[0160] Example 13 Preparation of (S)-methyl 4-(2,6-dioxo-4-(1-phenylethylamino)-2,3-dihydropyrimidin-1(6H)-yl)piperidine-1-carboxylate.

[0161] [ka]

[0162] Compound 13.1. Methyl 4-(4-chloro-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)piperidine-1-carboxylate. To a mixture of 12.4 (115 mg, 0.5 mmol, 1.0 equiv) and CHCl (2 mL), EtN (0.14 mL, 1.5 mmol, 3.0 equiv) was added, followed by methyl chloroformate (95 mg, 1.0 mmol, 2.0 equiv). The mixture was stirred at room temperature for 1 h, diluted with CHCl (8 mL), washed with saturated aqueous NaHCO (1 mL), HO (1 mL), brine (1 mL), dried over anhydrous NaSO, and concentrated to give 105 mg (73%) of an off-white solid. LC / MS: m / z (ES+) 288 (M+H). + .

[0163] [ka]

[0164] Compound 13. (S)-Methyl 4-(2,6-dioxo-4-(1-phenylethylamino)-2,3-dihydropyrimidin-1(6H)-yl)piperidine-1-carboxylate. A mixture of 13.1 (58 mg, 0.20 mmol) and (S)-α-methylbenzylamine (240 mg, 1.5 mmol) was stirred at 120° C. for 0.5 h. The title compound was prepared using a procedure similar to that used for the preparation of 9 to provide 40 mg (63%) of the title compound as an off-white solid. LC / MS: m / z (ES+) 373 (M+H). + . 1 H-NMR (400MHz, CDCl3): δppm 9.85(s,1H),7.29-7.15(m,5H),5.75(br s,1),4.80(m,1H),4.60(s,1H),4.35(m,1H),4.20-4.00(m,2H),3.58(s, 3H),2.80-2.70(m,2H),2.46(m,2H),1.50(m,2H),1.38(d,J=6.7Hz,3H).

[0165] Example 14 Preparation of 3-(R)-sec-butyl-6-((S)-1-(3-methoxyphenyl)ethylamino)pyrimidine-2,4(1H,3H)-dione.

[0166] [ka]

[0167] Compound 14.1. (R)-1-sec-Butylurea. Benzoyl isocyanate (5.36 g, 36.5 mmol, 1.05 equiv.) was dissolved in CHCl (20 mL) and cooled to 0 °C in an ice bath. (R)-Butan-2-amine (2.54 g, 34.7 mmol, 1 equiv.) in CHCl (10 mL) was carefully added with stirring. The mixture was allowed to stir at room temperature for 3 h. After the reaction was deemed complete, the mixture was concentrated. The residue was suspended in EtO (20 mL) and filtered. The solid was taken up in a 1:1 mixture of CHOH and HO (200 mL), followed by the addition of NaOH (6.9 g, 174 mmol, 5 equiv.). The reaction was stirred overnight at room temperature. CH3OH was evaporated from the solution and the resulting precipitate (1.66 g, 39%) was collected. LC / MS: m / z (ES+) 117 (M+H). + .

[0168] [ka]

[0169] Compound 14.2. (R)-1-sec-butylpyrimidine-2,4,6(1H,3H,5H)-trione. Compound 14.1 (1.66 g, 14.3 mmol, 1.0 equiv.) was dissolved in EtOH (10 mL), and diethyl malonate (1.8 mL, 15.7 mmol, 1.1 equiv.) and NaOEt (5.6 mL, 17.1 mmol, 1.2 equiv.) were added. The reaction was stirred at 80 °C for 2 h and then cooled to room temperature. Water (20 mL) was added, and then EtOH was removed by evaporation. KHSO (excess) was added to saturate the aqueous layer, which was then extracted with EtOAc. The combined organics were dried over anhydrous MgSO and concentrated to give the title compound as a crude residue, 1.6 g (61%), which was used without further purification. LC / MS: m / z(ES-)183(MH) - .

[0170] [ka]

[0171] Compound 14.3. (R)-3-sec-butyl-6-chloropyrimidine-2,4(1H,3H)-dione. A mixture of 14.2 (1.6 g, 8.7 mmol, 1 equiv) and POCl3 (648 μL, 7.0 mmol, 0.8 equiv) in CH3CN (10 mL) was stirred at 90 °C for 2 h. Additional POCl3 (0.8 equiv) was added and stirred at 90 °C for 3 h. The reaction was cooled to room temperature, carefully quenched with CH3OH (10 mL), stirred for 30 min, and purified by normal-phase HPLC with 0–25% CH3OH / CHCl2, followed by a CH3OH flash. The product and starting material coeluted. The mixture was concentrated, and the residue was taken up in CH3CN (10 mL), and POCl3 (648 μL) was added. The reaction was stirred at 90 °C for 3 h and then cooled to room temperature. The reaction was carefully quenched with CHOH (10 mL) and stirred for 30 min. The reaction mixture was purified by normal phase HPLC under the previous conditions, concentrated, and dried under vacuum to give 450 mg (32%) of the title compound as an off-white solid. LC / MS: m / z (ES-) 201 (MH). - .

[0172] [ka]

[0173] Compound 14. 3-(R)-sec-butyl-6-((S)-1-(3-methoxyphenyl)ethylamino)pyrimidine-2,4(1H,3H)-dione. Mixture 14.3 (150 mg, 0.74 mmol, 1.0 equiv) in pure (S)-1-(3-methoxyphenyl)ethanamine (400 μL) was stirred overnight at 90 °C. The reaction was purified using preparative RP-HPLC on an Agilent system with a gradient of 0-40% CHCN in HO over 45 min to yield 13 mg (6%) of the title compound as an off-white solid. LC / MS: m / z (ES+) 318 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 9.79(s,1H),7.28(t,J=8.1Hz,1H),6.94-6.88(m,2H),6.84(dd,J=8.2,1.7Hz,1H),6.51(d,J=6.4Hz,1H),4.72-4.59(m,1H),4.47(m ,1H),4.35(s,1H),3.76(s,3H),1.98-1.84(m,1H),1.61(m,1H),1.39(d,J=6.7Hz,3H),1.25(d,J=6.9Hz,3H),0.70(t,J=7.4Hz,3H).

[0174] Example 15 Preparation of (S)-6-(1-phenylethylamino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione.

[0175] [ka]

[0176] Compound 15.1. 1-(Pyridin-3-yl)urea. Benzoyl isocyanate (3.28 g, 22.3 mmol, 1.05 equiv) was taken up in CHCl (30 mL) and cooled to −10 °C. Pyridin-3-amine (2 g, 21.2 mmol, 1 equiv) was added portionwise with stirring. The mixture was allowed to stir at room temperature for 3 h. After the reaction was deemed complete, it was concentrated and then taken up in a 1:1 mixture of CHOH and HO (100 mL), followed by the addition of NaOH (4.25 g, 106.3 mmol, 5 equiv). The reaction was allowed to stir at room temperature overnight, concentrated to dryness, and then azeotroped with toluene three times. A mixture of 10% CHOH in EtOAc (100 mL) was added to the solid, stirred for 10 minutes, and then filtered. The solid was suspended and filtered two more times. The combined filtrate was filtered again to remove any solids that had passed through the filter and concentrated. The residue was triturated with EtOAc (5 mL) and dried under vacuum to give 3.5 g of crude material (off-white solid), which was used without further purification. LC / MS: m / z (ES+) 138 (M+H). + .

[0177] [ka]

[0178] Compound 15.2. 1-(Pyridin-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione. Compound 15.1 (3.0 g, 21.8 mmol, 1.0 equiv) was taken up in EtOH (20 mL), followed by the addition of diethyl malonate (2.75 mL, 24.1 mmol, 1.1 equiv) and NaOEt (8.5 mL, 26.3 mmol, 1.2 equiv). The reaction was stirred at 85 °C overnight and then cooled to room temperature. Water (100 mL) was added slowly, followed by the careful addition of sodium bicarbonate (8 g). The resulting mixture was washed three times with EtOAc. The aqueous layer was concentrated to 50 mL, and CHOH (150 mL) was added. The precipitate was removed by filtration, and the filtrate was concentrated. The resulting residue was purified by flash chromatography (silica gel, 0-25% CHOH / CHCl) to give 1.70 g (38%) of the title compound as a pale yellowish solid. LC / MS: m / z (ES+) 206 (M+H). + .

[0179] [ka]

[0180] Compound 15.3. 6-Chloro-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione. A mixture of 15.2 (700 mg, 3.41 mmol, 1.0 equiv) and POCl (255 μL, 2.7 mmol, 0.8 equiv) in CHCN (10 mL) was stirred at 90 °C for 2 h. Additional POCl (0.8 equiv) was added, and stirring was continued at 90 °C for 2 h. Additional POCl (1.6 equiv) was added, followed by careful addition of HO (150 μL, 2.5 equiv). The reaction was stirred at 90 °C overnight. After cooling to room temperature, the mixture was filtered, and the solid was carefully washed with CHOH (1 mL). Ethyl acetate (20 mL) was added to the filtrate and the resulting precipitate was collected by filtration and dried under vacuum to give 230 mg (30%) of the title compound as a pale yellowish solid. LC / MS: m / z (ES+) 224 (M+H).+ .

[0181] [ka]

[0182] Compound 15. (S)-6-(1-phenylethylamino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione. A mixture of 15.3 (100 mg, 0.45 mmol, 1 equiv.) in pure (S)-(-)-α-methylbenzylamine (500 μL) was stirred at 100° C. overnight. After cooling, the reaction was purified using preparative RP-HPLC on an Agilent system with a gradient of 0-40% CHCN in HO over 45 min, followed by a second purification on a preparative TLC plate (2000 μm) with 7% CHOH / CHCl to yield 39.5 mg (28%) of the title compound. LC / MS: m / z (ES+) 309 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 11.15(s,1H),8.49(dd,J=4.8,1.4Hz,1H),8.34(d,J=2.4Hz,1H),7.65-7.58(m,1H),7.44(dd,J= 8.1,4.8Hz,1H),7.37(m,5H),7.26(m,1H),4.61-4.53(m,1H),4.48(s,1H),1.39(d,J=6.8Hz,3H).

[0183] Example 16 Preparation of (S)-3-(isoxazol-3-yl)-6-(1-phenylethylamino)pyrimidine-2,4(1H,3H)-dione (16). [ka] The title compound was prepared using a procedure similar to that used to prepare compound 15, except that isoxazol-3-amine was used instead of pyridin-3-amine. LC / MS: m / z (ES+) 299 (M+H). + . 1H-NMR(400MHz,DMSO-d6):δppm 8.96(s,1H),7.38(d,J=3.9Hz,4H),7.28(dd,J=8.4,4.3Hz,2H),7.10(s, 1H),6.63(s,1H),4.74-4.52(m,1H),4.48(s,1H),1.44(d,J=6.6Hz,3H).

[0184] Example 17 Preparation of (S)-6-((1-(3-(1H-pyrazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (17). [ka] The title compound was prepared by Ullmann coupling of 35 with 1H-pyrazole in the presence of copper iodide, cesium carbonate, and trans-N,N'-dimethylcyclohexane-1,2-diamine (P.E. Fanta, "The Ullmann Synthesis of Biaryls", Synthesis, 1974, pp. 9-21). LC / MS: m / z (ES+) 340 (M+H). + . 1 H-NMR(400MHz,CD3OD):δppm 8.26(s,1H),7.70(m,2H),7.66(m,1H),7.51(m,1H),7.34(m,1H),6.55(s,1H),5.05(m,1H),4.62(m,1H),1.58(d,J=6.8Hz,3H),1.37(m,6H).

[0185] Example 18 Preparation of additional pyrimidinedione compounds. The compounds in Table 1 were prepared according to the Examples above.

[0186] [Table 1]

[0187] [Table 2]

[0188] [Table 3]

[0189] [Table 4]

[0190] [Table 5]

[0191] [Table 6]

[0192] Example 48 Preparation of (S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione.

[0193] [ka]

[0194] Compound 48.1. 1-Propylurea. To a stirred solution of n-propylamine (2.15 g, 36.5 mmol, 1.00 equiv) in CHCl (35 mL) at 0 °C was added trimethylsilyl isocyanate (4.94 g (85% purity), 36.5 mmol, 1.00 equiv) dropwise. The reaction mixture was stirred at room temperature for 72 h and then cooled to 0 °C. The cooled mixture was quenched by the dropwise addition of CHOH (10 mL) and concentrated under reduced pressure. The resulting solid was suspended in EtO (30 mL) and filtered. The solid was further washed with EtO (30 mL) and dried to provide 2.0 g (38%) of the title compound as a white solid.

[0195] [ka]

[0196] Compound 48.2. 1-Propylpyrimidine-2,4,6(1H,3H,5H)-trione. To 48.1 (600 mg, 5.88 mmol, 1.00 equiv.) in CHOH (1 mL) was added diethyl malonate (960 mg, 6.0 mmol, 1.02 equiv.) and sodium methoxide (1 mL, 25% by weight NaOCH in CHOH). The reaction mixture was heated at 130 °C in a microwave reactor for 1 h. The mixture was cooled, and the mixture was carefully adjusted to pH = 3 with concentrated HCl. Volatiles were removed, and HO was added (10 mL). A solid precipitated and was filtered. It was further washed with additional HO (10 mL) and dried to provide 560 mg (56%) of the title compound as a white solid.

[0197] [ka]

[0198] Compound 48.3. 6-Chloro-3-propylpyrimidine-2,4(1H,3H)-dione. Compound 48.2 (560 mg, 3.30 mmol) and POCl3 (2 mL) were added to a heavy-walled pressure vessel, which was then sealed. The resulting solution was heated to 70 °C and stirred for 50 min behind an explosion shield. The reaction mixture was cooled and concentrated under reduced pressure. To the resulting residue was added CHCl2 (30 mL), which was then removed under reduced pressure. One additional addition and evaporation of CHCl2 (30 mL) was performed, and then the resulting residue was diluted with CHCl2 (50 mL). Saturated aqueous NaHCO3 (50 mL) was carefully added to the organic layer. The layers were separated, and the organics were further washed with H2O (30 mL) and brine (30 mL). The organic layer was concentrated and purified by flash column chromatography (silica gel, 10% EtOAc in CH2Cl2) to provide 160 mg (26%) of the title compound as a white solid.

[0199] [ka]

[0200] Compound 48. (S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione. To 48.3 (160 mg, 0.85 mmol, 1.0 equiv) in 1,4-dioxane (1.5 mL) was added EtN (200 μL) and (S)-α-methylbenzylamine (235 mg, 1.94 mmol, 2.3 equiv). The mixture was heated in a microwave reactor at 130 °C for 2 h. The mixture was cooled and concentrated. The resulting residue was treated with an 8:3 mixture of HO:CHCN, which resulted in precipitation. The solid was filtered and washed successively with HO (10 mL) and EtOAc (10 mL). The solid was dried to give 67 mg (29%) of the title compound as a white solid. LC / MS: m / z (ES+) 274 (M+H) + . 1H-NMR(400MHz,DMSO-d6):δppm 9.92(br s,1H),7.36-7.22(m,5H),6.54(d,J=7.0Hz,1H),4.50(quintet,J=6.7Hz,1H),4.35 (s,1H),3.54(dd,J=8.0,6.9Hz,2H),1.42-1.36(m,5H),0.76(t,J=7.6Hz,3H).

[0201] Example 49 Preparation of (S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0202] [ka]

[0203] Compound 49.1. 1-(3,5-Difluorophenyl)urea. To a stirred solution of 3,5-difluoroaniline (4.0 g, 31 mmol, 1.00 equiv) in CHCl (50 mL) under argon at room temperature was added trimethylsilyl isocyanate (3.56 g, 30.90 mmol, 1.00 equiv) dropwise. The reaction mixture was stirred overnight and quenched by the dropwise addition of CHOH (50 mL). The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by flash chromatography (silica gel, eluting with CHCl / CHOH (10:1 to 7:1)) to yield 2.0 g (38%) of the title compound as a white solid. 1 H-NMR (400MHz, DMSO-d6): δppm 8.96 (s, 1H), 7.16-7.10 (m, 2H), 6.72-6.66 (m, 1H), 6.07 (br s, 2H).

[0204] [ka]

[0205] Compound 49.2. 1-(3,5-Difluorophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione. To a stirred solution of 49.1 (1.6 g, 0.0093 mol, 1.1 equiv.) in CHOH (20 mL) was added diethyl malonate (1.4 g, 0.0087 mol, 1.0 equiv.) and sodium methoxide (1.25 g, 0.0231 mol, 2.7 equiv.). The resulting mixture was stirred at 65 °C overnight. After cooling to ambient temperature, the pH was carefully adjusted to 5 with 1 N aqueous HCl. The resulting solution was extracted with EtOAc (3 × 50 mL). The organic layers were combined and concentrated under reduced pressure. The residue was washed with CHOH (50 mL), and the resulting solid was isolated by filtration to give 700 mg (31%) of the title compound as a white solid. 1 H-NMR (400MHz, DMSO-d6): δppm 11.66 (s, 1H), 7.43-7.35 (m, 1H), 7.11-7.08 (m, 2H), 3.77 (s, 2H).

[0206] [ka]

[0207] Compound 49.3. 6-Chloro-3-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione. To a 25 mL round-bottom flask under argon containing 49.2 (740 mg, 3.08 mmol, 1.00 equiv.) was added triethylbenzylammonium chloride (840 mg, 1.20 equiv.) and POCl3 (3 mL). The resulting solution was stirred at 50 °C for 4 h. The reaction was cooled and quenched by the careful addition of water / ice (20 mL). The pH of the solution was adjusted to 5 with 2 N sodium hydroxide. The resulting solution was extracted with EtOAc (2 × 10 mL), and the organic layers were combined. The organic layer was washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. This gave 500 mg (crude) of the title compound as a white solid. 1H-NMR (400MHz, DMSO-d6): δppm 12.60 (br, 1H), 7.38-7.32 (m, 1H), 7.21-7.16 (m, 2H), 6.05 (s, 1H).

[0208] [ka]

[0209] Compound 49. (S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To 49.3 (200 mg, 0.77 mmol) was added (S)-α-methylbenzylamine (1.5 mL). The resulting solution was stirred at 120° C. for 2 h. The reaction mixture was diluted with DMF (3 mL), and the crude product (100 mg) was purified using the following conditions: XBridge Prep C18 OBD Column, 5 μm, 19 * Purified by preparative RP-HPLC at 150 mm; mobile phase, HO and CHCN with 0.05% TFA (40.0% CHCN to 90.0% in 10 min). This yielded 21.6 mg (8%) of the title compound as a white solid. LC / MS: m / z (ES+) 344 (M+H). + . 1 H-NMR(300MHz,DMSO-d6):δppm 10.25(br s,1H),7.38-7.35(m,4H),7.28-7.21(m,2H),7.03-6.98(m,2H),6.76(d,J=6.9 Hz,1H),4.59(quintet,J=6.7Hz,1H),4.50(d,J=2.0Hz,1H),1.42(d,J=6.7Hz,3H).

[0210] Example 50 Preparation of (S)-3-isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0211] [ka]

[0212] Compound 50.1. (R,E)-2-Methyl-N-(1-(m-tolyl)ethylidene)propane-2-sulfinamide. To a stirred solution of 1-(3-methylphenyl)ethanone (1.61 g, 12.0 mmol, 1.00 equiv) and (R)-(+)-2-methyl-2-propanesulfinamide (1.94 g, 14 mmol, 1.33 equiv) in THF (50 mL) was added Ti(OEt) (3.19 g, 14 mmol, 1.17 equiv). The reaction mixture was stirred at 60 °C for 16 h, cooled to room temperature, and quenched with saturated aqueous NaHCO (50 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 100 mL). The combined organics were concentrated and the resulting residue was purified by flash chromatography (silica gel, eluting with 0-5% CHOH in CHCl) to provide 1.51 g (53%) of the title compound as a white solid. LC / MS: m / z (ES+) 238 (M+H). + .

[0213] [ka]

[0214] Compound 50.2. (R)-2-Methyl-N-((S)-1-(m-tolyl)ethyl)propane-2-sulfinamide. To a solution of 50.1 (1.51 g, 6.37 mmol) in THF (30 mL) at -78 °C under a N atmosphere was added L-selectride (dropwise, 10 mL, 1.0 M in THF, 10 mmol). The reaction mixture was warmed to 0 °C, stirred for 1 h, and carefully quenched with saturated aqueous NH4Cl (30 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 50 mL). The combined organics were concentrated, and the resulting residue was purified by flash chromatography (silica gel, eluting with 0–5% CH3OH in CHCl2) to provide 0.85 g (56%) of the title compound. LC / MS: m / z (ES+) 240 (M+H). + .

[0215] [ka]

[0216] Compound 50.3. (S)-1-(m-Tolyl)ethan-1-amine hydrochloride. To anhydrous EtOH (10 mL) was added AcCl (1.5 mL, dropwise). The mixture was stirred for 10 minutes and then added to 50.2 (0.85 g, 3.56 mmol) in EtOH (3 mL). The reaction mixture was stirred at ambient temperature for 2 h and concentrated. The resulting solid was suspended in EtO and filtered. The solid was washed with additional EtO and dried to give 402 mg (66%) of the title compound as a white solid. LC / MS: m / z (ES+) 136 (M+H). + .

[0217] [ka]

[0218] Compound 50.4. (S)-1-(m-Tolyl)ethan-1-amine. To a stirred solution of 50.3 (205 mg, 1.20 mmol) in CHCl (10 mL) was added MP-carbonate (1.0 g, 3.18 mmol / g). The reaction mixture was stirred at room temperature for 1 h and then filtered. The solid beads were washed with an additional 10 mL of CHCl, and the combined filtrate was concentrated to give the title compound, which was carried forward without any purification.

[0219] [ka]

[0220] Compound 50. (S)-3-Isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione. To 50.4 (estimated from the previous reaction at approximately 1.2 mmol, 2.0 equiv.) in a 0.5-2.0 mL microwave tube was added compound 1.3 (110 mg, 0.59 mmol, 1.0 equiv.). The microwave tube was sealed and heated at 120 °C for 2.5 h behind an explosion shield. Upon cooling (to approximately 60 °C), NMP (2.5 mL) was added to the reaction mixture. The mixture was sonicated and heated (to approximately 60 °C) until the solid was completely dissolved. The resulting solution was cooled to 40 °C, and a 3:1 mixture of HO / CHCN (5 mL) was added. A solid precipitated and was collected by filtration. The pale beige solid was then washed with HO and dried to give 97 mg (57%) of the title compound as a white solid. LC / MS: m / z (ES+) 288 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 9.73(br s,1H),7.22(t,J=8.0Hz,1H),7.12-7.04(m,3H),6.45(d,J=8.0Hz,1H),4.90-4.86(m,1H),4.42 (q,J=6.7Hz,1H),4.31(d,J=2.4Hz,1H),2.29(s,3H),1.36(d,J=6.7Hz,3H),1.27-1.23(m,6H).

[0221] Example 51 Preparation of (S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0222] [ka]

[0223] Compound 51.1. 2-(4-Fluorophenyl)-N-methoxy-N-methylacetamide. To a stirred solution of 2-(4-fluorophenyl)acetic acid (15 g, 97.32 mmol, 1.00 equiv.) in CHCl (300 mL) was added methoxy(methyl)amine hydrochloride (11.1 g, 113.79 mmol, 1.20 equiv.), 4-dimethylaminopyridine (12 g, 98.22 mmol, 1.00 equiv.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.2 g, 147.10 mmol, 1.50 equiv.), and DIEA (37.5 g, 290.14 mmol, 3.00 equiv.). The resulting solution was stirred at room temperature for 16 h and then diluted with EtOAc (150 mL). The organic layer was washed with 1N aqueous HCl (2 × 150 mL) and brine (2 × 150 mL). It was then dried over anhydrous NaSO and concentrated under reduced pressure. The crude residue was purified by flash chromatography (silica gel, eluted with EtOAc / petroleum ether (1:3)). This afforded 18 g (88%) of the title compound as a yellow oil. 1 H-NMR (400MHz, CDCl3): δppm 7.29-7.25(m,2H),7.03-6.99(m,2H),3.75(s,2H),3.65(s,3H),3.21(s,3H).

[0224] [ka]

[0225] Compound 51.2. 2-(4-Fluorophenyl)acetaldehyde. To a stirred solution of 51.1 (3 g, 15.21 mmol, 1.00 equiv) in THF (60 mL) under argon at −10 °C was added LiAlH (1.15 g, 30.30 mmol, 2.00 equiv) in several portions (Caution: Exothermic reaction). The resulting solution was stirred at room temperature for 1 h before being cooled to −10 °C. The reaction was then quenched by the careful addition of saturated aqueous NH Cl (50 mL). The resulting solid was filtered, and the filtrate was extracted with EtOAc (3 × 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na SO , and concentrated under reduced pressure to give 2.5 g (crude) of the title compound as a yellow oil.

[0226] [ka]

[0227] Compound 51.3. (S)-1-(4-fluorophenyl)propan-2-amine hydrochloride. The title compound was synthesized according to the method described for the preparation of 5.3, using 51.2 instead of 3,5-difluorobenzaldehyde. LC / MS: m / z (ES+) 154 (M+H). + .

[0228] [ka]

[0229] Compound 51.4. (S)-1-(4-fluorophenyl)propan-2-amine. To a solution of 1N NaOH in water (5 mL) was added 51.3 (300 mg, 1.59 mmol). The resulting mixture was stirred at 25° C. for 1 h. The resulting solution was extracted with EtOAc (2×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 160 mg (65%) of the title compound. LC / MS: m / z (ES+) 154 (M+H). + .

[0230] [ka]

[0231] Compound 51. (S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione. To a stirred solution of 51.4 (160 mg, 1.04 mmol, 2.00 equiv.) in NMP (0.5 mL) was added 1.3 (99 mg, 0.52 mmol, 1.00 equiv.) and proton sponge (168 mg, 0.78 mmol, 1.50 equiv.). The resulting solution was stirred in an oil bath at 100° C. for 5 h. The reaction mixture was concentrated under reduced pressure. The residue (100 mg) was purified by preparative RP-HPLC to provide the title compound as a gray solid (30 mg, 19%). LC / MS: m / z (ES+) 306 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 9.81(br s,1H),7.27(dd,J=8.8,5.6Hz,2H),7.17-7.12(m,2H),5.89(d,J=7.6Hz,1H),5.00-4.92(m,1H),4 .58(s,1H),3.69-3.65(m,1H),2.74(d,J=6.4Hz,2H),1.31(d,J=6.8Hz,6H),1.08(d,J=6.4Hz,3H).

[0232] Example 52 Preparation of (R)-3-isopropyl-6-((2,2,2-trifluoro-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (52). [ka] To a 0.2-0.5 mL microwave vial was added 1.3 (85 mg, 0.45 mmol) and (R)-2,2,2-trifluoro-1-phenylethan-1-amine (200 μL, excess). The reaction mixture was sealed in a microwave reactor and heated to 180 °C for 40 min. The reaction mixture was cooled to ambient temperature, and then NMP (1 mL) was added to completely dissolve the solid. Next, a 2:1 mixture of HO / CHCN (6 mL) was added, which resulted in precipitation. The solid was isolated by filtration, washed with HO, and dried to give 50 mg (34%) of the title compound as a white solid. LC / MS: m / z (ES+) 328 (M+H). + . 1 H-NMR (400MHz, DMSO-d6): δppm 9.79 (br s, 1H), 7.50-7.40 (m, 5H), 5.66-5.56 (m, 2H), 4.92-4.87 (m, 2H), 1.28-1.25 (m, 6H).

[0233] Example 53 Preparation of 3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0234] [ka]

[0235] Compound 53.1. (R)-1-(1-hydroxypropan-2-yl)urea. To a stirred solution of (R)-(−)-2-amino-1-propanol (0.65 g, 8.68 mmol, 1 equiv) in CHCl (10 mL) under N at 0 °C was added trimethylsilyl isocyanate (1.00 g, 8.68 mmol, 1.0 equiv) dropwise. The reaction mixture was stirred overnight while slowly warming to room temperature. After cooling to 0 °C, CHOH (10 mL) was added dropwise. The resulting solution was stirred at room temperature for 2 h and then concentrated under reduced pressure to provide the title compound (1.02 g, 99%) as a white solid.

[0236] [ka]

[0237] Compound 53.2. (R)-1-(1-(benzyloxy)propan-2-yl)urea. To a suspension of sodium hydroxide (0.52 g, 13.2 mmol, 1.5 equiv) in THF (10 mL) at 0 °C was added 53.1 (1.02 g, 8.67 mmol, 1 equiv). The reaction mixture was stirred at 0 °C under N for 20 min, after which benzyl bromide (1.03 mL, 8.67 mmol, 1 equiv) was added. The reaction mixture was stirred overnight while slowly warming to room temperature. The reaction mixture was quenched with HO (3 mL), extracted into EtOAc (15 mL), dried over anhydrous NaSO, filtered, and concentrated. The resulting residue was purified by flash chromatography (10% CHOH in CHCl) to provide 510 mg (28%) of the title compound. LC / MS: m / z (ES+) 209 (M+H) + . 1 H-NMR (400MHz, CDCl3): δppm 7.42-7.27(m,5H),4.79(d,J=6.7Hz,1H),4.52(d,J=2.7Hz,2H),3.91(s,1H),3 .51(dd,J=9.4,3.9Hz,1H),3.40(dd,J=9.2,5.3Hz,1H),1.19(d,J=7.0Hz,3H).

[0238] [ka]

[0239] Compound 53.3. (R)-1-(1-(benzyloxy)propan-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione. To a microwave vial containing 53.2 (0.51 g, 2.42 mmol, 1 equiv) in CHOH (10 mL) was added diethyl malonate (2.55 g, 2.55 mmol, 1.05 equiv), followed by sodium methoxide (25 wt% solution in CHOH, 1.31 g, 6.06 mmol, 2.5 equiv). The vial was capped, and the reaction mixture was heated in a microwave reactor at 150 °C for 15 min. After cooling to room temperature, the reaction mixture was quenched with HO (2 mL), and the pH was adjusted to 3 with concentrated HCl. The reaction mixture was transferred to a round-bottom flask and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5% CHOH in CHCl) to provide 0.62 g (92%) of the title compound as a white solid. LC / MS: m / z (ES+) 277 (M+H). + . 1 H-NMR (400MHz, CDCl3): δppm 7.99(s,1H),7.38-7.22(m,5H),5.16-5.11(m,1H),4.52(d,J=12.0Hz,1H),4.45(d,J =12.0Hz,1H),4.02(t,J=9.8Hz,1H),3.56(q,J=1.57Hz,2H),1.37(d,J=7.00Hz,3H).

[0240] [ka]

[0241] Compound 53.4. (R)-3-(1-(benzyloxy)propan-2-yl)-6-chloropyrimidine-2,4(1H,3H)-dione. To a microwave vial containing 53.3 (0.25 g, 0.91 mmol, 1 equiv.) was added triethylbenzylammonium chloride (0.28 g, 1.26 mmol, 1.4 equiv.) and POCl3 (1 mL). The vial was capped, and the reaction mixture was heated at 130 °C in a microwave reactor for 1 min. The reaction mixture was transferred to a round-bottom flask and concentrated under reduced pressure. The resulting residue was dissolved in CHCl2 (5 mL), and water (2 mL) was carefully added. The mixture was stirred for 10 min. The layers were separated, and the organic layer was dried over NaSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 5% CHOH in CHCl) to provide 150 mg (55%) of the title compound. LC / MS: m / z (ES+) 295 (M+H). + . 1 H-NMR (400MHz, CDCl3): δppm 10.27(s,1H),7.36-7.20(m,5H),5.32-5.21(m,2H),4.57(d,J=12.0Hz,1H), 4.48(d,J=12.0Hz,1H),4.10(dd,J=10.0,9.2Hz,1H),1.40(d,J=7.0Hz,3H).

[0242] [ka]

[0243] Compound 53. 3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a microwave vial containing (S)-α-methylbenzylamine (1.5 mL) was added 53.4 (0.12 g, 0.42 mmol). The vial was capped, and the reaction mixture was heated at 150 °C in a microwave reactor for 10 min. After cooling, the reaction mixture was filtered through a plug of silica gel (10% CHOH in CHCl), and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in CHCl (10 mL) and washed with 10% HCl (5 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated to provide 150 mg (94%) of the title compound. LC / MS: m / z (ES+) 380 (M+H) + . 1 H-NMR (400MHz, CDCl3): δppm 9.96 (br s 1H), 7.35-7.24 (m, 10H), 4.70 (br s,1H),4.53-4.41(m,4H),4.03-3.99(m,1H),3.65-3.61(m,1H),1.49(d,J=6.7Hz,3H),1.37(d,J=7.0Hz,3H).

[0244] Example 54 Preparation of 3-((R)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (54). [ka] To a solution of 53 (0.10 g, 0.26 mmol, 1 equiv.) in EtOH (2 mL) was added palladium on carbon (10 wt. % loading (dry basis), matrix activated carbon, wet support, Degussa type, 0.025 g). The reaction flask was purged with nitrogen and then with H 2(g) A balloon was attached. The reaction mixture was evacuated and then H 2(g)The mixture was filled with HCl. This pump / purge process was repeated three times, and the reaction mixture was stirred at room temperature for 4 h. After purging with nitrogen, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended in CHCN (2 mL), and the precipitate was isolated by filtration. The precipitate was dissolved in CHCl:CHOH (1:1, 2 mL), filtered through a 2 μM PTFE 25 mm filter, and concentrated under reduced pressure to provide 27 mg (35%) of the title compound. LC / MS: m / z (ES+) 290 (M+H). + . 1 H-NMR (400MHz, CDCl3): δppm 9.67(s,1H),7.35-7.24(m,5H),5.64(d,J=5.5Hz,1H),5.08-5.04(m,1H),4.66(s,1H),4.42-4.35(m,1 H),4.24(s,1H),4.04-3.91(m,1H),3.78-3.68(m,1H),1.50(d,J=6.70Hz,3H),1.35(d,J=7.00Hz,3H).

[0245] Example 55 Preparation of (S)-3-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0246] [ka]

[0247] Compound 55.1. (S)-1-(3-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride. The title compound was synthesized according to the method described for the preparation of 5.3, using 3-(trifluoromethyl)benzaldehyde instead of 3,5-difluorobenzaldehyde.

[0248] [ka]

[0249] Compound 55. (S)-3-Isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a stirred solution of 55.1 (59.8 mg, 0.27 mmol, 1.00 equiv.) in DMSO (1.5 mL) under an inert argon atmosphere was added EtN (0.2 mL) and 1.3 (50 mg, 0.27 mmol, 1.00 equiv.). The resulting solution was stirred in an oil bath at 120° C. for 6 h. After cooling, the mixture was concentrated under reduced pressure, and the resulting residue (75 mg) was purified by preparative RP-HPLC to give the title compound as a white solid (6.5 mg, 7%). LC / MS: m / z (ES+) 342 (M+H). + . 1 H-NMR (300MHz, DMSO-d6): δppm 7.78(s,1H),7.74-7.60(m,3H),7.20(br,1H),6.02(br,1H),4.96(dt,J=10.1,5.1 Hz,1H),4.67-4.64(m,1H),4.36(s,1H),1.44(d,J=6.8Hz,3H),1.31-1.28(m,6H).

[0250] Example 56 Preparation of (S)-3-isopropyl-6-((1-(2-cyanophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (56). [ka] Intermediate 56.1 was prepared using 1.3 and (S)-1-(2-bromophenyl)ethan-1-amine hydrochloride (synthesized from the corresponding 2-bromobenzaldehyde using the method described for 6.3, for example) using a procedure similar to that used for the preparation of compound 35. To a stirred solution of 56.1 (40 mg, 0.11 mmol, 1.00 equiv.) in DMF (2 mL) was added Zn(CN) (20 mg, 0.17 mmol, 1.50 equiv.) and tetrakis(triphenylphosphine)palladium (131 mg, 0.11 mmol, 0.20 equiv.). Caution: Reactions containing cyanide. The resulting solution was stirred under an argon atmosphere at 100 °C in an oil bath for 2 h. Upon cooling, the reaction was quenched with saturated aqueous FeSO (5 mL). The resulting mixture was diluted with EtOAc (20 mL) and washed with saturated aqueous FeSO4 (2 x 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product (5 mg) was purified using the following conditions: column, Phenomenex Lux-2 5u Cellulose-2, 30 * Purification by chiral preparative HPLC with 150 mm; mobile phase, hexane and EtOH (hold 50.0% EtOH for 35 min), yielded 2.1 mg (6%) of the title compound. LC / MS: m / z (ES+) 299 (M+H). + . 1 H-NMR(300MHz,CD3CN):δppm 8.59(br s,1H),7.73(d,J=8.4Hz,1H),7.61-7.56(m,1H),7.48-7.45(m,2H),5.09-4.94(m,3H),1.46(d,J=6.6Hz,3H),1.34-1.26(m,6H).

[0251] Example 57 Preparation of (S)-3-benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0252] [ka]

[0253] Compound 57.1. 3-Ethoxy-3-oxo-1-(1-ethoxy)propan-1-iminium chloride. To a stirred solution of ethyl cyanoacetate (5.0 g, 44 mmol) in anhydrous EtO (5 mL) was added anhydrous EtOH (3 mL). The reaction mixture was cooled to 0 °C and HCl gas was bubbled through for 10 min. The reaction mixture was warmed to room temperature and stirred for 16 h. The white precipitate that formed was filtered, washed with EtO (40 mL), and dried to give the title compound (6.99 g) as a white solid. LC / MS: m / z (ES+) 160 (M+H). + .

[0254] [ka]

[0255] Compound 57.2. (S,E / Z)-3-amino-3-((1-phenylethyl)amino)ethyl acrylate. To a stirred solution of 57.1 (585 mg, 3.0 mmol) in EtOH (15 mL) was added DIEA (0.8 mL) and (S)-α-methylbenzylamine (290 mg, 2.4 mmol). The reaction was stirred for 16 h and concentrated. The crude was purified by flash column chromatography (silica gel, eluting with CHOH (0-10%) in CHCl) to give 0.57 g (98%) of the title compound as a clear oil. NMR analysis revealed the product to be a mixture of E / Z isomers. LC / MS: m / z (ES+) 235 (M+H). + .

[0256] [ka]

[0257] Compound 57.3. (S,Z)-3-(3-benzylureido)-3-((1-phenylethyl)amino)ethyl acrylate. Two reactions were set up in parallel and, since both resulted in product formation (by HPLC), were subsequently combined. In the first reaction, benzyl isocyanate (150 μL, 1.2 mmol) was added to a stirred solution of 57.2 (143 mg, 0.61 mmol) in CH3CN (1 mL). After 10 min, DIEA (300 μL) was added. The reaction was stirred for an additional 10 min and quenched with HO (12 mL). A solid precipitated and was removed by filtration. In the second reaction, benzyl isocyanate (150 μL, 1.2 mmol) was added to a stirred solution of 57.2 (143 mg, 0.61 mmol) and DIEA (300 μL) in CH3CN (1 mL). After 10 min, the reaction mixture was quenched with HO (10 mL). The resulting mixture was diluted with EtOAc (40 mL) and the layers were separated. To the organic layer was added the filtrate from the first reaction. The layers were separated and the organics were concentrated to give the title compound, which was used without further purification.

[0258] [ka]

[0259] Compound 57. (S)-3-Benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. Two reactions were performed, both of which resulted in the formation of the product (by HPLC) and were subsequently combined. The first reaction used one-third of crude 57.3 in CHOH (1 mL). It was heated in a microwave reactor at 120 °C for 10 min. The remaining two-thirds of crude 57.3 in CHOH (2 mL) was heated in a microwave reactor at 120 °C for 20 min. After cooling to ambient temperature, the reactions were combined and CHOH was removed under reduced pressure. A 50 / 50 mixture of CHCN / HO containing 0.1% TFA (5 mL) was added to the resulting residue. A solid precipitated and was filtered. The resulting brown solid was washed with EtOAc to give 7 mg of the title compound as a white solid. LC / MS: m / z (ES+) 322 (M+H) + . 1 H-NMR(400MHz,DMSO-d6):δppm 10.05(br s,1H),7.35-7.31(m,4H),7.26-7.16(m,6H),6.61(d,J=7.0Hz,1H),4.79(s ,2H),4.52(quintet,J=6.8Hz,1H),4.42(d,J=2.3Hz,1H),1.39(d,J=6.7Hz,3H).

[0260] Example 58 Preparation of (S)-3-(2,6-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione (58). [ka] The title compound was synthesized according to a slightly modified procedure described in Example 50, where 1,4-dioxane was used as the solvent and the reaction was heated at 110° C. for 16 h. The resulting mixture was cooled and concentrated under reduced pressure. The crude was purified by preparative RP-HPLC to give 19 mg of the title compound as a white solid. LC / MS: m / z (ES+) 344 (M+H). + . 1H-NMR(400MHz,DMSO-d6):δppm 10.44(br s,1H),7.52-7.42(m,2H),7.39-7.36(m,3H),7.34-7.16(m,3H),6.91(br s,1H),4.65-4.56(m,1H),4.52(s,1H),1.43(d,J=6.7Hz,3H).

[0261] Example 59 Preparation of (S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0262] [ka]

[0263] Compound 59.1. 2,6-Difluorobenzaldehyde. The title compound was synthesized according to the method described for the preparation of 51.2, where commercially available 2,6-difluorobenzoic acid was used instead of 2-(4-fluorophenyl)acetic acid.

[0264] [ka]

[0265] Compound 59.2. (S)-1-(2,6-difluorophenyl)ethan-1-amine hydrochloride. The title compound was synthesized according to the method described for the preparation of 5.3, where 59.1 was used instead of 3,5-difluorobenzaldehyde.

[0266] [ka]

[0267] Compound 59. (S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione. The reaction of 59.1 with 1.3 was carried out in a manner similar to the procedure described in Example 51. However, the reaction mixture was heated at 130° C. for 5 h. Analysis of the reaction mixture by chiral HPLC revealed non-trivial amounts of enantiomers. Separation of the enantiomers was achieved using Phenomenex Lux-2 5 μl cellulose-2, 30 μl cellulose acetate. * Performed using preparative chiral HPLC with an isocratic mixture of EtOH:Hexane (1:4) as eluent from a 150 mm column (40 min run). LC / MS: m / z (ES+) 310 (M+H) + . 1 H-NMR(400MHz,DMSO-d6):δppm 9.80(br s,1H),7.45-7.41(m,1H),7.18-7.14(m,2H),6.52(d,J=8.0Hz,1H),4.94-4.88(m,1 H),4.79(quintet,J=7.6Hz,1H),4.41(s,1H),1.56(d,J=6.8Hz,3H),1.30-1.26(m,6H).

[0268] Example 60 Preparation of (R)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (60R). [ka] The title compound was generated as a by-product of the chemical reaction carried out in Example 59. It was synthesized by dissolving Phenomenex Lux-2 5μ cellulose-2, 30 * Isolated by preparative chiral HPLC using an isocratic mixture of EtOH:hexane (1:4) as eluent from a 150 mm column (40 min run). LC / MS: m / z (ES+) 310 (M+H) + . 1H-NMR(400MHz,DMSO-d6):δppm 9.98-9.61(br,1H),7.45-7.41(m,1H),7.18-7.14(m,2H),6.52(d,J=8.0Hz,1H),4.94-4. 88(m,1H),4.79(quintet,J=7.6Hz,1H),4.41(s,1H),1.56(d,J=6.8Hz,3H),1.30-1.26(m,6H).

[0269] Example 61 Preparation of (S)-3-Isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione.

[0270] [ka]

[0271] Compound 61.1. N-Methoxy-N-methyl-2-(pyridin-4-yl)acetamide. The title compound was synthesized according to the method described for the preparation of 51.1, where commercially available 4-pyridineacetic acid was used instead of 2-(4-fluorophenyl)acetic acid.

[0272] [ka]

[0273] Compound 61.2. 1-(Pyridin-4-yl)propan-2-one. To a 250 mL three-necked round-bottom flask purged and maintained under an inert atmosphere with argon was added THF (70 mL) and N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (7.0 g, 0.039 mol, 1.0 equiv.). The mixture was cooled to 0 °C, and CHMgBr (3 M in THF, 65 mL, 5.0 equiv.) was added dropwise. The resulting solution was warmed to ambient temperature and stirred for 16 h. The reaction mixture was cooled to 0 °C and quenched by the addition of saturated NHCl solution (aqueous, 100 mL). The resulting solution was extracted with EtOAc (3 × 200 mL). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure. The crude was purified by flash chromatography (silica gel, CH2Cl2 / CH3OH (20:1)) to give 2.7 g (51%) of the title compound as a yellow oil. 1 H-NMR (400MHz, CDCl3): δppm 8.58(m,2H),7.17(d,J=0.4Hz,2H),3.75(s,2H),2.24(s,3H).

[0274] [ka]

[0275] Compound 61.3. (R)-2-methyl-N-((S)-1-(pyridin-4-yl)propan-2-yl)propane-2-sulfinamide. The title compound was prepared according to the procedure described in Example 50, using 61.2 instead of 1-(3-methylphenyl)ethanone. Here, reduction using L-selectride resulted in the isolation of the title compound (61.3) (20% enantiomeric excess).

[0276] [ka]

[0277] Compound 61.4. (S)-1-(pyridin-4-yl)propan-2-amine. The title compound was prepared using the two-step procedure described in Example 5. First, sulfonamide 61.3 was converted to the hydrochloride salt by treatment with HCl in 1,4-dioxane (see protocol for compound 5.3). Subsequent purification of the hydrochloride salt (see protocol for compound 5) afforded the title compound (approximately 20% ee).

[0278] [ka]

[0279] Compound 61. (S)-3-Isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione. The title compound was prepared according to the protocol described for 51, where the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue (100 mg) was purified by preparative HPLC to give 13.1 mg of the title compound as a mixture of enantiomers. The enantiomers were separated by Chiralpak IC, 2 using an isocratic mixture of EtOH:hexane (1:3) as the eluent. * Separation was achieved by chiral preparative HPLC (20 min run) on a 25 cm, 5 μm column (13.1 mg). This yielded 8.2 mg (8%) of the title compound as a pale yellow solid. LC / MS: m / z (ES+) 289 (M+H). + . 1 H-NMR(300MHz,CD3OD):δppm 8.41(d,J=5.7Hz,2H),7.29(d,J=6.0Hz,2H),5.06-4.96(m,1H),4.68(s,1H),3. 82-3.75(m,1H),2.87-2.83(m,2H),1.36(d,J=7.2Hz,6H),1.12(d,J=7.2Hz,3H).

[0280] Example 62 Preparation of (S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0281] [ka]

[0282] Compound 62.1. (S)-2-(1-(4-(methoxy)phenyl)ethyl)isoindoline-1,3-dione. To phthalimide (1.3 g, 0.0088 mol) in a 2.5 mL microwave vial was added (S)-1-(4-methoxyphenyl)ethan-1-amine (2.20 mL, 0.015 mol) and K2CO3 (1.2 g, 0.0087 mol). The reaction mixture was capped and heated at 160 °C for 2 min. The crude solid was suspended in n-BuOH and filtered. The filtrate was set aside. The solid was washed with HO and the filtrate was discarded. The solid was washed with CHCl2 and the filtrate was partitioned with HO. The organics (n-BuOH and CHCl2 layers) were combined and concentrated. The crude residue was purified by silica gel column chromatography using CH2Cl2 as eluent to give 1.6 g (64%) of the title compound. LC / MS: m / z (ES+) 282 (M+H). + .

[0283] [ka]

[0284] Compound 62.2. (S)-2-(1-(4-hydroxyphenyl)ethyl)isoindoline-1,3-dione. To a stirred solution of 62.1 (640 mg, 2.28 mmol) in CHCl (8 mL) at 0 °C was added BBr (1.0 M in CHCl, dropwise). The reaction was allowed to warm to room temperature over 30 min. Significant starting material remained, so the reaction was cooled back to 0 °C. Additional BBr (2 mL, 1.0 M in CHCl) was added, and the reaction was allowed to warm to room temperature over 30 min. The reaction mixture was poured onto 5% NaHCO (aq) in ice. The layers were separated, and the aqueous layer was further extracted with CHCl. The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated to give 500 mg (82%) of the title compound as a white solid. LC / MS: m / z (ES+) 268 (M+H). + .

[0285] [ka]

[0286] Compound 62.3. (S)-2-(1-(4-(benzyloxy)phenyl)ethyl)isoindoline-1,3-dione. To a stirred solution of 62.2 (500 mg, 1.87 mmol) in DMF (10 mL) was added K2CO3 (560 mg, 4.05 mmol, 2.17 equiv) and benzyl bromide (0.30 mL, 420 mg, 2.45 mmol, 1.3 equiv). The reaction was stirred at 120 °C for 5 h. The reaction was cooled and filtered. Water (20 mL) was added, and EtOAc (60 mL) was used to extract the product. The organic layer was washed successively with HO, 10% Na2CO3 (aq), HO, and brine (2x). The organics were dried over anhydrous MgSO4 and concentrated. The crude residue was purified by flash chromatography (silica gel, eluted with CH2Cl2) to give 480 mg (72%) of the title compound. LC / MS: m / z (ES+) 358 (M+H). - .

[0287] [ka]

[0288] Compound 62.4. (S)-1-(4-(benzyloxy)phenyl)ethan-1-amine. To a stirred solution of 62.3 (480 mg, 1.34 mmol) in a 70 / 30 EtOH / H2O mixture (20 mL) was added N2H4·H2O (1.5 mL). The reaction was stirred for 16 h and concentrated. The resulting material was partitioned between EtOAc and 5% Na2CO3 (aq). The layers were separated, and the EtOAc layer was washed with brine and concentrated to give 280 mg (92%) of the title compound, which was used without further purification. LC / MS: m / z (ES+) 228 (M+H). + .

[0289] [ka]

[0290] Compound 62. (S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione. To a 0.5-2.0 mL microwave vial was added 1,4-dioxane (1 mL), 62.4 (280 mg, 1.23 mmol), 1.3 (250 mg, 1.33 mmol), and DIEA (400 μL). The reaction mixture was capped and heated in a microwave reactor at 135 °C for 1.5 h, allowed to cool, and then concentrated. The crude reaction mixture was treated with 50 / 50 CH3CN / HO (0.1% TFA), which led to precipitation. The solid was isolated by filtration and dried to give 45 mg (10%) of a white solid. LC / MS: m / z (ES+) 380 (M+H). + . 1H-NMR(400MHz,DMSO-d6):δppm 9.73(br,1H),7.43-7.29(m,5H),7.23(d,J=14.5Hz,2H),6.97(d,J=14.5Hz,2H),6.42(d,J=7.0Hz,1H),5. 06(s,2H),4.93-4.85(m,1H),4.42(quintet,J=6.8Hz,1H),4.32(d,J=1.6Hz,1H),1.35(d,J=6.7Hz,3H),(m,1H) 1.27-1.23(m,6H).

[0291] Example 63 Preparation of (S)-6-((1-(4-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (63). [ka]

[0292] To a stirred solution of 62 (43 mg, 0.11 mmol) in CHOH (20 mL) was added palladium on carbon (50 mg, 10 wt% loading (dry basis), matrix activated carbon, wet support, Degussa type). The vessel was purged with nitrogen, followed by hydrogen. The reaction mixture was stirred under an H atmosphere for 2 h. After purging the system with nitrogen, the mixture was filtered through celite and concentrated. The resulting solid was dissolved in 8 mL of CHCN, and then 20 mL of H0 (0.1% TFA) was added. The solution was frozen and lyophilized to give 29 mg (90%) of the title compound as a white solid. LC / MS: m / z (ES+) 290 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 9.70(br,1H),9.32(s,1H),7.10(d,J=8.6Hz,2H),6.71(d,J=8.6Hz,2H),6.36(d,J=7.0 Hz,1H),4.92-4.85(m,1H),4.37-4.33(m,2H),1.33(d,J=6.7Hz,3H),1.27-1.23(m,6H).

[0293] Example 64 Preparation of (R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

[0294] [ka]

[0295] Compound 64.1. (R)-2-(2-Hydroxy-1-phenylethyl)isoindoline-1,3-dione. To a 2.0-5.0 mL microwave vial was added (R)-2-amino-2-phenylethan-1-ol (1.53 g, 0.0112 mol) and phthalic anhydride (1.65 g, 0.0112 mol). The reaction mixture was capped and heated to 150 °C for 2 min in a microwave reactor. The mixture was cooled, diluted with CHCN (2 mL), recapped, and heated a second time at 140 °C for 20 min in a microwave reactor. The volatiles were removed under reduced pressure, and the resulting solid was suspended in EtOAc (50 mL). The organic layer was washed with 5% NaHCO (aq), HO, and brine, dried over anhydrous MgSO, and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with CHOH (0-5%) in CHCl) to give 2.81 g (94%) of the title compound. LC / MS: m / z (ES+) 268 (M+H). + .

[0296] [ka]

[0297] Compound 64.2. (R)-2-(2-(benzyloxy)-1-phenylethyl)isoindoline-1,3-dione. The title compound was made in a manner similar to the procedure described for 62.3. However, in this case, NaH (60% dispersion in mineral oil, 1.2 equiv.) was used instead of K2CO3. Specifically, NaH was added at 0°C and stirred at room temperature for 45 minutes. The reaction was cooled back to 0°C, and then benzyl bromide (1.2 equiv.) was added. Workup procedure described for 62.3 followed by flash chromatography (silica gel, eluting with CHCl2) afforded the title compound in 59% yield. LC / MS: m / z (ES+) 358 (M+H). + . 1 H-NMR (400MHz, CDCl3): δppm 7.84-7.79(m,2H),7.72-7.67(m,2H),7.52-7.48(m,2H),7.37-7.20(m,8H),5.62 (dd,J=10.2,5.9Hz,1H),4.63(t,J=10.2Hz,1H),4.58(s,2H),4.06-4.01(m,1H).

[0298] [ka]

[0299] Compound 64.3. (R)-2-(benzyloxy)-1-phenylethan-1-amine. The title compound was prepared in a manner similar to the procedure described for 62.4. LC / MS: m / z (ES+) 228 (M+H). + . 1 H-NMR (400MHz, CDCl3): δppm 7.40-7.24(m,10H),4.56(d,J=2.0Hz,2H),4.25(dd,J=8.8,3.7Hz,1H),3.65-3.60(m,1H),3.49-3.44(m,1H).

[0300] [ka]

[0301] Compound 64. (R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione. The title compound was prepared in a manner similar to the procedure described for 62, except that the reaction was heated at 140° C. for 1 h. After cooling, the crude reaction mixture was treated with 50 / 50 CH CN / H O (0.1% TFA), which led to precipitation. LC / MS: m / z (ES+) 380 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 10.01(br,1H),7.36-7.26(m,10H),6.62(d,J=6.7Hz,1H),4.93-4.83(m,1H),4.67-4.62 (m,1H),4.50(dd,J=12.0,2.0Hz,2H),4.30(s,1H),3.68-3.64(m,1H),3.60-3.55(m,1H) 1.27-1.23(m,6H).

[0302] Example 65 Preparation of (S)-3-(6-methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0303] [ka]

[0304] Compound 65.1. 1-(6-Methylpyridin-2-yl)urea. To a 25 mL round-bottom flask purged and maintained with an inert atmosphere of argon was added urea (1.48 g, 24.64 mmol, 1.00 equiv.) and 6-methylpyridin-2-amine (3 g, 27.74 mmol, 1.00 equiv.). The resulting mixture was stirred at 145 °C for 2 h. After cooling, the crude product (4 g) was purified using a CombiFlash column, C18 silica gel, utilizing a mobile phase of CHCN:HO = 0:100 to CHCN:HO = 50:50. This resulted in the isolation of 1.2 g (32%) of the title compound as a white solid. 1 H-NMR (400MHz, DMSO-d6): δppm 9.07(s,1H),7.56-7.52(m,1H),7.18-7.14(m,1H),6.80-6.75(m,1H),2.36(s,3H).

[0305] [ka]

[0306] Compound 65.2. 1-(6-methylpyridin-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione. The title compound was prepared in a manner similar to the procedure described for 1.2. However, after stirring overnight at 65 °C, the reaction mixture was concentrated under reduced pressure, and the crude product was precipitated from CHOH:EtO (1:50). The solid was collected by filtration and dissolved in CHOH (50 mL). The pH of the solution was adjusted to 7 with cation exchange resin (Dowex 50WX8-100, 5 g). The solid was filtered, and the filtrate was concentrated under reduced pressure to provide 0.5 g (29%) of the title compound as a white solid. 1 H-NMR (400MHz, DMSO-d6): δppm 9.27(br s,1H),7.69(t,J=7.6Hz,1H),7.17(d,J=7.6Hz,1H),6.93(d,J=7.6Hz,1H),3.18(s,2H),2.44(s,3H).

[0307] [ka]

[0308] Compound 65.3. 6-Chloro-3-(6-methylpyridin-2-yl)pyrimidine-2,4(1H,3H)-dione. To a stirred solution of 65.2 (500 mg, 2.28 mmol, 1.00 equiv) in POCl (5 mL) at 0 °C, 1 drop (approximately 20 μL) of HO was added. The resulting solution was warmed to room temperature and stirred for 30 min, then heated to 70 °C and stirred for 2 h. After cooling, the resulting mixture was concentrated under reduced pressure. The resulting residue was carefully dissolved in 10 mL of ice water. The pH was adjusted to 7 with anion exchange resin (activated 201×4 (711) strong basic styrenic anion exchange resin, 20 g), and the solid was filtered. The filtrate was concentrated under reduced pressure to provide 0.2 g (37%) of the title compound as a yellow solid.

[0309] [ka]

[0310] Compound 65. (S)-3-(6-Methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a 10 mL round-bottom flask purged and maintained under an inert atmosphere of argon was added (S)-α-methylbenzylamine (0.5 mL) and 65.3 (200 mg, 0.84 mmol, 1.00 equiv.). The resulting solution was stirred at 110° C. for 3 h. After cooling, the resulting mixture was concentrated under vacuum. The residue (100 mg) was purified using the following conditions: Column, XBridge Prep C18 OBD Column, 5 μm, 19 *Purification by preparative RP-HPLC at 150 mm; mobile phase: 0.05% NH(HCO) in H2O and CH3CN (15% CH3CN to 80% in 8 min). This yielded 28.8 mg (11%) of the title compound as a white solid. LC / MS: m / z (ES+) 323 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 7.76(t,J=7.6Hz,1H),7.39-7.22(m,7H),7.05(d,J=7.6Hz,1H),6.82(br ,1H),4.63-4.59(m,1H),4.46(s,1H),2.43(s,3H),1.44(d,J=6.4Hz,3H).

[0311] Example 66 Preparation of (S)-3-(2,2-difluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0312] [ka]

[0313] Compound 66.1. 6-Chloro-3-(2,2-difluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione. To a stirred solution of 11.1 (130 mg, 0.47 mmol) and EtN (0.2 mL) in CHCl at 0 °C was added 2,2-difluoroethyl trifluoromethanesulfonate (0.10 mL). The reaction was warmed to room temperature and stirred for 30 minutes. The mixture was concentrated to give the title compound as a crude mixture.

[0314] [ka]

[0315] Compound 66.2. 6-Chloro-3-(2,2-difluoroethyl)pyrimidine-2,4(1H,3H)-dione. Crude 65.1 was dissolved in CHCl / TFA (1:1, 4 mL), stirred for 3 h, and concentrated. The resulting material was treated with 5% NaHCO (aq) until the pH was 7. Ethyl acetate was added to the mixture and the layers were separated. The aqueous layer was concentrated. The resulting solid was suspended in CHCN (15 mL) and removed by filtration. The filtrate was concentrated to give 52 mg of the title compound.

[0316] [ka]

[0317] Compound 66. (S)-3-(2,2-difluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To 66.2 (52 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL) was added EtN (100 μL) and (S)-α-methylbenzylamine (188 mg, 1.55 mmol). The reaction mixture was heated in a microwave reactor at 100 °C for 32 min, cooled to room temperature, and then concentrated. The resulting residue was dissolved in 2:3 CHCN / HO (10 mL) with 2 drops of TFA (approximately 40 μL). The mixture was purified by preparative RP-HPLC to provide 8 mg (11%) of the title compound as a white solid. LC / MS: m / z (ES+) 296 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 10.20(br s,1H),7.37-7.32(m,4H),7.26-7.23(m,1H),6.71(d,J=7.0Hz,1H),6.07(tt,J=56.0,4.5Hz,1H),4 .54(quintet, J=6.8Hz,1H),4.43(d,J=2.3Hz,1H),4.02(td,J=14.3,4.7Hz,2H),1.40(d,J=6.7Hz,3H).

[0318] Example 67 Preparation of (S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione.

[0319] [ka]

[0320] Compound 67.1. 2H-1,3-Benzodioxole-5-carbaldehyde. To a stirred solution of 3,4-dihydroxybenzaldehyde (10 g, 72.40 mmol, 1.00 equiv.) in DMF (150 mL) was added cesium carbonate (35.4 g, 108.31 mmol, 1.50 equiv.) and dibromomethane (18.7 g, 107.57 mmol, 1.50 equiv.). The resulting solution was stirred at 110 °C for 2 h. The solution was cooled to room temperature, and the solid was removed by filtration. The filtrate was diluted with HO (300 mL). The resulting solution was extracted with EtOAc (2 × 300 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography eluted with EtOAc / petroleum ether (1:9) to provide 8 g (74%) of the title compound as a yellow solid. 1 H-NMR (300MHz, CDCl3): δppm 9.81(s,1H),7.41(d,J=8.1Hz,1H),7.34(s,1H),6.93(d,J=8.1Hz,1H),6.08(s,2H).

[0321] [ka]

[0322] Compound 67.2. (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine hydrochloride. The title compound was synthesized according to the method described for the preparation of 5.3, where 67.1 was utilized instead of 3,5-difluorobenzaldehyde. LC / MS: m / z (ES+) 166 (M+H). + .

[0323] [ka]

[0324] Compound 67. (S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione. The title compound was synthesized according to the method described in Example 59, where 67.2 was utilized instead of (S)-1-(2,6-difluorophenyl)ethan-1-amine hydrochloride, and 6-chloro-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione was utilized instead of 1.3 (synthesized according to the method described in Example 1). LC / MS: m / z (ES+) 358 (M+H). + . 1 H-NMR(300MHz,DMSO-d6):δppm 10.27(br s,1H),6.94(d,J=1.2Hz,1H),6.89-6.82(m,3H),6.72(d,J=6.9Hz,1H),5.99(s,2H),4.48-4.40(m,4H),1.38(d,J=6.9Hz,3H).

[0325] Example 68 Preparation of (S)-3-isopropyl-6-((1-(o-tolyl)ethyl)amino)pyrimidine-2,4-(1H,3H)-dione (68). [ka] To a stirred solution of (1S)-1-(2-methylphenyl)ethan-1-amine (310 mg, 2.29 mmol, 1.50 equiv.) in NMP (1 mL) was added proton sponge (491.4 mg, 2.30 mmol, 1.50 equiv.) and 1.3 (288 mg, 1.53 mmol, 1.00 equiv.). The resulting solution was stirred in an oil bath at 130 °C for 1 h, cooled to room temperature, and then diluted with DMSO (2 mL). The solid was filtered, and the filtrate was purified using the following conditions: Column: X Bridge C18, 19 * The product was purified by flash-prep-HPLC using a 150 mm column, 5 μm column; mobile phase A: HO / 0.05% TFA, mobile phase B: CHCN; flow rate: 20 mL / min; gradient: 30% B to 70% B in 10 min. This provided 50 mg of crude product, which was then purified using the following conditions: column, Chiralpak IC, 2 * Separation was achieved by chiral preparative HPLC using a 25 cm, 5 μm mixture of hexane and ethanol (9:1, 15 min). This afforded 35.6 mg (8%) of the title compound as a white solid. LC / MS: m / z (ES+) 288 (M+H). + . 1 H-NMR(300MHz,DMSO-d6):δppm 9.76(br s,1H),7.28(d,J=7.2Hz,1H) 7.24-7.14(m,3H),6.48(d,J=6.3Hz,1H),4.95-4.86(m,1H),4.60(quintet,J=6.9H) z,1H),4.19(s,1H),2.34(s,3H),1.37(d,J=6.6Hz,3H),1.27(d,J=6.9Hz,6H).

[0326] Example 69 Preparation of (S)-3-cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0327] [ka]

[0328] Compound 69.1. 1-Cyclobutylurea. To a stirred solution of cyclobutanamine (40 g, 562.42 mmol, 1.00 equiv) in CHCl (400 mL) at 0 °C, trimethylsilyl isocyanate (64.70 g, 561.60 mmol, 1.00 equiv) was added portionwise. The resulting solution was stirred at room temperature overnight and quenched by the addition of CHOH (80 mL). The resulting mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was washed with EtO (2 × 100 mL) and filtered, which provided 53 g (83%) of the title compound as a white solid. 1 H-NMR (300MHz, DMSO-d6): δppm 6.17(d,J=9.0Hz,1H),5.33(s,2H),3.99-3.91(m,1H),2.16-2.07(m,2H),1.81-1.68(m,2H),1.61-1.45(m,2H).

[0329] [ka]

[0330] Compound 69.2. 1-Cyclobutylpyrimidine-2,4,6(1H,3H,5H)-trione. To a stirred solution of sodium methoxide (62.43 g, 1.156 mol, 2.40 equiv) in CHOH (500 mL) was added dimethyl malonate (76.42 g, 0.578 mol, 1.20 equiv) and 69.1 (55 g, 0.48 mol, 1.00 equiv). The resulting solution was heated to 65 °C and stirred overnight. The reaction was cooled and quenched by the addition of HO (100 mL). The pH of the solution was adjusted to 1 with concentrated HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CHCl / CHOH (20:1) as eluent to provide 60 g (68%) of the title compound as a white solid. 1H-NMR (400MHz, DMSO-d6): δppm 11.20(s,1H),4.95-4.86(m,1H),3.56(s,2H),2.72-2.62(m,2H),2.16-2.09(m,2H),1.78-1.60(m,2H).

[0331] [ka]

[0332] Compound 69.3. 6-Chloro-3-cyclobutylpyrimidine-2,4(1H,3H)-dione. To 69.2 (80 g, 0.44 mol, 1.00 equiv.) and triethylbenzylammonium chloride (140.2 g, 0.615 mol, 1.40 equiv.) was added POCl3 (300 mL). The reaction was stirred at 65 °C for 1 h and then concentrated under reduced pressure. The reaction was quenched by careful addition of 1 L of water / ice, and then the pH of the solution was adjusted to 1 with 2 N NaOH (aq.). The solid was filtered, washed with CH3OH (300 mL) and Et2O (2 × 300 mL), and dried. This yielded 78 g (89%) of the title compound as a pale yellow solid. 1 H-NMR (300MHz, DMSO-d6): δppm 12.23(s,1H),5.82(s,1H),5.13-5.01(m,1H),2.87-2.73(m,2H),2.13-2.03(m,2H),1.80-1.56(m,2H).

[0333] [ka]

[0334] Compound 69. (S)-3-Cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a 500 mL round-bottom flask purged and maintained with an inert atmosphere of argon was added 69.3 (78 g, 388.79 mmol, 1.00 equiv.) and (S)-α-methylbenzylamine (150 mL, 2.00 equiv.). The reaction mixture was stirred at 120 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with CHOH (1 L), and further cooled to 0 °C. The resulting solid was filtered, washed with EtO (2 × 300 mL), and dried under vacuum to provide 57.25 g (52%) of the title compound as a white solid. LC / MS: m / z (ES+) 286 (M+H). + . 1 H-NMR (400MHz, DMSO-d6): δppm 9.94 (br s, 1H), 7.40-7.32 (m, 4H), 7.30-7.26 (m, 1H), 6.40 (br s,1H),5.19-5.10(m,1H),4.56-4.49(m,1H),4.35(s,1H),2.91-2.81(m,2H),2.02-1.95(m,2H),1.76-1.58(m,2H),1.42(d,J=6.8Hz,3H).

[0335] Example 70 Preparation of (S)-3-isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0336] [ka]

[0337] Compound 70.1. (R,E)-2-Methyl-N-(2-(trifluoromethyl)benzylidene)propane-2-sulfinamide. To a 100 mL round-bottom flask purged and maintained with an inert atmosphere of argon was added CHCl (50 mL), 2-(trifluoromethyl)benzaldehyde (2.01 g, 11.54 mmol, 1.00 equiv), (R)-(+)-2-methylpropane-2-sulfinamide (1.68 g, 13.86 mmol, 1.20 equiv), pyridinium p-toluenesulfonate (0.145 g, 0.05 equiv), and magnesium sulfate (6.93 g, 5.00 equiv). The resulting solution was stirred at 40 °C for 48 h. The mixture was cooled to room temperature, and the solid was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography (silica gel, eluting with EtOAc / petroleum ether (1:20)) to afford 0.96 g (30%) of the title compound as a pale yellow solid. LC / MS: m / z (ES+) 278 (M+H). + . 1 H-NMR(300MHz,DMSO-d6):δppm 8.82-8.80(m,1H),8.24(d,J=7.2Hz,1H),7.95-7.80(m,3H),1.22(s,9H).

[0338] [ka]

[0339] Compound 70.2. (R)-2-Methyl-N-((1S)-1-(2-(trifluoromethyl)phenyl)-ethyl)propane-2-sulfinamide. To a stirred solution of 70.1 (578 mg, 2.08 mmol, 1.00 equiv) in THF (20 mL) at −50 °C was added dropwise 3 M methylmagnesium bromide in EtO (1.4 mL, 4.20 mmol, 2.0 equiv). The resulting solution was stirred at −50 °C for 2.5 h and at room temperature for an additional 10 h. The reaction was quenched by the addition of saturated aqueous NHCl (10 mL) and then concentrated under reduced pressure. The resulting residue was treated with HO (50 mL) and extracted with CHCl (2 × 50 mL). The organic layers were combined, dried over NaSO, and concentrated under reduced pressure. This gave 700 mg (60% de) of the title compound as a yellow solid. LC / MS: m / z (ES+) 294 (M+H) + . 1 H-NMR (300MHz, DMSO-d6): δppm 7.77-7.74(m,1H),7.67-7.60(m,2H),7.43-7.38(m,1H),5.53(d,J=4.5Hz,1H),4.70-4.60(m,1H),1.42(d,J=6.6Hz,3H),1.02(s,9H).

[0340] [ka]

[0341] Compound 70.3. (S)-1-(2-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride. To a stirred solution of 70.2 (700 mg, 2.39 mmol, 1.00 equiv) in CHOH (4 mL) was added 4 N HCl in 1,4-dioxane (2 mL) dropwise. The resulting solution was stirred at room temperature for 1 h and then concentrated under reduced pressure. A solid precipitated upon addition of EtO (5 mL). The solid was filtered and dried to provide the title compound as a white solid (0.32 g, 60%).

[0342] [ka]

[0343] Compound 70.4. (S)-1-(2-(trifluoromethyl)phenyl)ethan-1-amine. To a 50 mL round-bottom flask was added 70.3 (320 mg, 1.43 mmol, 1.00 equiv) and sodium hydroxide (80 mg, 2.00 mmol, 1.40 equiv) in HO (20 mL). The resulting solution was stirred at room temperature for 1 h and then extracted with EtOAc (20 mL). The organic layers were combined and concentrated under reduced pressure. This provided 190 mg (70%) of the title compound as a pale yellow oil.

[0344] [ka]

[0345] Compound 70. (S)-3-Isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a 10 mL round-bottom flask purged and maintained under an inert atmosphere of argon was added NMP (2 mL), 70.4 (160 mg, 0.85 mmol, 1.00 equiv.), 1.3 (160 mg, 0.85 mmol, 1.00 equiv.), and proton sponge (273 mg, 1.28 mmol, 1.5 equiv.). The resulting solution was stirred at 130 °C for 4 h. The crude product (200 mg) was purified using the following conditions: column, Phenomenex Lux-2 5μ cellulose-2, 30 * The product was purified by chiral preparative HPLC using the following conditions: 150 mm; mobile phase, hexane-HPLC and ethanol-HPLC (20% ethanol-HPLC held in 14 min); detector, UV 254 / 220 nm. 160 mg of crude product was obtained. The resulting material (60 mg) was purified by chiral preparative HPLC using the following conditions: column, Phenomenex Lux-2 5μ cellulose-2, 30 *Further purification was carried out using chiral preparative HPLC with 150 mm; mobile phase and gradient: hexane:EtOH=80:20; retention time (peak 2) (min): 11.106. This gave 30 mg of the title compound as a white solid. LC / MS: m / z (ES+) 342 (M+H). + . 1 H-NMR(400MHz,DMSO-d6):δppm 9.84(br,1H),7.78-7.68(m,3H),7.56-7.52(m,1H),6.75(br s,1H),4.93-4.86(m,1H),4.68-4.63(m,1H),4.13(s,1H),1.46(d,J=6.8Hz,3H),1.25(d,J=7.2Hz,6H).

[0346] Example 71 Preparation of (S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

[0347] [ka]

[0348] Compound 71.1. 1-(1-Methylcyclopropyl)urea. To a stirred solution of 1-methylcyclopropan-1-amine hydrochloride (429 mg, 3.99 mmol, 1.00 equiv) and triethylamine (268 mg, 2.65 mmol, 1.00 equiv) in CHCl (6 mL) was added trimethylsilyl isocyanate (366 mg, 3.18 mmol, 1.20 equiv). The resulting mixture was stirred at room temperature overnight and quenched by the dropwise addition of CHOH (2 mL) at 0 °C. The resulting solution was warmed to room temperature and stirred for an additional 1 h. The resulting mixture was concentrated under reduced pressure. The crude product was precipitated from CHOH:EtO (1:40) to provide 300 mg (66%) of the title compound as a white solid.

[0349] [ka]

[0350] Compound 71.2. 1-(1-methylcyclopropyl)pyrimidine-2,4,6(1H,3H,5H)-trione. To a stirred solution of 71.1 (320 mg, 2.80 mmol, 1.0 equiv) in CHOH (2 mL) was added sodium methoxide (390 mg, 7.2 mmol, 2.5 equiv) and dimethyl malonate (380 mg, 2.88 mmol, 1.0 equiv). The resulting solution was stirred at 65 °C overnight. After cooling, the reaction was quenched by the addition of HO (100 mL). The pH of the solution was adjusted to 2 with concentrated HCl, and the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using EtOAc / petroleum ether (1:3) as eluent. This provided 100 mg (20%) of the title compound as a white solid. 1 H-NMR (300MHz, CDCl3): δppm 8.04(br,1H),3.61(s,2H),1.41(s,3H),1.00-,0.86(m,4H).

[0351] [ka]

[0352] Compound 71.3. 6-Chloro-3-(1-methylcyclopropyl)pyrimidine-2,4(1H,3H)-dione. To 71.2 (100 mg, 0.55 mmol, 1.00 equiv) and triethylbenzylammonium chloride (180 mg, 0.79 mmol, 1.00 equiv) was added POCl (2 mL). The resulting solution was stirred at 50 °C for 3 h and then concentrated under reduced pressure. The residue was carefully quenched by the addition of 10 mL of water / ice and extracted with EtOAc (2 × 30 mL). The organic layers were combined and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using CHCl / CHOH (10:1) as eluent to provide 40 mg (36%) of the title compound as a yellow solid.

[0353] [ka]

[0354] Compound 71. (S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To 71.3 (40 mg, 0.20 mmol, 1.00 equiv.) was added (S)-α-methylbenzylamine (0.5 mL). The reaction mixture was stirred at 130° C. for 2 h and then concentrated under reduced pressure. The resulting residue was purified using the following conditions: Column: X Bridge C18, 19 * Purification by preparative RP-HPLC with 150 mm, 5 μm; mobile phase A: HO / 0.05% TFA, mobile phase B: CHCN; flow rate: 20 mL / min; gradient: 30% B to 70% B in 10 min. This provided 15.1 mg (27%) of the title compound as a white solid. LC / MS: m / z (ES+) 286 (M+H). + . 1H-NMR(300MHz,CD3CN):δppm 8.41(br,1H),7.42-7.29(m,5H),5.79(br,1H),4.48-4.44(m,1H),4.30(s,1H),1.47(d,J=6.9Hz,3H),1.27(s,3H),0.87-0.77(m,4H).

[0355] Example 72 Preparation of additional pyrimidinedione compounds. The compounds in Table 1B were prepared according to the examples described above (exemplary methods provided as "Reference Example Number").

[0356] [Table 7]

[0357] [Table 8]

[0358] [Table 9]

[0359] [Table 10]

[0360] [Table 11]

[0361] [Table 12]

[0362] [Table 13]

[0363] [Table 14]

[0364] [Table 15]

[0365] [Table 16]

[0366] [Table 17]

[0367] [Table 18]

[0368] [Table 19]

[0369] [Table 20]

[0370] Example 73 Myosin inhibition assay Small molecule drugs were evaluated for their ability to inhibit the enzymatic activity of bovine cardiac myosin using a biochemical assay that couples the release of ADP (adenosine diphosphate) from cardiac myosin to an enzyme coupling system consisting of pyruvate kinase and lactate dehydrogenase (PK / LDH) and monitors the decrease in absorbance of NADH (at 340 nm) as a function of time. PK converts ADP to ATP (adenosine triphosphate) by converting PEP (phosphoenolpyruvate) to pyruvate. Pyruvate is then converted to lactate by LDH by converting NADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamide adenine dinucleotide). The source of cardiac myosin was bovine heart in the form of skinned myofibrils. Prior to testing small molecule drugs, the bovine myofibrils were assessed for their calcium responsiveness, with 50% (pCa) of the myofibrillar system as the final condition for evaluating the inhibitory activity of the small molecule drugs. 50 ) or 75%(pCa 75 The calcium concentration required to achieve activation of the PEP myofibrils was selected. All enzyme activities were measured in a pH 6.8 buffer (PM12 buffer) containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)) and 2 mM magnesium chloride. The final assay conditions were 1 mg / mL bovine cardiac myofibrils, 0.4 mM PK / LDH, 50 μM ATP, 0.1 mg / mL BSA (bovine serum albumin), 10 ppm antifoam, 1 mM DTT, 0.5 mM NADH, and 1.5 mM PEP, with the desired free calcium concentration required to achieve 50% or 75% activation of PEP myofibrils.

[0371] A series of compound dilutions was made in DMSO to achieve the final desired compound concentration in a 100 μL volume with a fixed 2% DMSO concentration (v / v). Typically, 2 μL of the dilution series was placed in a 96-well plate to achieve an 8- or 12-point dose response. Following the addition of 50 μL of a solution containing bovine cardiac myofibrils, PK / LDH, and calcium (which achieved the desired activation), the enzymatic reaction was initiated by the addition of 50 μL of a solution containing ATP, PEP, and NADH. The reaction progress was followed in a Molecular Devices M5e plate reader at ambient temperature using a clear half-area plate. The plate reader was set to read absorbance at 340 nm in kinetic mode for 15 minutes. Data were recorded as the slope of the absorbance response versus time. The slope of the absorbance response as a function of time was normalized to the slope of the plate containing DMSO. This normalized ratio was then plotted as a function of small molecule concentration, and the data was fitted to a four parameter fit using GraphPad Prism. The midpoint of this plot is the IC50, the concentration at which 50 percent of the overall response is inhibited. Any agent that failed to achieve 50 percent inhibition at the highest concentration tested was reported as having an IC50 greater than the highest concentration tested (i.e., IC50 > 25 μM).

[0372] [Table 21]

[0373] [Table 22]

[0374] [Table 23]

[0375] [Table 24]

[0376] Selectivity for rabbit skeletal muscle myofibrils was assessed as described above, except that the source of myosin was compacted skeletal muscle myosin from rabbits in myofibril form. The dose response for rabbit skeletal muscle myofibrils was also determined as described above.

[0377] Example 74 Stereochemical preferences for activity Matched pairs of stereoisomers were tested for their ability to inhibit myosin activity as described above, and the results are summarized in Table 3. In all cases, the (R) stereoisomer is significantly less active than the (S) stereoisomer.

[0378] [Table 25]

[0379] Example 75 Cardiomyocyte contractile force assay Contractile force of adult rat ventricular myocytes is measured by edge detection using the IonOptix contractile force system. An aliquot of myocytes in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl, 1.5 mM CaCl, 4 mM HEPES, 11 mM glucose) is placed in a perfusion chamber (Series 20RC-27NE; Warner Instruments), allowed to adhere to a coverslip, and then perfused with 37°C Tyrode's buffer. Myocytes are stimulated at 1 Hz and 10 V for file transfer. Only myocytes with resting clear striations before pacing, with a cell length of 120–180 microns, a basal shortening fraction equal to 3–8% of the cell length, and a contraction velocity greater than 100 microns per second, are used for contractile experiments. To measure the response to compounds, myocytes were first perfused with Tyrode's buffer for 60 seconds, followed by 5 minutes of compound and a 140-second washout with Tyrode's buffer. Data were continuously recorded using IonOptix software. Contractile force data were analyzed using Ionwizard software (IonOptix). For each cell, 10–20 contractile force transients were averaged and compared under basal (no compound) and compound-treated conditions. Compound activity was measured by its effect on fractional shortening (FS), where fractional shortening is the ratio of the peak length of the cell during contraction divided by the basal cell length, normalized to 100% for untreated cells.

[0380] [Table 26]

[0381] Example 76 Acute pharmacodynamic effects in rats. Representative compounds were tested for their ability to modulate myocardial contractility in rats as a measure of in vivo target engagement. Fractional shortening, a measure of contractility, was measured by recording the change in left ventricular end-systolic diameter (LVESd) relative to left ventricular end-diastolic diameter (LVEDd) and expressing this change as the ratio FS = (LVEDd - LVESd) / LVEDd. Fed male Sprague-Dawley rats were lightly anesthetized with isoflurane, and baseline fractional shortening was measured using transthoracic echocardiography (TTE) in the parasternal position. Following this measurement, the animals were recovered and received a single dose of compound (4 mg / kg) by oral gavage. Three hours after administration, second and third echocardiograms were collected under light anesthesia to measure drug effects on contractility. Effects are expressed as a percent reduction in baseline fractional shortening in Table 5.

[0382] [Table 27]

[0383] Although the foregoing invention has been described in some detail by way of illustrations and examples for clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present invention and the references provided herein, the present invention will control.

[0384] [Claim 1] formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1is a member selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-C1-C4 alkyl, 4- to 7-membered heterocycloalkyl, phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-C1-C4 alkyl, wherein each R 1 may contain 1 to 3 R a is replaced by; R 2 is a member selected from the group consisting of phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heteroaryl-C1-C4 alkyl, where each R 2 may contain 1 to 5 R b is replaced by; R 3 is a member selected from the group consisting of C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein each R 3 may contain 1 to 3 R c is replaced by; R 4 is H; X is a member selected from the group consisting of H and F; Each R a is halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenyl, phenyl-C1-C4 alkyl, phenyl-C1-C4 alkoxy, phenoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , and -CONR a1 R a2 where each R is independently selected from the group consisting of a1 and R a2 are independently selected from the group consisting of H, C1-C4 alkyl and phenyl, or optionally R a1 and R a2 when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; Each R b is halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenoxy, phenyl-C1-C4 alkoxy, methylenedioxy, difluoromethylenedioxy, -COR b1 , -CO2R b1 , -SO2R b1 , -SO2NR b1 R b2 , -CONR b1 R b2 , N.R. b1 R b2 , 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted by oxo, wherein each R b1 and R b2 are independently selected from the group consisting of H and C1-C4 alkyl, or optionally R b1 and R b2 when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; Each R c are independently selected from the group consisting of halo, hydroxyl, and C1-C2 alkoxy; A compound having the above formula or a pharmaceutically acceptable salt thereof. [Claim 2] R 1 is a member selected from the group consisting of C1-C8 alkyl, C3-C8 cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein each R 1 may contain 1 to 3 R a is replaced by; R 2 However, in some cases, 1 to 5 R b is phenyl substituted by; R 3 is a member selected from the group consisting of C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein each R 3 may contain 1 or 2 R c is replaced by; R 4 But H; X is a member selected from the group consisting of H and F; Each R a halo, CN, C1-C4 alkyl, C1-C4 alkoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , and -CONR a1 R a2 where each R is independently selected from the group consisting of a1 and R a2 are independently selected from the group consisting of H and C1-C4 alkyl, or optionally R a1 and R a2 when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; Each R b halo, CN, C1-C4 alkyl, C1-C4 alkoxy, -COR b1 , -CO2R b1 , -SO2R b1 , -SO2NR b1 R b2 , -CONR b1 R b2 , N.R. b1 R b2 , 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted by oxo, wherein each R b1 and R b2 are independently selected from the group consisting of H and C1-C4 alkyl, or optionally R b1 and R b2 when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; Each R c are independently selected from the group consisting of halo and C1-C2 alkoxy; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof. [Claim 3] 3. The compound of claim 1 or 2, wherein X is H, or a pharmaceutically acceptable salt thereof. [Claim 4] R 1 is selected from the group consisting of C-C alkyl, C-C cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein each R 1 is 1 to 2 R a 3. The compound of claim 1 or 2, optionally substituted by: or a pharmaceutically acceptable salt thereof. [Claim 5] R 1 is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each R 1 is 1 to 3 R a 3. The compound of claim 1 or 2, optionally substituted by: or a pharmaceutically acceptable salt thereof. [Claim 6] R 1 is selected from the group consisting of C3-C4 alkyl, C3-C5 cycloalkyl, and 4- to 6-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof. [Claim 7] R 1 is C1-C4 alkyl, C1-C4 alkoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , and -CONR a1 R a2 One to two R selected from the group consisting of a and wherein each R is a 4- to 6-membered heterocycloalkyl optionally substituted by a1 and R a2 is independently selected from the group consisting of H and C1-C4 alkyl, or a pharmaceutically acceptable salt thereof. [Claim 8] R 1is selected from the group consisting of cyclobutyl, isopropyl, isobutyl, 1-methoxypropan-2-yl, cyclopentyl, cyclohexyl, 4-tetrahydropyranyl, 1-(methylsulfonyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 4,4-difluorocyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, and 1-methyl-3-pyrazolyl, or a pharmaceutically acceptable salt thereof. [Claim 9] R 2 But 1-2 R b 3. The compound of claim 1 or 2, optionally substituted by: or a pharmaceutically acceptable salt thereof. [Claim 10] R 2 is selected from the group consisting of phenyl, 3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3-(3-oxazolidin-2-onyl)phenyl, 3-(2-methyl-1-imidazyl)phenyl, 3-(1-pyrazolyl)phenyl, and 3-(1,2,4-triazol-1-yl)phenyl, or a pharmaceutically acceptable salt thereof. [Claim 11] R 3 is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxyalkyl, and C3-C4 cycloalkyl, or a pharmaceutically acceptable salt thereof. [Claim 12] R 3 3. The compound of claim 1 or 2, wherein is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl, and 2-methoxymethyl, or a pharmaceutically acceptable salt thereof. [Claim 13] R 3 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein is methyl. [Claim 14] R 1 is isopropyl; R 2 But 1-2 R b optionally substituted by R 3 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is methyl. [Claim 15] R 1 is C1-C4 alkyl, C1-C4 alkoxy, -COR a1 , -CO2R a1 , -SO2R a1 , -SO2NR a1 R a2 , and -CONR a1 R a2 One to two R selected from the group consisting of a and wherein each R is a 4- to 6-membered heterocycloalkyl optionally substituted by a1 and R a2 is independently selected from the group consisting of H and C1-C4 alkyl; R 2 But 1-2 R b optionally substituted by R 3 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is methyl. [Claim 16] R 1 is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each R 1 is 1 to 3 R a optionally substituted by R 2 But 1-2 R b optionally substituted by R 3 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is methyl. [Claim 17] 17. A pharmaceutical composition comprising the compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [Claim 18] [ka] 2. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof. [Claim 19] 19. A method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having pathophysiological characteristics associated with HCM, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-16, or 18, or a pharmaceutically acceptable salt thereof. [Claim 20] 19. A method for treating a disease or disorder selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, the method comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof. [Claim 21] 19. A method for treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload and selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic elevated blood pressure, in conjunction with treatment comprising valve repair / replacement or effective antihypertensive therapy aimed at correcting or alleviating the underlying cause of the volume or pressure overload, the method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-16 or 18, or a pharmaceutically acceptable salt thereof. [Claim 22] 19. A method for treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having pathophysiological characteristics associated with HCM, comprising administering to a subject in need thereof an effective amount of the compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, in combination with a therapy that attempts to slow the progression of heart failure by downregulating cardiac neurohormonal stimulation and prevent cardiac remodeling (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor), a therapy that improves cardiac function by stimulating myocardial contractility (e.g., a positive inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone), and a therapy that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (a vasodilator of any class, including, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

Claims

1. formula: 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein R １ is C １ ~C ８ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ Cycloalkyl-C １ ~C ４ Alkyl, 4- to 7-membered heterocycloalkyl, phenyl, phenyl-C １ ~C ４ Alkyl, 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl-C １ ~C ４ alkyl, wherein each R １ may contain 1 to 3 R ａ is substituted by R ２ is phenyl, phenyl-C １ ~C ４ Alkyl, 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl-C １ ~C ４ alkyl, wherein each R ２ may contain 1 to 5 R ｂ is substituted by R ３ is C １ ~C ４ Alkyl, C ３ ~C ４ cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein each R ３ may contain 1 to 3 R ｃ is substituted by R ４ is H; X is a member selected from the group consisting of H and F; Each R ａ is halo, CN, hydroxyl, C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Alkoxy, phenyl, phenyl-C １ ~C ４ Alkyl, phenyl-C １ ~C ４ Alkoxy, phenoxy, -COR ａ１ , -CO ２ R ａ１ , -SO ２ R ａ１ , -SO ２ NR ａ１ R ａ２ , and -CONR ａ１ R ａ２ wherein each R is independently selected from the group consisting of ａ１ and R ａ２ is H, C １ ~C ４ independently selected from the group consisting of alkyl and phenyl, or optionally R ａ１ and R ａ２ when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; Each R ｂ is halo, CN, hydroxyl, C １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C １ ~C ４ Alkoxy, phenoxy, phenyl-C １ ~C ４ Alkoxy, methylenedioxy, difluoromethylenedioxy, -COR ｂ１ , -CO ２ R ｂ１ , -SO ２ R ｂ１ , -SO ２ NR ｂ１ R ｂ２ , -CONR ｂ１ R ｂ２ , N.R. ｂ１ R ｂ２ , 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted by oxo, wherein each R ｂ１ and R ｂ２ is H and C １ ~C ４ alkyl, or optionally R ｂ１ and R ｂ２ when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; Each R ｃ is halo, hydroxyl and C １ ~C ２ independently selected from the group consisting of alkoxy, A compound having the above formula or a pharmaceutically acceptable salt thereof.

2. R １ But C １ ~C ８ Alkyl, C ３ ~C ８ is a member selected from the group consisting of cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein each R １ may contain 1 to 3 R ａ is substituted by R ２ However, in some cases, 1 to 5 R ｂ is phenyl substituted with R ３ But C １ ~C ４ Alkyl, C ３ ~C ４ cycloalkyl, and 4- to 7-membered heterocycloalkyl, wherein each R ３ may contain one or two R ｃ is substituted by R ４ is H; X is a member selected from the group consisting of H and F; Each R ａ But, Haro, CN, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, -COR ａ１ , -CO ２ R ａ１ , -SO ２ R ａ１ , -SO ２ NR ａ１ R ａ２ , and -CONR ａ１ R ａ２ wherein each R is independently selected from the group consisting of ａ１ and R ａ２ is H and C １ ~C ４ alkyl, or optionally R ａ１ and R ａ２ when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; Each R ｂ But, Haro, CN, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, -COR ｂ１ , -CO ２ R ｂ１ , -SO ２ R ｂ１ , -SO ２ NR ｂ１ R ｂ２ , -CONR ｂ１ R ｂ２ , N.R. ｂ１ R ｂ２ , 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted by oxo, wherein each R ｂ１ and R ｂ２ is H and C １ ~C ４ alkyl, or optionally R ｂ１ and R ｂ２ when attached to a nitrogen atom, combine to form a 4- to 6-membered ring; Each R ｃ But halo and C １ ~C ２ independently selected from the group consisting of alkoxy, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. 3. The compound of claim 1 or 2, wherein X is H, or a pharmaceutically acceptable salt thereof.

4. R １ But C ３ ~C ４ Alkyl, C ３ ~C ５ cycloalkyl, and 4- to 6-membered heterocycloalkyl, wherein each R １ is 1 to 2 R ａ 3. The compound of claim 1 or 2, optionally substituted by: or a pharmaceutically acceptable salt thereof.

5. R １ is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each R １ is 1 to 3 R ａ 3. The compound of claim 1 or 2, optionally substituted by: or a pharmaceutically acceptable salt thereof.

6. R １ But C ３ ~C ４ Alkyl, C ３ ~C ５ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of cycloalkyl, and 4- to 6-membered heterocycloalkyl.

7. R １ But C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, -COR ａ１ , -CO ２ R ａ１ , -SO ２ R ａ１ , -SO ２ NR ａ１ R ａ２ , and -CONR ａ１ R ａ２ One to two R selected from the group consisting of ａ and a 4- to 6-membered heterocycloalkyl optionally substituted by ａ１ and R ａ２ is H and C １ ~C ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of alkyl.

8. R １ is selected from the group consisting of cyclobutyl, isopropyl, isobutyl, 1-methoxypropan-2-yl, cyclopentyl, cyclohexyl, 4-tetrahydropyranyl, 1-(methylsulfonyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl, 4,4-difluorocyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, and 1-methyl-3-pyrazolyl, or a pharmaceutically acceptable salt thereof.

9. R ２ But one or two R ｂ 3. The compound of claim 1 or 2, optionally substituted by: or a pharmaceutically acceptable salt thereof.

10. R ２ is selected from the group consisting of phenyl, 3-methylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3-(3-oxazolidin-2-onyl)phenyl, 3-(2-methyl-1-imidazyl)phenyl, 3-(1-pyrazolyl)phenyl, and 3-(1,2,4-triazol-1-yl)phenyl, or a pharmaceutically acceptable salt thereof.

11. R ３ But C １ ~C ４ Alkyl, C １ ~C ４ Alkoxyalkyl, and C ３ ~C ４ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of cycloalkyl.

12. R ３ 3. The compound according to claim 1 or 2, wherein is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl and 2-methoxymethyl, or a pharmaceutically acceptable salt thereof.

13. R ３ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein is methyl.

14. R １ is isopropyl; R ２ But one or two R ｂ optionally substituted by R ３ 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is methyl.

15. R １ But C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, -COR ａ１ , -CO ２ R ａ１ , -SO ２ R ａ１ , -SO ２ NR ａ１ R ａ２ , and -CONR ａ１ R ａ２ One to two R selected from the group consisting of ａ and a 4- to 6-membered heterocycloalkyl optionally substituted by ａ１ and R ａ２ is H and C １ ~C ４ independently selected from the group consisting of alkyl; R ２ But one or two R ｂ optionally substituted by R ３ 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is methyl.

16. R １ is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl, wherein each R １ is 1 to 3 R ａ optionally substituted by R ２ But one or two R ｂ optionally substituted by R ３ 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is methyl.

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 【Request Item 18】 【Chemistry 2】 2. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

19. 19. A method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having pathophysiological characteristics associated with HCM, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 16, or 18, or a pharmaceutically acceptable salt thereof.

20. 19. A method for treating a disease or disorder selected from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy, said method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

21. 19. A method for treating a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload and selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic elevated systemic blood pressure, in conjunction with treatments comprising valve repair / replacement or effective antihypertensive therapy aimed at correcting or alleviating the underlying cause of the volume or pressure overload, said method comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof.

22. 20. A method of treating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having pathophysiological characteristics associated with HCM, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, in combination with a therapy that attempts to slow the progression of heart failure by downregulating cardiac neurohormonal stimulation and prevent cardiac remodeling (e.g., an ACE inhibitor, an angiotensin receptor blocker (ARB), a beta-blocker, an aldosterone receptor antagonist, or a neuroendopeptidase inhibitor), a therapy that improves cardiac function by stimulating myocardial contractility (e.g., a positive inotropic agent such as the beta-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone), and a therapy that reduces cardiac preload (e.g., a diuretic such as furosemide) or afterload (a vasodilator of any class including, but not limited to, a calcium channel blocker, a phosphodiesterase inhibitor, an endothelin receptor antagonist, a renin inhibitor, or a smooth muscle myosin modulator).

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