NZ715456B2 - Pyrimidinedione compounds against cardiac conditions - Google Patents

Abstract

Provided are novel pyrimidine dione compounds of formula (I) 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. of the compounds and pharmaceutically acceptable salts thereof, are described, as well as methods for treating HCM and other forms of heart disease.

Description

PYRIMIDINEDIONE COMPOUNDS AGAINST CARDIAC IONS CROSS-REFERENCES TO RELATED APPLICATIONS This application is an application claiming benefit under 35 U.S.C. § 119(e) of U.S.

Provisional Application No. 61/838,088 filed June 21, 2013, and U.S. Provisional Application No. 61/939,655 filed ry 13, 2014, and U.S. Provisional Application No. 61/981,366 filed April 18, 2014, each of which is herein orated by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT NOT APPLICABLE BACKGROUND OF THE INVENTION Genetic (heritable) hypertrophic cardiomyopathy (HCM) comprises a group of highly penetrant, monogenic, autosomal dominant myocardial diseases. HCM is caused by one or more of over 1,000 known point mutations in any one of the structural protein genes contributing to the functional unit of myocardium, the sarcomere. About 1 in 500 individuals in the general tion are found to have left ventricular hypertrophy unexplained by other known causes (e.g., hypertension or valvular e), and many of these can be shown to have HCM, once other heritable (e.g., lysosomal storage es), metabolic, or infiltrative causes have been excluded.

Sarcomere gene mutations that cause HCM are highly penetrant, but there is wide variability in clinical severity and clinical . Some pes are associated with a more malignant course, but there is considerable variability between and even within families carrying the same mutation. Sex ences have also been noted, with male patients generally more severely affected than female patients. While many patients with HCM report minimal or no symptoms for extended s of time, HCM is a progressive disease with a significant cumulative burden of morbidity. Symptoms of effort intolerance predominate, and can be exacerbated by exercise and other maneuvers that increase heart rate and/or decrease d. As with many other disorders, symptoms tend to worsen with age. By far the most prevalent clinical burden for ts with HCM is onal dyspnea, which limits their activities of daily living and can be debilitating.

Patients with HCM are often symptomatic in the absence of documented hemodynamic abnormalities like left ventricular outflow tract obstruction (with or without mitral regurgitation). Patients’ symptoms of exertional dyspnea can rapidly worsen with the onset of atrial fibrillation, a common complication ofHCM that can precipitate acute pulmonary edema that increases the risk of systemic al thromboembolic disease, including stroke. Other adverse events associated with HCM include intolerance of hypovolemia or hypervolemia, and syncope. Concomitant coronary artery disease may confer a higher risk of acute ry syndromes than in patients without HCM. Sudden cardiac death (SCD) in patients with HCM is both uncommon and difficult to t but is a g cause of non-traumatic death in young adults. For survivors of SCD, ICD placement is standard practice, and in other HCM patients risk profiling, while imprecise, is used to identify those for whom 1CD placement for primary prevention is deemed prudent.

Medical therapy for HCM is limited to the treatment of symptoms and does not address the fundamental, underlying cause of e — disruptions in normal sarcomere function. tly available therapies are variably effective in alleviating symptoms but typically show decreased efficacy with increasing disease duration. Patients are thus empirically managed with beta-blockers, hydropyridine calcium channel blockers, and/or ramide. None of these agents carry labeled tions 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 l therapies for HCM have been identified for many years. For patients with hemodynamically significant outflow tract obstruction (resting gradient >30mmHg), in appropriately selected patients surgical myectomy or alcohol septal on is usually required to alleviate the hemodynamic obstruction. Provided are new therapeutic agents and methods that remedy the long-felt need for improved treatment ofHCM and related cardiac disorders.

BRIEF SUMNIARY OF THE INVENTION [0006a] In a first aspect, the present ion provides a compound having the formula: x ,R‘ R? R4 R2X5] INAO H H or a pharmaceutically acceptable salt thereof, wherein R1 is a member selected from the group consisting of C3-C4 alkyl, C3-C5 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein each R1 is optionally substituted with from 1-3 R“; R2 is a member selected from the group consisting of phenyl, phenyl-C1-C4 alkyl, 5- to 6—membered heteroaryl and 5- to ered heteroaryl-Cl-C4 alkyl, wherein each R2 is optionally substituted with from 1-5 Rb; R3 is a member selected from the group consisting of C1—C4 alkyl, C3—C4 cycloalkyl, and 4— to 7-membered heterocycloalkyl wherein each R3 is optionally tuted with from 1- 3 R“; R4 is H; X is a member selected from the group consisting ofH and F; each Ra is independently selected from the group consisting of halo, CN, yl, C1- C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenyl, phenyl-Cl-C4 alkyl, phenyl-Cl-C4 , phenoxy, -COR'1, -C02Ral, -SOzR"1, -SOzNRalR"2, and -CONR“1R“2, wherein each Rall and Ra2 is independently selected from the group consisting of H, C1-C4 alkyl and phenyl, or optionally Rall and Ral2 when attached to a nitrogen atom are ed to form a 4- to 6- membered ring; each R" is independently selected from the group consisting of halo, CN, hydroxyl, C1- C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, y, phenyl-C1-C4 alkoxy, methylenedioxy, difluoromethylenedioxy, -C0Rb1, -C02R"1, -sosz1, -sozNRb1Rb2, CONRbleZ, , 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally tuted with 0x0, wherein each R1’1 and R1,2 is independently selected from the group consisting of H and C1-C4 alkyl or optionally Rbl and R” when ed to a nitrogen atom are combined to form a 4- to 6— membered ring; and each Rc is independently selected from the group consisting of halo, hydroxyl and C1- C2 alkoxy; wherein each cycloalkyl is a saturated or partially unsaturated ring system. [0006b] In a second aspect, the present ion provides a pharmaceutical composition comprising a compound of the first aspect, or a ceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0006c] In a third aspect, the present invention provides use of a compound of the first aspect: or a pharmaceutically acceptable salt thereof, for the cture of a medicament for the treatment of hypertrophic cardiomyopathy (HCM). [0006d] In a fourth aspect, the present invention provides use of a compound of the first aspect: or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diastolic heart e with preserved ejection fraction.

] In a fifth aspect, the present invention provides use of a compound of the first aspect: or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diastolic dysfunction. [0006f] In a sixth aspect, the present invention provides use of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a hysiological feature associated with HCM. [0006g] In a seventh aspect, the t invention provides use of a compound of the first aspect, or a pharmaceutically able salt thereof, for the cture of a medicament for failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy.

] In an eighth aspect, the present invention provides use of a nd of the first aspect, or a pharmaceutically able salt thereof, for the manufacture of a medicament for the ent of a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload, said disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; in conjunction with therapies aimed at correcting or ating the primary cause of volume or pressure overload, including valve repair/replacement or effective antihypertensive therapy. [0006i] In a ninth aspect, the present invention provides use of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the ent of hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature associated with HCM, combined with one or more therapies that retard the progression of heart failure by down-regulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling said therapies selected from the group consisting of ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers,aldosterone receptor antagonists, and neural ptidase inhibitors. [0006j] In a tenth aspect, the t invention provides use of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of rophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature associated with HCM, combined with one or more therapies that improve cardiac function by ating cardiac contractility, said therapies being one or more positive inotropic . [0006k] In an th aspect, the present invention provides use of a compound of the first aspect, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature associated with HCM, combined with one or more ies that reduce cardiac preload or afterload, wherein the therapy that reduces cardiac preload is a diuretic and the therapy that reduces cardiac afterload is a vasodilator.

In one , provided is a compound having the formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the above formula, R1 is a member ed from C1-Cs alkyl, C3-Cs cycloalkyl, C3-Cs cycloalkyl-C1-C4 alkyl, 4- to 7- membered heterocycloalkyl, phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered aryl and 5- to 6-membered heteroaryl-C1-C4 alkyl, wherein each R1 is optionally substituted with from 1- 3 R\ R2 is a member selected from phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl-C1-C4 alkyl, wherein each R2 is optionally substituted with from 1-5 R\ R3 is a member selected from C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7-membered heterocycloalkyl wherein each R3 is optionally substituted with from 1-3 R\ R4 is H; Xis a member selected from Hand halo, and in some embodiments Xis selected from Hand F. Each Ra ,when present, is independently selected from halo, CN, yl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 , phenyl, phenyl-C1-C4 alkyl, phenyl-C1- C4 alkoxy, phenoxy, -CORa1, -CO2Ra1, -SO2Ra1, -SO2NRa1Ra2, and -CONRa1Ra2, wherein each Ra1 and Ra2 is independently selected from H, C1-C4 alkyl and phenyl, or optionally Ra1 and Ra2 when attached to a en atom are combined to form a 4- to 6- membered ring. Similarly, each R\ when present, is ndently selected from halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenoxy, phenyl-C1-C4 alkoxy, methylenedioxy, romethylenedioxy, -CORb1 , -CO2Rb1, -SO2Rb1, -SO2NRb1Rb2, CONRb1Rb2, NRb1Rb2, - to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted with oxo, wherein each Rb1 and Rb2 is independently ed from Hand C1-C4 alkyl or optionally Rb1 and Rb2 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring ; and each RC, when present, is independently selected from halo, hydroxyl and C1-C2 alkoxy.

In another aspect, ed is a pharmaceutical composition containing a nd or or ceutically acceptable salt described herein and a pharmaceutically acceptable excipient.

In r aspect, provided is a method oftreating hypertrophic cardiomyopathy (HCM) or a cardiac disorder having one or more pathophysiological features associated with HCM. The method includes administering to a subject in need thereof an effective amount of a compound or pharmaceutically acceptable salt described herein.

BRIEF PTION OF THE DRAWINGS Figure 1 shows a schematic route for the sis of the compounds or ceutically acceptable salts described herein e 1A) and a route for the preparation of chiral amines e 1B).

DETAILED DESCRIPTION OF THE INVENTION 1. General A series of pyrimidine dione compounds and pharmaceutically acceptable salts thereof has been found to reduce excess contractility in hypercontractile states and/or promote cardiac relaxation in hearts with diastolic dysfilnction by stabilizing the conformation of beta cardiac myosin post-ATP hydrolysis but prior to strongly binding the actin filament and releasing phosphate, thus reducing the proportion of myosin molecules that are available to participate in the “powerstroke” portion of the muscle contraction cycle. As such, the compounds can improve cardiac elasticity, reduce dynamic and/or static left ventricular outflow obstruction, improve diastolic left ventricular relaxation, reduce left ventricular diastolic (filling) pressures, reduce functional mitral regurgitation, and/or reduce left atrial and pulmonary capillary wedge res in patients with HCM helping overcome the debilitating exertional dyspnea and/or symptoms referable to left ventricular outflow obstruction (presyncope or syncope) that often accompanies the disease. The compounds can also be used to treat other cardiac disorders. 11. Definitions As used herein, the term “alkyl” refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated. Alkyl can include any number of S, SllCh as C1—2, C1—3, C1—4, Ci—s, C1—6, C1—7, Ci—s, C2—3, C2—4, Cz—s, C2—6, C3—4, Cs—s, C3—6, C4—5, C4_6 and C5_6. For example, C1_6 alkyl includes, but is not d to, methyl, ethyl, propyl, pyl, butyl, yl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Unless stated otherwise, alkyl groups are tituted. A “substituted alkyl” group can be substituted with one or more es selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the term “cycloalkyl” 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. lkyl can include any number of carbons, such as C3_6, C4_6, C5_6, C3_g, C4_g, C5_g, and C6_g. ted monocyclic cycloalkyl rings e, for e, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.

Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbomane, [2.2.2] bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, haVing one or more double bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not d to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (l,3- and l,4-isomers), eptene, cycloheptadiene, cyclooctene, cyclooctadiene (l,3-, l,4- and l,5-isomers), norbomene, and norbomadiene. Unless otherwise stated, cycloalkyl groups are unsubstituted. A “substituted cycloalkyl” group can be substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the term ocycloalkyl” refers to a saturated ring system haVing from 3 to 12 ring members and from 1 to 4 heteroatoms selected from N, O and S.

Additional heteroatoms including, but not limited to, B, Al, Si and P can also be present in a cycloalkyl group. The heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, or 4 to 7 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as l, 2, 3, or 4, or 1 to 2, l to 3, l to 4, 2 to 3, 2 to 4, or 3 to 4. es of heterocycloalkyl groups include, but are not limited to, aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (l,2-, l,3- and l,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane hydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or ne.

Heterocycloalkyl groups are unsubstituted, but can be described, in some embodiments as substituted. “Substituted heterocycloalkyl” groups can be substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the term “heteroaryl” refers to a monocyclic or fused ic or tricyclic aromatic ring assembly ning 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, O or S. Additional heteroatoms including, but not limited to, B, Al, Si and P can also be t in a heteroaryl group. The heteroatoms can be oxidized to form moieties such as, but not limited to, -S(O)— and -S(O)2-. Heteroaryl groups can include any number ofring atoms, such as, 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or to 12 ring members. Any suitable number of heteroatoms can be included in the aryl groups, suchas l,2,3,4,or5,or l t02, l to 3, l to4, l toS,2to3,2to4,2toS,3to4,or3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. Examples of heteroaryl groups include, but are not limited to, e, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine -, 1,2,4- and 1,3,5- isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. aryl groups are unsubstituted, but can be described, in some embodiments as substituted. “Substituted heteroaryl” groups can be substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the term “alkoxy” refers to an alkyl group haVing an oxygen atom that connects the alkyl group to the point of attachment: z'.e., alkyl-O-. As for the alkyl portion, alkoxy groups can have any suitable number of carbon atoms, such as C1_6 or C1_4.

Alkoxy groups e, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, utoxy, pentoxy, hexoxy, etc. Alkoxy groups are unsubstituted, but can be bed, in some embodiments as tuted. “Substituted alkoxy” groups can be substituted with one or more moieties selected from halo, hydroxy, amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the terms “halo” and “halogen” refer to fluorine, chlorine, bromine and iodine.

As used herein, the term “pharmaceutically acceptable” refers to a substance that is compatible with a compound or salt as described herein, as well as with any other ingredients with which the compound is formulated. Furthermore, a pharmaceutically able substance is not deleterious to the recipient of the substance.

As used herein, the term “salt” refers to an acid or base salt of a compound described herein. Pharmaceutically acceptable salts can be derived, for e, from mineral acids chloric acid, hydrobromic acid, oric acid, and the like), organic acids (acetic acid, propionic acid, glutamic acid, citric acid and the like), and nary ammonium ions. It is understood that the pharmaceutically able salts are non-toxic.

Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference. The neutral form of a compound may be regenerated by ting the salt with a base or acid and isolating the parent compound in the conventional .

As used , the term “pharmaceutical composition” refers to a product comprising a compound or ceutically acceptable salt described herein, an excipient as defined herein, and other optional ingredients in specified amounts, as well as any product which results directly or indirectly from ation of the specified ingredients in the specified amounts.

As used herein, the term “excipient” refers to a substance that aids the administration of an active agent to a subject. Pharmaceutical excipients include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors.

One of skill in the art will recognize that other excipients can be useful.

[0022] As used herein, the terms “treat,” “treating” and “treatment” refer to any indicia of success in the treatment or amelioration of a pathology, injury, condition, or symptom related to hypertrophic cardiomyopathy, including any objective or subjective ter such as abatement; remission; diminishing of symptoms; making the pathology, injury, condition, or symptom more tolerable to the patient; decreasing the frequency or duration of the pathology, injury, condition, or symptom; or, in some ions, preventing the onset of the pathology, injury, ion, or symptom. Treatment or amelioration can be based on any objective or subjective parameter; including, e.g, the result of a physical examination.

III. Compounds and Pharmaceutically Acceptable Salts Thereof In one aspect, provided is a compound having the formula: 1010 or a pharmaceutically able salt thereof.

In the above formula, R1 is a member ed from C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl-Cl-C4 alkyl, 4- to 7-membered heterocycloalkyl, phenyl, phenyl-C1-C4 alkyl, 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl-Cl-C4 alkyl, wherein each R1 is optionally substituted with from 1-3 Ra; R2 is a member ed from phenyl, phenyl-Cl-C4 alkyl, 5- to 6-membered heteroaryl and 5- to 6-membered heteroaryl-Cl-C4 alkyl, wherein each R2 is optionally substituted with from 1-5 Rb; R3 is a member selected from C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7-membered heterocycloalkyl wherein each R3 is ally tuted with from 1-3 RC; R4 is H; X is a member selected from H and halo, and in selected embodiments is selected from H and F. Each Ra ,when present, is independently selected from halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, , -Cl-C4 alkyl, phenyl-Cl-C4 , phenoxy, -CORa1, c0211“, 602R“, — SOZNRalRaZ, and -CONRa1Ra2, wherein each R211 and R812 is independently selected from H, C1-C4 alkyl and phenyl, or optionally R211 and R812 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring. Similarly, each Rb, when present, is independently selected from halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenoxy, phenyl-C1-C4 alkoxy, methylenedioxy, difluoromethylenedioxy, -CORb1, -C02Rb1, -SOsz1, b1Rb2, CONRble2,NRb1Rb2, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted with oxo, wherein each Rb1 and sz is ndently selected from H and C1-C4 alkyl or optionally Rb1 and sz when attached to a nitrogen atom are combined to form a 4- to 6- ed ring; and each RC, when present, is independently selected from halo, hydroxyl and C1-C2 alkoxy.

In some embodiments, R1 is ed from C1-C8 alkyl, C3-C8 cycloalkyl, 4- to 7- membered heterocycloalkyl, phenyl, or 5- to 6-membered heteroaryl, wherein each R1 is optionally substituted with from 1-3 Ra. R2 is phenyl, which is optionally substituted with from 1-5 Rb. R3 is selected from C1-C4 alkyl, C3-C4 cycloalkyl, or 4- to 7-membered cycloalkyl, wherein each R3 is optionally substituted with from 1-2 RC. R4 is H, and X is H or F. In some embodiments, each Ra, when present, is independently halo, CN, C1-C4 alkyl, C1-C4 alkoxy, -CORa1, c0211“, 602R“, -SOZNRa1Ra2, or -CONRa1Ra2, wherein each R211 and R812 is independently H or C1-C4 alkyl. Alternatively, Rall and Raz, when attached to a 11ll nitrogen atom, are optionally ed to form a 4- to 6- membered ring. Each Rb, when present, is independently halo, CN, C1-C4 alkyl, C1-C4 alkoxy, , 1, -SOsz1, - SOZNRbleZ, eZ, NRbleZ, 5- to 6-membered heteroaryl, or 5- to ered heterocyclyl optionally substituted with oxo, wherein each Rb1 and sz is independently H or C1-C4 alkyl. Alternatively, Rb1 and sz, when attached to a nitrogen atom, are optionally combined to form a 4- to 6- membered ring. Each RC, when present, is independently halo or C1-C2 alkoxy.

In some embodiments, X is H.

In some embodiments, R1 is C3-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycloalkyl, wherein each R1 is optionally substituted with from 1-2 Ra.

In some embodiments, R1 is phenyl or 5- to 6-membered heteroaryl, wherein each R1 is optionally substituted with from 1-3 Ra.

In some embodiments, R1 is C3-C4 alkyl, C3-C5 cycloalkyl, or 4- to 6-membered heterocycloalkyl.

[0030] In some embodiments, R1 is 4- to 6-membered heterocycloalkyl, ally substituted with from 1—2 Ra selected from C1-C4 alkyl, C1-C4 , -CORa1, c0211“, 602R“, —so2 NRalRaZ, and -CONRa1Ra2, wherein each R211 and R812 is independently H or C1-C4 alkyl.

In some ments, R1 is cyclobutyl, isopropyl, isobutyl, 1-methoxypropanyl, cyclopentyl, cyclohexyl, 4-tetrahydropyranyl, hylsulfonyl)piperidinyl, l- (methoxycarbonyl)piperidinyl, 4,4-difluorocyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 3- isoxazolyl, 5-isoxazolyl, or l-methylpyrazolyl.

In some embodiments, R2 is optionally substituted with from 1-2 Rb.

In some embodiments, R2 is phenyl, 3-methylphenyl, 2-fluorophenyl, 3- fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl, 3-chlorophenyl, 3- methoxyphenyl, 3-(3-oxazolidinonyl)phenyl, 3-(2-methyl-l-imidazyl)phenyl, 3-(l- pyrazolyl)phenyl, or 3-(1 ,2,4-triazol- l -yl)phenyl.

In some embodiments, R3 is C1-C4 alkyl, C1-C4 alkoxyalkyl, or C3-C4 cycloalkyl.

In some embodiments, R3 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl or 2- methoxymethyl. 1212 In some embodiments, R3 is methyl.

The compounds or ceutically acceptable salts described herein can have any ation of the R1, R2, R3, R4, Ra, Ral, Raz, Rb, Rbl, sz, RC, and X groups recited above.

Selected ments recited for R2, for example, can be combined with any of the selected embodiments recited for R1 which, in turn, can be combined with any of the selected embodiments d for R3 .

In some embodiments, for example, R1 is C3-C8 alkyl; R3 is C3-C4 cycloalkyl or 4- to 7-membered heterocycloalkyl; and R2 is phenyl. In other embodiments, R1 is 4- to 7- membered cycloalkyl or 5- to 6-membered heteroaryl which is optionally substituted with C1-C4 alkyl, -C02Ra1, -SOZNRa1Ra2, or 602R“; R3 is C3-C4 cycloalkyl or 4- to 7- membered heterocycloalkyl; and R2 is . In still other embodiments, R1 is C3-C8 cycloalkyl or phenyl, R3 is C3-C4 cycloalkyl or 4- to 7-membered heterocycloalkyl; and R2 is phenyl.

In other embodiments, R1 is C3-C8 alkyl; R3 is C1-C4 alkyl; and R2 is phenyl. In yet other embodiments, R1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl which is optionally substituted with C1-C4 alkyl, @0211“, or some”; R3 is C1-C4 alkyl; and R2 is . In still other embodiments, R1 is C3-C8 cycloalkyl or phenyl; R3 is C1-C4 alkyl; and R2 is phenyl.

In some embodiments, R1 is C3-C8 alkyl; R3 is C3-C4 cycloalkyl or 4- to 7- membered heterocycloalkyl; and R2 is phenyl substituted with 1-2 C1-C4 alkoxy or halo. In still other embodiments, R1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered aryl which is optionally substituted with C1-C4 alkyl, £0211“, or 602R“; R3 is C3-C4 cycloalkyl or 4- to 7-membered cycloalkyl; and R2 is phenyl substituted with 1-2 C1- C4 alkoxy or halo. In yet other embodiments, R1 is C3-C8 cycloalkyl or phenyl; R3 is C3-C4 lkyl or 4- to 7-membered heterocycloalkyl; and R2 is phenyl substituted with 1-2 C1- C4 alkoxy or halo.

In some embodiments, R1 is C3-C8 alkyl; R3 is C1-C4 alkyl; and R2 is phenyl substituted with 1-2 C1-C4 alkoxy or halo. In other embodiments, R1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl which is optionally substituted with C1-C4 alkyl, -C02Ra1, or 602R“; R3 is C1-C4 alkyl; and R2 is phenyl substituted with 1-2 C1-C4 alkoxy or halo. In other embodiments, R1 is C3-C8 cycloalkyl or phenyl; R3 is C1-C4 alkyl; and R2 is phenyl substituted with 1-2 C1-C4 alkoxy or halo. 13l3 In some embodiments, R1 is C3-C8 alkyl; R3 is C3-C4 cycloalkyl or 4- to 7- membered heterocycloalkyl; and R2 is phenyl substituted with 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl optionally substituted with oxo. In other embodiments, R1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl which is optionally substituted with C1-C4 alkyl, -C02Ra1, or 602R“; R3 is C3-C4 lkyl or 4- to 7- membered cycloalkyl; and R2 is phenyl substituted with 5- to 6-membered heteroaryl or 5- to ered heterocyclyl optionally substituted with oxo. In other embodiments, R1 is C3-C8 cycloalkyl or phenyl, R3 is C3-C4 cycloalkyl or 4- to ered heterocycloalkyl; and R2 is phenyl substituted with 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl optionally substituted with 0X0.

In some embodiments, R1 is C3-C8 alkyl; R3 is C1-C4 alkyl; and R2 is phenyl substituted with 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl optionally substituted with oxo. In other embodiments, R1 is 4- to 7-membered heterocycloalkyl or 5- to ered heteroaryl which is optionally substituted with C1-C4 alkyl, -C02Ra1, or 602R“; R3 is C1-C4 alkyl; and R2 is phenyl substituted with 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl optionally tuted with oxo. In other embodiments, R1 is C3-C8 cycloalkyl or phenyl; R3 is C1-C4 alkyl; and R2 is phenyl substituted with 5- to 6- membered heteroaryl or 5- to 6-membered heterocyclyl optionally substituted with oxo.

In some embodiments, R1 is C3-C8 alkyl; R3 is C3-C4 cycloalkyl or 4- to 7- membered heterocycloalkyl; and R2 is phenyl substituted with CN, C1-C4 alkyl, , -C02Rb1, -SOsz1, -SOZNRb1Rb2, CONRbleZ, or NRbleZ. In other embodiments, R1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl which is ally tuted with C1-C4 alkyl, @0211“, or 602R“; R3 is C3-C4 cycloalkyl or 4- to ered heterocycloalkyl; and R2 is phenyl substituted with CN, C1-C4 alkyl, -CORb1, 1, -SOsz1, CONRbleZ, or NRbleZ. In other embodiments, R1 is C3- C8 cycloalkyl or phenyl; R3 is C3-C4 lkyl or 4- to 7-membered heterocycloalkyl; and R2 is phenyl substituted with CN, C1-C4 alkyl, -CORb1, -C02Rb1, -SOsz1,CONRb1Rb2,or NRbleZI In some embodiments, R1 is C3-C8 alkyl; R3 is C1-C4 alkyl; and R2 is phenyl substituted with CN, C1-C4 alkyl, -CORb1, -C02Rb1, -soszl, CONRbleZ, or NRbleZ. In other embodiments, R1 is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroaryl which is optionally substituted with C1-C4 alkyl, @0211“, or 602R“; R3 is C1-C4 alkyl; and 1414 R2 is phenyl substituted with CN, C1-C4 alkyl, -CORb1, 1, -SOsz1, CONRbleZ, or . In other embodiments, R1 is C3-C8 cycloalkyl or phenyl; R3 is C1-C4 alkyl; and R2 is phenyl substituted with CN, C1-C4 alkyl, -CORb1, -C02Rb1, -SOsz1, CONRbleZ, , or -CONRa1Ra2.

In some embodiments, R1 is isopropyl; R2 is optionally substituted with l-2 Rb; and R3 is methyl.

In some embodiments, R1 is 4- to ered heterocycloalkyl, optionally substituted with from 1—2 Ra selected from C1-C4 alkyl, C1-C4 alkoxy, -CORa1, £0211“, 602R“, —so2 Z, and -CONRa1Ra2, wherein each R211 and R812 can independently be H or C1-C4 alkyl; R2 is optionally substituted with l-2 Rb; and R3 is methyl.

In some embodiments, R1 is phenyl or 5- to 6-membered heteroaryl, wherein each R1 is optionally substituted with from l-3 Ra; R2 is optionally substituted with from l-2 Rb; and R3 is methyl.

[0049] 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, compounds provided herein with an identified stereochemistry (indicated as R or S, or with dashed or wedge bond designations) will be understood by one of skill in the art to be substantially free of other isomers (e.g., at least 80%, 90%, 95% up to 100% free of the other isomer).

[0050] In some embodiments, the compound is selected from: (S)-3 -isopropyl(( l -phenylethyl)amino)pyrimidine-2,4( l H,3H)-dione; (S)—5-fluoro-3 -isopropyl((l -phenylethyl)amino)pyrimidine-2,4( lH,3H)-dione; (S)—5-bromoisopropyl(( l -phenylethyl)amino)pyrimidine-2,4( l H,3H)-dione; (S)(( l -(3 -chlorophenyl)ethyl)amino)fluoro-3 opylpyrimidine-2,4( l H,3H)-dione; (S)(( l -(3 ,5 -difluorophenyl)ethyl)amino)-3 -isopropylpyrimidine-2,4( l H,3H)-dione; (S)((cyclopropyl(phenyl)methyl)amino)isopropylpyrimidine-2,4( l H,3H)-dione; (S)((cyclopropyl(3-methoxyphenyl)methyl)amino)isopropylpyrimidine-2,4( l H,3H)- dione; ((cyclobutyl(phenyl)methyl)amino)isopropylpyrimidine-2,4( l H,3H)-dione; (S)(( l -(3 -fluorophenyl)ethyl)amino)-3 -(tetrahydro-2H-pyranyl)pyrimidine-2,4( l H,3H)- dione; 1515 (S)(( l -(3 -rneth0xyphenyl)ethyl)arnino)-3 -(tetrahydr0-2H-pyranyl)pyrirnidine- ,3H)—dione; 6-(((S)- l -phenylethyl)arnino)—3 -(tetrahydr0furan-3 -yl)pyrirnidine-2,4( lH ,3H)-di0ne; (S)-3 -(l -(rnethylsulfonyl)piperidin—4-yl)—6-(( l -phenylethyl)amino)pyrirnidine-2,4 ( l H,3H)- dione; methyl (S)—4-(2 ,6-di0xo(( l lethyl)arnin0)-3 ,6-dihydr0pyrirnidin- 1 (2H)- yl)piperidine- l -carb0xylate; 3 -((R)-sec-butyl)(((S)- l -(3-rnethoxyphenyl)ethyl)arnin0)pyrirnidine-2,4( lH,3H)-di0ne; (S)—6-(( l -phenylethyl)arnino)-3 din—3 -yl)pyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -(isoxazol-3 -yl)(( l -phenylethyl)arnin0)pyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(3 -( l H-pyrazol- l -yl)phenyl)ethyl)amin0)-3 -isopr0pylpyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -isopropyl(( l -(3 -rnethoxyphenyl)ethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; (S)-3 -isopropyl(( l -(2-rnethoxyphenyl)ethyl)amino)pyrimidine-2,4( l di0ne; (S)-3 -isopr0pyl(( l -phenylpropyl)arnino)pyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -isopr0pyl-5 -rnethyl((l -phenylethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; (S)(( l -(2-flu0r0phenyl)ethyl)amin0)-3 opylpyrimidine-2,4( lH,3H)-di0ne; (( l -(3 -fluor0phenyl)ethyl)amin0)-3 -isopropylpyrimidine-2,4( lH,3H)-di0ne; (S)(( l -(3 -chlor0phenyl)ethyl)amin0)-3 -isopr0pylpyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(4-flu0r0phenyl)ethyl)amin0)-3 -isopropylpyrimidine-2,4( -di0ne; (S)—5-fluoro-3 -isopropyl((l -phenylpropyl)amino)pyrirnidine-2,4( 1 H,3H)-dione; (S)-5 -fluor0(( l -(3 -flu0r0phenyl)ethyl)amino)—3 -isopr0pylpyrirnidine-2,4( l H,3H)-di0ne; (S)fluoro-3 -isopropyl((l -(3 -rnethoxyphenyl)ethyl)amino)pyrirnidine-2,4( lH,3H)-di0ne; (( l -(2 ,5 -difluorophenyl)ethyl)amin0)-3 -isopr0pylpyrimidine-2,4( l di0ne; (S)—6-(( l -(3 -br0rn0phenyl)ethyl)amino)-3 -isopr0pylpyrimidine-2,4( l H,3H)-di0ne; (S)-3 -ethyl((l -phenylpropyl)amino)pyrirnidine-2,4( l di0ne; (S)—3 -cyclopr0pyl(( l -phenylethyl)amino)pyrirnidine-2,4( l H,3H)-di0ne; (S)—6-(( l -phenylethyl)arnino)-3 -(pyridin—2-yl)pyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -( 1 -methyl- 1 zol-3 -yl)((l -phenylethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; (S)-3 -(isoxazol-5 -yl)(( l -phenylethyl)arnin0)pyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(3 -( l H-l ,2,4-triazol- l -yl)phenyl)ethyl)arnino)-3 -isopropylpyrirnidine-2,4( l H,3H)- dione; (S)—3 -isopr0pyl((l -(3 -(2-methyl- 1 H-imidazol- l -yl)phenyl)ethyl)arnino)pyrirnidine- 2,4(1H,3H)—dione; 16l6 (S)-3 -isopr0pyl(( l -(3 -(2-oxooxazolidin-3 -yl)phenyl)ethyl)amino)pyrirnidine-2,4( lH,3H)- dione; (S)-3 -cyclohexyl(( l -phenylethyl)amino)pyrirnidine-2,4( lH,3H)-di0ne; (S)-3 -phenyl((l -phenylethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; (S)-3 -ethyl((l -phenylethyl)arnino)pyrirnidine-2,4( l di0ne; (S)-3 -rnethyl(( l -phenylethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; (S)(( l -phenylethyl)arnino)-3 -propylpyrirnidine-2,4( l H,3H)-di0ne; (S)—3 -(3 ,5 -diflu0r0phenyl)(( l -phenylethyl)arnino)pyrirnidine-2 ,4( l H,3H)-di0ne; (S)-3 -isopropyl(( l -(rn-tolyl)ethyl)amino)pyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(4-flu0r0phenyl)propanyl)amin0)-3 -isopr0pylpyrirnidine-2,4( l H,3H)-di0ne; (R)-3 -isopr0pyl((2,2,2-trifluor0- l -phenylethyl)amino)pyrirnidine-2,4( lH,3H)-di0ne; 3 -((R)- l yloxy)pr0panyl)(((S)- l -phenylethyl)arnino)pyrirnidine-2,4( l H,3H)- dione; 3 -((R)- l -hydroxypr0panyl)(((S)- l lethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; (S)-3 -isopr0pyl((l -(3 -(triflu0rornethyl)phenyl)ethyl)arnino)pyrirnidine-2,4( l H,3H)-di0ne; (S)( l -(( l -isopropyl-2 x0- l ,2 ,3 ,6-tetrahydr0pyrirnidinyl)amino)ethyl)benzonitrile (S)-3 -benzyl((l lethyl)amino)pyrirnidine-2,4( lH,3H)-di0ne; (S)—3 -(2 ,6-difluorophenyl)(( l -phenylethyl)arnino)pyrirnidine-2 ,4( l H,3H)-di0ne; (S)(( l -(2 ,6-difluorophenyl)ethyl)amin0)-3 -isopr0pylpyrimidine-2,4( l H,3H)-di0ne; (S)-3 -isopropyl(( l -(pyridinyl)propanyl)arnin0)pyrirnidine-2,4( l H,3H)-di0ne; (S)(( l enzyloxy)phenyl)ethyl)amino)—3 -isopr0pylpyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(4-hydr0xyphenyl)ethyl)amin0)isopr0pylpyrimidine-2,4( l di0ne; (R)((2-(benzyloxy)— l -phenylethyl)amin0)-3 -isopr0pylpyrirnidine-2,4( l H,3H)-di0ne; (S)—3 -(6-rnethylpyridinyl)—6-(( l -phenylethyl)amino)pyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -(2,2-difluoroethyl)(( l -phenylethyl)amino)pyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(benz0 [d] [l ,3 ] dioxol-S -yl)ethyl)arnin0)—3 -(2,2,2-trifluor0ethyl)pyrirnidine- 2,4(1H,3H)—dione; (S)-3 -isopr0pyl(( l -(0-tolyl)ethyl)amino)pyrirnidine-2,4( l H,3H)-di0ne; (S)—3 -cyclobutyl(( l -phenylethyl)amino)pyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -isopr0pyl((l -(2-(trifluor0rnethyl)phenyl)ethyl)arnino)pyrirnidine-2,4( l di0ne; (S)—3 -(l -rnethylcyclopr0pyl)(( l lethyl)amino)pyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(3 -( l H-imidazol- l -yl)phenyl)ethyl)arnino)-3 -isopr0pylpyrirnidine-2,4( l H,3H)- dione; (S)(( l -phenylethyl)arnino)-3 dazinyl)pyrirnidine-2,4( l H,3H)-di0ne; 17l7 (S)(( 1 -phenylethyl)arnino)-2H- [1 ,5 '-bipyrirnidine] -2,6(3H)-di0ne; (S)—6-((1-phenylethyl)arnino)-3 -(pyraziny1)pyrirnidine-2,4(1H,3H)-di0ne; (S)-3 -isopropy1—6-(( 1 -(pyridin-3 -y1)ethyl)amino)pyrirnidine-2,4(1H,3H)-di0ne; (S)-3 -(1-rnethy1—1H-pyraz01—4-yl)((1-phenylethyl)amino)pyrirnidine-2,4(1 H,3H)-di0ne; (S)-3 -isopropy1—6-((1-pheny1buty1)arnino)pyrirnidine-2,4( 1 H,3H)—di0ne; 6-(((S)—1-phenylethyl)arnino)-3 -((R)-tetrahydr0-2H-pyran-3 -y1)pyrirnidine-2,4(1 H,3H)- dione; (S)-3 -cyc10penty1—6-((1-phenylethyl)amino)pyrirnidine-2,4(1H,3H)-di0ne; (S)-3 -isopr0py1—6-((2-methylphenylpropy1)arnino)pyrirnidine-2,4( 1 H,3H)—di0ne; (S)-3 -(4,4-difluorocyc10hexy1)—6-((1-phenylethyl)amino)pyrirnidine-2,4( 1 H,3H)—di0ne; (S)-3 -(pentan-3 -y1)((1-phenylethy1)arnino)pyrirnidine-2 ,4(1H,3H)-di0ne; (S)-3 -( 1 -benzoylpiperidiny1)(( 1 -phenylethy1)amino)pyrimidine-2,4( 1 di0ne; (S)-3 -isopr0py1—6-((4-phenylbutany1)amino)pyrimidine-2,4(1 H,3H)-di0ne; methyl (S)—2-(2 xo(( 1 -phenylethy1)amin0)-3 ,6-dihydr0pyrirnidin- 1 (2H)-y1)acetate (S)-3 -isopropy1—6-(( 1 -pheny1pr0pany1)amino)pyrimidine-2,4( 1 H,3H)—di0ne; 3 -((S)—1-(benzyloxy)propanyl)(((S)phenylethyl)amino)pyrirnidine-2,4(1H,3H)- dione; 3 -((S)—1-hydr0xypr0pany1)(((S)pheny1ethyl)arnino)pyrirnidine-2,4(1H,3H)-di0ne; (R)((2-hydr0xyphenylethyl)arnino)isopr0pylpyrimidine-2,4(1H,3H)-di0ne; 6-(((S)—1-phenylethyl)arnino)-3 1 ,1 , 1-trifluor0pr0pany1)pyrirnidine-2,4(1H,3H)- dione; 6-(((S)—1-phenylethyl)arnino)-3 -((S)— 1 , 1 , 1 or0pr0pany1)pyrirnidine-2 ,4( 1 H,3H)- dione; 6-(((S)phenylethyl)arnino)-3 4-trifluor0butany1)pyrirnidine-2,4( 1 H,3H)—di0ne; (S)((1-phenylethyl)arnino)-3 -(2,2,2-trifluoroethy1)pyrirnidine-2,4(1H,3H)-di0ne; (S)-3 -(tert-buty1)((1 -phenylethyl)amino)pyrirnidine-2,4(1H,3H)-di0ne; (S)-3 -(2-rneth0xyethy1)—6-((1 -phenylethy1)amino)pyrimidine-2,4( 1 H,3H)—di0ne; 6-(((S)— 1 -pheny1propyl)amino)-3 -((S)-1,1,1-triflu0ropropany1)pyrirnidine-2,4(1H,3H)- dione; 3 -((R)cyclopropylethyl)(((S)phenylethyl)amino)pyrirnidine-2,4( 1 H,3H)-di0ne; 3 -((S)cyclopr0pylethy1)—6-(((S)phenylethyl)amino)pyrirnidine-2,4(1H,3H)-di0ne; ((cyc10buty1(phenyl)rnethyl)amin0)-3 -ethy1pyrirnidine-2,4(1H,3H)-di0ne; (S)((1-(benzo[d][1,3]di0x01-5 -y1)ethy1)arnino)—3 -isopropy1pyrirnidine-2,4(1H,3H)-di0ne; (S)((1-(benzo[d][1,3]diox01-5 -y1)ethy1)arnino)—3-ethy1pyrimidine-2,4(1H,3H)-di0ne; 1818 (S)(( l -phenylpr0pyl)amin0)-3 -(2,2,2-triflu0roethyl)pyrirnidine-2,4( l H,3H)-di0ne; (S)—3 -(cyclopropylrnethyl)(( l -phenylethyl)arnino)pyrirnidine-2,4( l H,3H)-di0ne; (S)((cyclopropyl(phenyl)rnethyl)amin0)-3 -(2,2,2-trifluoroethyl)pyrirnidine-2,4( lH,3H)- dione; (S)((cyclobutyl(phenyl)rnethyl)amin0)-3 -(2,2,2-trifluoroethyl)pyrirnidine-2,4( lH,3H)- dione; (S)-3 -(l ,3 -dihydroxypr0panyl)(( l lethyl)arnino)pyrirnidine-2,4( l H,3H)-di0ne; 6-(((S)— l -(4-flu0r0phenyl)propanyl)amino)—3 -((S)— l , l , l -trifluoropr0panyl)pyrirnidine- 2,4(1H,3H)—dione; (S)(( l -(3 -hydroxyphenyl)ethyl)amin0)-3 0pylpyrimidine-2,4( l H,3H)-di0ne; 6-(( l -(2-hydr0xyphenyl)ethyl)amino)isopr0pylpyrimidine-2,4( l H,3H)-di0ne; (S)(( l -phenylethyl)arnino)—3 -( l -(triflu0r0rnethyl)cyclopropyl)pyrirnidine-2,4( l H,3H)- dione; (S)—3 -(3 ,5 -diflu0r0phenyl)—6-(( l -(4-fluor0phenyl)propanyl)amino)pyrimidine-2,4( l H,3H)- dione; (S)(( l -(2,2-diflu0robenzo [d] [ l ,3 ] dioxol-S hyl)arnin0)-3 -isopr0pylpyrirnidine- 2,4(1H,3H)—dione; (S)(( l -(2-chlor0phenyl)ethyl)amin0)-3 0pylpyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -isopropyl(( l -(4-rnethoxyphenyl)ethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; ((cyclopropyl(phenyl)rnethyl)arnino)-3 -ethylpyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(3 -chlor0phenyl)ethyl)amin0)-3 -ethylpyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -ethyl((l -(3 -(triflu0rornethyl)phenyl)ethyl)arnino)pyrirnidine-2,4( l H,3H)-di0ne; (S)—3 -(cyclopropylrnethyl)(( l -(3 -flu0r0phenyl)ethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; (S)—3 -(cyclopropylrnethyl)((l -(3 -(triflu0rornethyl)phenyl)ethyl)amino)pyrirnidine- ,3H)—dione; (S)(( l -(3 -chlor0phenyl)ethyl)amino)—3 -(cyclopropylrnethyl)pyrirnidine-2,4( l H,3H)-di0ne; (S)—5 -chloro(( l -(2,2-difluorobenzo [d] [ l ,3 ] dioxol-S -yl)ethyl)arnino)—3 - pylpyrimidine-2,4( l H,3H)-di0ne; (S)(( l -(3 -fluor0phenyl)ethyl)amino)—3 -pr0pylpyrirnidine-2,4( l H,3H)-di0ne; (S)(( l -(3 0phenyl)ethyl)amin0)-3 -pr0pylpyrirnidine-2,4( l H,3H)-di0ne; (S)-3 -pr0pyl(( l -(3 -(trifluorornethyl)phenyl)ethyl)amino)pyrimidine-2,4( l H,3H)-di0ne; (S)—3 -cyclobutyl(( l -(4-flu0r0phenyl)ethyl)arnino)pyrirnidine-2,4( l H,3H)-di0ne; (S)(( l dr0xyphenyl)ethyl)amin0)isopr0pylpyrimidine-2,4( l H,3H)-di0ne; (S)(( l -(3 ,4-difluor0phenyl)ethyl)amin0)-3 -ethylpyrirnidine-2,4( lH,3H)-di0ne; 19l9 3 -((S)-sec-butyl)(((S)- l -(4-fluorophenyl)ethyl)amino)pyrimidine-2,4( l H,3H)-dione; (S)(( l -(4-fluorophenyl)ethyl)amino)propylpyrimidine-2,4( l H,3H)—dione; and (S)-3 oropyridinyl)—6-(( l -phenylethyl)amino)pyrimidine-2,4( l H,3H)—dione, or a pharmaceutically acceptable salt of any of the above.

[0051] In some embodiments, the compound is selected from . fix '01“ flip A0, and @W or a pharmaceutically acceptable salt thereof.

The compounds or pharmaceutically able salts described herein (1) can be prepared via any suitable method. Compounds can be prepared, for example, by the route ed in Figure 1. As shown in Figure 1A, a pyrimidine trione V can be synthesized via condensation of a urea iii with a malonate iv. The urea iii can be ed via reaction of an amine i with an appropriate cyanate ii. The pyrimidine trione V is derivatized with a suitable leaving group (Lg) to provide intermediate vi. The leaving group can be, but is not limited to, a halogen such as a chloride or iodide. A halogenated intermediate vi can be prepared 2020 from pyrimidine triones by methods such as those bed by Brown (The Chemistry of Heterocyclic Compounds, The Pyrimidines, John Wiley & Sons, 2009). ediates vi can be converted to compounds of formula I via reaction with amines vii. Certain chiral amines can be prepared from a ketone or aldehyde ix as shown in Figure 1B; a sulf1nyl imine xii derived from the ketone or aldehyde can be reacted with a Gringard t xiii to provide a chiral amine vii. One of skill in the art will iate that the nds described herein can be prepared via other methods, such as those described by LaRock (Comprehensive Organic Transformations.‘ A Guide to Functional Group Preparations, Wiley, 1999).

IV. Compositions

[0053] Also provided is a pharmaceutical composition containing a compound or pharmaceutically acceptable salt described herein and a ceutically acceptable excipient. The compositions may be useful for treating hypertrophic cardiomyopathy in humans and other subjects.

The pharmaceutical compositions for the administration of the compounds or pharmaceutically acceptable salts described herein may conveniently be presented in unit dosage form and may be prepared by any of the methods 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 ients. In l, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition, the active agent is generally included in an amount sufficient to e the desired effect upon myocardial contractility (i.e. to decrease the often supranormal systolic contractility in HCM) and to improve left ventricular relaxation in diastole. Such improved tion can alleviate symptoms in hypertrophic cardiomyopathy and other etiologies of diastolic dysfunction. It can also ameliorate the s of diastolic ction causing impairment of coronary blood flow, improving the latter as an adjunctive agent in angina pectoris and ischemic heart disease. It can also confer benefits on ry left ventricular remodeling in HCM and other causes of left ventricular hypertrophy due to chronic volume or pressure overload from, e.g., valvular heart disease or ic hypertension.

The pharmaceutical compositions containing the active ient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, 2121 dispersible powders or granules, emulsions, hard or soft capsules, syrups, elixirs, solutions, buccal patch, oral gel, chewing gum, chewable s, effervescent powder and effervescent s. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may n one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating , for e, corn starch, or alginic acid; binding agents, for e PVP, cellulose, PEG, starch, gelatin or acacia, and ating agents, for e magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated, enterically or ise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay al such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated to form c therapeutic tablets for controlled release.

[0056] ations for oral use may also be ted as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

Additionally, emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as iglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture with excipients le for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring atide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy- ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation ts of ethylene 2222 oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The s suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or rin.

Oily suspensions may be formulated by suspending the active ingredient in a ble oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may n a thickening agent, for example beeswax, hard in or cetyl alcohol. ning agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for ation of an aqueous suspension by the addition of water provide the active ingredient in ure with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable sing or wetting agents and suspending agents are exemplified by those already mentioned above.

Additional excipients, for example sweetening, flavoring and ng agents, may also be present.

The pharmaceutical compositions described herein may also be in the form of oil- in-water ons. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or l esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for e polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. Oral solutions can be ed in combination with, for example, cyclodextrin, PEG and surfactants. 2323 The ceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic erally-acceptable diluent or solvent, for example as a solution in l,3-butane diol. Among the able vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed ing synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of inj ectables.

The compounds or pharmaceutically acceptable salts described herein may also be administered in the form of itories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary atures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene s. Additionally, the compounds or pharmaceutically acceptable salts can be administered via ocular delivery by means of solutions or ointments. Still filrther, transdermal delivery of the subject compounds or pharmaceutically acceptable salts can be accomplished by means of iontophoretic patches and the like. For topical use, creams, ointments, s, solutions or sions, etc., containing the nds or pharmaceutically acceptable salts described herein are employed. As used herein, topical application is also meant to include the use of mouth washes and gargles.

The compounds or pharmaceutically acceptable salts described herein may also be coupled to a carrier that is a suitable polymer for targetable drug rs. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide- phenol, droxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds or pharmaceutically acceptable salts described herein may be coupled to a carrier that is a biodegradable polymer useful in achieving controlled e of a drug, such as polylactic acid, polyglycolic acid, copolymers of polylactic and ycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels. Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like. 2424 V. Methods of treating cardiac disorders The mutations that lead to HCM cause significant perturbations in myosin mechanics. These ons exert their effects Via distinct mechanisms depending on their locations in the myosin gene. The well-studied HCM ons, R403Q and R453C, are located in different sections of the motor domain and cause distinct mechanistic perturbations that lead to the common outcome of increased force production. t wishing to be bound by any particular theory, it is believed that the compounds or pharmaceutically acceptable salts described herein can bind directly to the mutant sarcomeric proteins and correct for their aberrant fimction, either in 02's (by affecting the same specific function) or in trans (by ng a complementary function). As such, they can provide eutic benefit for HCM patients by counteracting the hypercontractile and/0r impaired relaxation associated with this disease. .

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

The compounds of the invention or their pharmaceutically acceptable salts can alter the natural history of HCM and other diseases rather than merely palliating symptoms. The mechanisms conferring al benefit to HCM patients can extend to patients with other forms of heart disease sharing similar pathophysiology, with or without demonstrable genetic influence. For example, an effective treatment for HCM, by improving ventricular relaxation during diastole, can also be effective in a broader population characterized by diastolic dysfunction. The compounds of the invention or their pharmaceutically acceptable salts can specifically target the root causes of the conditions or act upon other downstream pathways. Accordingly, the nds of the invention or their pharmaceutically able salts can also confer benefit to patients suffering from diastolic heart e with preserved ejection fraction, ischemic heart disease, angina pectoris, or ctive myopathy. Compounds of the invention or their pharmaceutically acceptable salts can also promote salutary ventricular ling of left ventricular hypertrophy due to volume or re overload; e.g, chronic mitral regurgitation, c aortic is, or chronic systemic hypertension; in conjunction with therapies aimed at correcting or alleviating the primary cause of volume or pressure ad (valve repair/replacement, effective 2525 antihypertensive therapy). By ng left ventricular filling pressures the compounds could reduce the risk of pulmonary edema and respiratory failure. Reducing or eliminating functional mitral regurgitation and/or lowering left atrial pressures may reduce the risk of paroxysmal or permanent atrial fibrillation, and with it reduce the attendant risk of arterial thromboembolic complications including but not limited to cerebral arterial embolic stroke. ng or ating either c and/or static left ventricular outflow obstruction may reduce the likelihood of requiring septal reduction therapy, either surgical or percutaneous, with their attendant risks of short and long term complications. The compounds or their pharmaceutically acceptable salts may reduce the severity of the chronic ischemic state associated with HCM and thereby reduce the risk of Sudden Cardiac Death (SCD) or its lent in patients with table cardioverter-defibrillators (frequent and/or repeated ICD discharges) and/or the need for potentially toxic antiarrhythmic medications. The compounds or their ceutically acceptable salts could be valuable in reducing or eliminating the need for concomitant medications with their attendant potential toxicities, drug-drug interactions, and/or side effects. The compounds or their pharmaceutically acceptable salts may reduce interstitial myocardial fibrosis and/or slow the progression, , or reverse left ventricular hypertrophy.

Depending on the disease to be treated and the subject’s condition, the compounds or pharmaceutically acceptable salts described herein may be administered by oral, parenteral (e. g., uscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection, or implant), by implantation (e.g., as when the compound or ceutically acceptable salt is d to a stent device), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit ations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and es appropriate for each route of administration.

In the treatment or prevention of conditions which require improved cular relaxation during diastole, an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.

In some embodiments, the dosage level will be about 0.01 to about 25 mg/kg per day; in some embodiments, about 0.05 to about 10 mg/kg per day. A suitable dosage level may be 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 may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per 2626 day. In some embodiments, for oral stration, the compositions are provided in the form of tablets containing 1.0 to 1000 milligrams of the active ient, particularly 1.0, .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 the active ingredient for the matic adjustment of the dosage to the patient to be treated. The compounds or pharmaceutically able salts may be administered on a regimen of l to 4 times per day, in some embodiments, once or twice per day.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound or pharmaceutically acceptable salt employed, the metabolic stability and length of action of that compound or pharmaceutically acceptable salt, the age, body weight, hereditary teristics, general health, sex and diet of the subject, as well as the mode and time of administration, rate of excretion, drug ation, and the severity of the particular condition for the subject undergoing y.

[0071] nds and compositions ed herein may be used in combination with other drugs that are used in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds and compositions provided herein are useful.

Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound or composition provided herein. When a compound or composition provided herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound or composition provided herein is preferred. Accordingly, the pharmaceutical compositions provided herein include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound or composition provided herein.

Suitable additional active agents include, for example: therapies that retard the progression of heart failure by down-regulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), [3- blockers, aldosterone receptor antagonists, or neural endopeptidase inhibitors); ies that improve cardiac function by stimulating cardiac contractility (e.g., positive pic , such as the B-adrenergic agonist dobutamine or the phosphodiesterase inhibitor milrinone); and therapies that reduce cardiac d (e.g., diuretics, such as furosemide) or afterload ilators of any class, including but not limited to calcium channel blockers, phosphodiesterase tors, endothelin receptor antagonists, renin inhibitors, or smooth 2727 muscle myosin modulators). The weight ratio of the compound provided herein to the second active ingredient may be varied and will depend upon the effective dose of each ingredient.

Generally, an effective dose of each will be used.

VI. Examples Abbreviations: aq: aqueous BBrg: boron tribromide CHzClzi dichloromethane CHgCN: acetonitrile CHgOH: ol DIAD: diisopropyl azodicarboxylate DIEA: diisopropyl ethylamine DMF: dimethyl formamide DMSO: dimethyl sulfoxide equiv.: equivalents Eth: triethylamine EtzO: diethyl ether EtOH: ethanol FeSO4: s sulfate h: hour(s) HCl: hydrogen chloride H20: water K2C03C potassium carbonate KHSO4: potassium bisulfate KNCO: potassium isocyanate LiBr: lithium e MgSO4: magnesium sulfate mL: iter MW: microwave (reaction done in microwave reactor) NaCl: sodium chloride NaH: sodium hydride NaHCOg: sodium bicarbonate NaOEt: sodium ethoxide NaOH: sodium hydroxide NaOMe: sodium methoxide NaZSO4: sodium sulfate NH4Cl: ammonium de NMP: n-methyl pyrrolidinone pH: -log [H+] POClg: 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 Exam le 1. Pre aration of Iso ro l l- hen leth 1 amino rimidine-2 4g lH,3H)—dione. 4/ o l ocw’ '\ JL k —> H2N N CH2C12 H

[0072] Compound 1.1. Isopropylurea. To a stirred solution of isopropylamine (15.3 g, 0.258 mol, 1.0 equiv) in CHzClz (200 mL) under argon at 0 0C was added dropwise trimethylsilyl isocyanate (30 g, 0.26 mol, 1.0 . The resulting mixture was allowed to reach ambient ature and stirred overnight. After cooling to 0 CC, CHgOH (100 mL) was added dropwise. The resulting solution was stirred for 2 hours (h) at room temperature and then concentrated under reduced pressure. The crude e was recrystallized from CH30H:Et20 (l :20) to yield 15.4 g (58%) the title nd as a white solid. LC/MS: m/z (ES+) 103 (M+H)+.

CH2(COOM9)2 H NaOMe, MeOH, reflux fi/ILKO HZNANKO O M O 2929 Compound 1.2. ropyl barbituric acid. To a stirred solution of 1.1 (14.4 g, 0.14 mol, 1.00 equiv) in CHgOH (500 mL) were added dirnethyl 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 overnight at 65 CC. After cooling to ambient temperature and then to 0 CC, the pH was carefully adjusted to 3 using aqueous concentrated 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 CHzClz/CHgOH (20: 1) as eluent to yield 16.8 g (50%) of the title compound as a white solid. . LC/MS: m/z (ES+) l7l (M+H)+.1 1H-NMR (300 MHz, d6-DMSO): 5 11.19 (s, 1H), 4.83 (m, 1H), 3.58 (s, 2H), 1.32 (d, J = 6.0 Hz, 6H). 0 k 0 fit: Pool3 0 ”kg TEBAC fiNk CI N/gO Compound 1.3. 6-chloroisopropylpyrimidine-2,4(1H,3H)—dione. To a 100- mL bottom flask containing compound 1.2 (11.4 g, 66.99 mmol, 1.00 equiv) under argon were added triethylbenzylammonium chloride (21.3 g, 93.51 mmol, 1.40 equiv) and POC13 (30 mL). The resulting mixture was stirred ght at 50 CC. After cooling to room temperature, the mixture was concentrated under reduced re. The residue was dissolved in CHzClz (150 mL) followed by slow on of H20 (100 mL). The phases were separated and the organic layer was washed with H20 (100 mL), dried with anhydrous Na2S04, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography using EtOAc/petroleum ether (1 :1) as eluent to yield 5.12 g (40%) of the title nd as a light yellow solid. 1H-NMR (300 MHz, d6-DMSO): 5 12.22 (s, 1H), 5.88 (s, 1H), 4.95 (m, 1H), 1.34 (d, J = 6.0 Hz, 6H). 111N ©on 0 1*“k I CI N/go Dioxane, 90°C N NAG H H

[0075] Compound 1. (S)Isopropyl((1-phenylethyl) amino) dine-2, 4(1H,3H)—dione. To a solution of 6-chloroisopropylpyrimidine-2,4(lH,3H)-dione (1.3, 3030 1.0 g, 5.31 mmol) in 1,4-dioxane (20 mL) was added -methylbenzylamine (Sigma- Aldrich, 1.43 g, 11.7 mmol, 2.2 equiv). The reaction mixture was stirred at 80 CC for 24 h.

After cooling to ambient temperature, the mixture was concentrated under reduced re.

The residual was taken up in EtOAc (70 mL) and washed with aqueous 1N HCl (2 X 50 mL) and brine (40 mL). The organic layer was dried with anhydrous Na2S04 and then concentrated under reduced pressure to half the original volume to yield 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 yield 1.0 g (69%) ofthe title compound as a white solid. LC/MS: m/z (ES+) 274 (M+H)+. 1H-NMR (400 MHz, O): 8 9.77 (s, 1H), 7.32 (m, 4H), 7.24 (m, 1H), 6.50 (d, J: 6.8 Hz, 1H), 4.87 (m, 1H), 4.52 (m, 1H), 4.31 (d, J=6.8 Hz, 1H), 1.37 (m, 3H ), 1.24 (m, 6H). 1H NMR (400 MHz, CDgOD) 5 ppm 7.39-7.20 (m, 5H), 5.01 (m, 1H), 4.48 (m, 1H), 1.49 (d, J = 6.7 Hz, 3H), 1.36 (m, 6H).

Exam le 2. Pre aration of Fluoroiso ro l 1- hen leth lamino ne- 2,411H,3H)-dione (2).

O k 63 _. 0N1 - N CH3COOH + rt]-—» @fis To a solution of 1 (80 mg, 0.293 mmol) in acetic acid (2.0 mL) was added fluor (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 hexanes to give 6 mg (7%) of the title compound as a white solid. LC/MS: m/z (ES+) 292 (M+H)+. 1H NMR (400 MHz, CD30D)C 5 ppm 7.36-7.24 (m, 5H), 5.04-4.97 (m, 1H), 4.94-4.88 (m, 1H), 1.54 (d, J = 8.0 Hz, 3H), 1.39 (m, 6H). 3131 Exam le 3. Pre aration of Bromoiso ro l 1- hen leth lamino rimidine- 2,41 1H,3H)-dione 13!.

CH3C02H To a solution of 1 (55 mg, 0.201 mmol) in acetic acid (1.0 mL) was added N- uccinamide (35 mg, 0.196 mmol). The mixture was stirred at room temperature for 1 hour. It was then concentrated under reduced pressure. The residue was purified by a silica gel column, eluted with 0-40% EtOAc in hexanes to give 52 mg (74%) of the title compound as a white solid. LC/MS: m/z (ES+) 352, 354 (M+H, bromine pattem)+. 1H-NMR (400 MHz, CDC13)5 ppm 8.96 (br s, 1H), 7.43-7.28 (m, 5H), 5.28 (d, J = 7.4 Hz, 1H), 5.14 (m, 1H), 4.87 (m, 1H), 1.62 (d, J = 6.7 Hz, 3H), 1.45-1.39 (m, 6H).

Exam le 4. Pre n of 1- ro hen leth lamino fluoro iso ro l rimidine-2 4 1H 3H -dione. thinNaOMe,MeOH, reflux Compound 4.1. 5-Flu0r0isopropylpyrimidine—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 CHgOH (15 mL) were 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 was stirred for 4 h in an oil bath heated at 85 CC. The reaction was cooled to 0 oC and was quenched with careful addition of concentrated HCl, adjusting to pH=2 with the addition of excess concentrated HCl. The reaction mixture was concentrated under reduced re and the resulting residue was dried for 18 h under high vacuum to provide 2.65 g of the title nd (98%). 1H-NMR (400 MHz, CDC13)C 8 ppm 5.53 (d, J = 24.0 Hz, 1H), 4.91 (m, 2H), 1.46 (m, 6H). 3232 FfiNk0”*0 I ”/KO POCI3 o TEBAC FfiNko Compound 4.2. 6-Chlorofluoroisopropylpyrimidine—2,4(1H,3H)—dione.

To a lOO-mL round-bottom flask equiped with a reflux sor containing 4.1 (2.65 g, 0.014 mmol, 1.00 equiv) were added triethylbenzylammonium chloride (4.50 g, 0.019 mmol, 1.40 equiv) and POC13 (25 mL). The on mixture was stirred for 4 h at 50 CC and then was cooled to room temperature. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in CHzClz (50 mL). Water (50 mL) was added slowly and the layers were separated. The organic layer was washed a second time with H20 (100 mL), dried with anhydrous MgSO4, and concentrated under reduced pressure. The ing residue was d by flash chromatography (silica gel, 30% EtOAc in hexanes) to yield 2.67 g (93%) of the title compound as a white solid. 1H-NMR (400 MHz, CDClg): 8 ppm .05 (m, 2H), 1.48 (d, J=7.04 Hz, 6H). o UF k : 3 F CI : fiN N + NH —> 3 2 I WP. 95°C N/gO H H H CI\©/\N Compound 4. (S)((1-(3-Chlorophenyl)ethyl)amino)fluoro isopropylpyrimidine—2,4(1H,3H)-dione. To a solution of 4.2 (150 mg, 0.70 mmol, 1 equiv) in DMF (2 mL) contained in a heavy wall pressure vessel were added (S)CthI'O-0.- 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 0C for 3 h behind a blast shield. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by ative RP- HPLC ing a Shimadzu, Prominence LC-20AP system equipped with a Phenomenex Gemini-NX C18 column (eluting with 10-90% CH3CN/H20 in 30 min., 20 mL/min (both containing 0.1% TFA)). The fractions containing 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)+. 1H-NMR (400 MHz, CDClg) 8 ppm 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 = 5.9 Hz, 1H), 1.59 (d, J = 6.7 Hz, 3H), 1.43 (m, 6H). 3333 Exam le 5. Pre aration of l- 3 5-Diflu0ro hen leth lamino iso r0 1 rimidine-2 4 1H 3H -dione.

O *8/0/ >L /OS/ NH2 /N PPTS, M9804, CHzclz F F F F Compound 5.1. ((R,E)-N-(3,5-difluorobenzylidene)—2-methylpropane sulfinamide. To a solution of 3,5-difluorobenzaldehyde (l .00 g, 7.04 mmol, 1.00 equiv) in CHzClz (20 mL) were added pyridinium p-toluenesulfonate (0.089 g, 0.35 mmol, 0.05 equiv), (R)-(+)methylpropanesulfinamide (0.852 g, 7.03 mmol, l.00 equiv), and MgSO4 (4.2 g, 35.00 mmol, 5.00 equiv). The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered and concentrated under reduced re. The ing residue was purified by flash chromatography a gel, 20% EtOAc in petroleum ether) to provide 500 mg (29%) of the title compound as a yellow oil. >LS/O >LS/O / N CHgMgBr //,,_ CHZCIZ Compound 5.2. (R)-N-((S)(3,5-difluorophenyl)ethyl)methylpropane—Z- sulfinamide. Methylmagnesium bromide (5. 17 mL, 3M, 2.00 equiv) was added dropwise to a solution of 5.1 (1.9 g, 7.75 mmol, l.00 equiv) in CHzClz (50 mL) under argon at -48 oC.

The reaction mixture was warmed to room temperature and stirred overnight. The reaction was carefully quenched with a saturated aqueous NH4Cl solution (20 mL). The layers were separated and the s layer was fiarther extracted with CHzClz (3 x 50 mL). The combined organic layers were dried over ous MgSO4 and concentrated under reduced pressure to provide 13 g (64%) of the title compound as a yellow oil. 1H NMR (300 MHz, CDClg): 5 ppm .81 (m, 2H), 6.75-6.65 (m, 1H), .55, (m, 1H), 3.46-3.42 (m, 1H), 1.53-1.44 (m, 3H), 1.26-1.22 (m, 9H). 3434 i ‘0 NH2HCI a,“ NH 4N HCI in 1 4-dioxane MeOH F F Compound 5.3. (S)(3,5-Difluorophenyl)ethan-l-amine hydrochloride. To a on of 5.2 (1.3 g, 4.97 mmol, 1.00 equiv) in CH30H (10 mL) was added 4N HCl in 1,4- e (2.67 mL, 2.00 equiv). The reaction mixture was stirred for 0.5 h at room temperature and then was concentrated under reduced re. The resulting residue was ved in CHgOH (3 mL) and EtzO (300 mL) was added. The resulting precipitate was isolated by filtration to provide 0.80 g (83%) of the title compound. 1H NMR (300 MHz, D20): 5 ppm 6.98-6.83 (m, 3H), 4.45-4.38 (m, 1H), 1.51-1.48 (d, J = 6.9 Hz, 3H).

E N n,“ NH2 1) 1N NaOH : I A N m o Compound 5. (S)((1-(3,5-Difluorophenyl)ethyl)amino) isopropylpyrimidine—2,4(1H,3H)—dione. Compound 5.3 (50 mg, 0.32 mmol, 1.00 equiv) was dissolved in 1N NaOH (lOmL), and the resulting mixture was stirred at 25 CC. After 1 h, the mixture was ted with EtOAc (5 x 10 mL). The combined c layers were dried with anhydrous Na2S04, filtered, and concentrated under reduced pressure. The resulting residue and compound 1.3 (35.6 mg, 0.19 mmol, 0.60 equiv) were combined. The mixture was stirred at 100 0C for 18 h, then was 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 (300 MHz, DMSO-d6): 5 ppm 9.83 (s, 1H), 7.06-7.12 (m, 3H), 6.54 (d, J = 6.6 Hz, 1H), 4.91-4.82 (m, 1H), 4.54-4.46 (m, 1H), 4.30 (m, 1H), 1.34 (d, J = 6.6 Hz, 3H), 1.22 (d, J = 6.9 Hz, 6H). 3535 Exam le 6. Pre aration of C clo r0 1 hen lmeth lamino iso r0 1 rimidine-2 4 1H 3H -dione. o fl\s/O/ i /OS’ NH2 / N PPTS, M9804, CHchZ Compound 6.1. (R,E)—N-benzylidenemethylpropane-Z-sulfinamide. The title compound was prepared in the same manner as 5.1 except benzaldehyde (5.0 g, 47. 12 mmol, 1.00 equiv) was used in place of 3,5-difluorobenzaldehyde to e 2.8 g (28%) of the title compound. 1H NMR (300 MHz, d6-DMSO): 8 ppm 8.62 (s, 1H), 7.89-7.87 (m, 2H), 7.55- 7.49 (m, 3H), 1.31 (s, 9H).

Compound 6.2. (S)-N-((S)-Cyclopropyl(phenyl)methyl)methylpropane—Z- sulfinamide. The title compound was prepared using a protocol similar to that used for the preparation of 5.2 except 6.1 (1.0 g, 4.78 mmol, 1.00 equiv) and cyclopropylmagnesium bromide (9.6 mL, lM, 2.00 equiv) were used in place of 5.1 and methylmagnesium bromide to provide 0.5 g (35%) of the title nd as a yellow oil. 1H NMR (300 MHz, DMSO- d6): 5 ppm 7.36-7.23 (m, 5H), 3.67-3.51 (m, 2H), 1.31 (m, 10H), 0.85-0.15 (m, 4H). >ks./0 A [ti—H30 ’n. NH 4M HCIIn 1 ,4-dioxane MeOH Compound 6.3. (S)-Cyclopropyl(phenyl)methanamine hydrochloride. The title nd was prepared using a protocol similar to that used for the preparation of 5.3 except 6.2 (500 mg, 1.69 mmol, 1.00 equiv) was used in place of 5.2 to provide 220 mg (88%) of the title nd as a yellow oil. 1H NMR (300 MHz, d6-DMSO): 8 ppm 7.37-7.31 (m, 5H), 3636 3.53 (d, J = 10.0 Hz, 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).

A,“NH3 on_ 1) 1N NaOH vaNkA0 2) Dioxane, ©/—\NH ONJO\H’g Compound 6. (S)((Cyclopropyl(phenyl)methyl)amino)—3- isopropylpyrimidine—2,4(1H,3H)-dione. The title nd was prepared using a procedure similar to that used for the preparation of 5 except 6.3 (200 mg, 1.36 mmol, 1.00 equiv) was used instead of 5.3 and 1,4-dioxane was utilized as a solvent. After concentration under reduced pressure, purificaiton utilizing a chiral HPLC (Phenomenex Lux 511 Cellulose- 4, 2.12*25, 5 urn column) with an isocratic e of EtOH: Hexane (1: 4) as eluent provided 22 mg (5%) of the title nd as a white solid. LC/MS: m/z (ES+) 300 (M+H)+. 1H-NMR (300 MHz, DMSO-d6) 8 ppm 9.82 (s, 1H), .25 (m, 5H), 7.25-7.32 (m, 1H), 6.72 (m, 1H), 4.90 (m, 1H), 4.22 (s, 1H), 3.78 (m, 1H), 1.27 (m, 6H), 1.57 (m, 1H), 0.60 (m, 1H), 0.56-0.32 (m, 2H).

Exam le 7. Pre aration of c clo r0 l3-meth0x hen lmeth lamino iso r0 1 rimidine-2 4 1H 3H -dione.

/O\©A [Rafi/'11:: NMP, 130°C /O\©:m/E;ii\ A solution of 6-chloroisopropylpyrimidine-2,4(1H,3H)-dione (1.3, 50 mg, 0.265 mmol), (S)-cyclopr0pyl-(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 0C 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 H20 (both ning 0.1% TFA). The ons containing 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)+. 1H-NMR (400 MHz, CD30D): 5 3737 ppm 7.26 (t, J = 7.8 Hz, H), 6.92-6.79 (m, 3H), 5.00 (m, 1H), 3.79 (s, 3H), 3.74 (d, J = 8.6 Hz, 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).

Exam le 8. Pre aration of C clobut l hen lmeth lamino iso ro l rimidine- 2,41 lH,3H)—dione. i $0 EK/O <9.

’ \N'S PPTS, MgSO4, CH2CI2 m W< Compound 8.1. (S,E)-N-(cyclobutylmethylene)methylpropane—2- sulfinamide. To a on of cyclobutanecarbaldehyde (1.0 g, 11.89 mmol, 1.00 equiv) in CHzClz (10 mL) were added pyridinium enesulfonate (0.143 g, 0.57 mmol, 0.05 equiv), (S)-(-)methylpropanesulfinamide (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 overnight at room temperature. 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. 1H NMR (400 MHz, CDClg) 6 ppm 8.08 (d, J = 10.8 Hz, 1H), 3.36-3.32 (m, 1H), 2.25-2.16 (m, 4H), 2.03—1.90 (m, 2H), 1.15 (s, 9H).

OMgBr C \SS-‘f 9 0”” K QCN'SK Compound 8.2. (S)-N-((S)-cyclobutyl(phenyl)methyl)—2-methylpropane—Z- sulfinamide. Phenylmagnesium bromide (3M in EtzO, 15.3 mL, 2.00 equiv) was added dropwise to a solution of 8.1 (4.3 g, 22.96 mmol, l.00 equiv) in THF (40 mL). The reaction e was heated for 3 h at 65 CC. It was then cooled to room temperature and carefully quenched with a saturated aqueous NH4Cl solution (30 mL). The resulting mixture was ted with EtOAc (3 x 30 mL), and the combined organic layers were dried with anhydrous Na2S04 and concentrated under reduced pressure to provide 5.8 g (95%) of the title nd as a white solid. 1H-NMR (300 MHZ, CDClg) 5 7.30-7.21 (m, 5H), 4.23 (d, J = 9.6 Hz, 1H), .68 (m, 1H), 1.95-1.60 (m, 6H), 1.14 (s, 9H). 3838 D + _ GUI. //,' NH3 CI 4N HCI in 1 ,4-dioxane MeOH nd 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 8.2 (5.8 g, 0.022 mol, 1.00 equiv) was used in place of 5.2 to provide 3.20 g (91%)of the title nd as a white solid. 1H NMR (300 MHz, D20): 8 ppm 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). <¥>+ 1) 1N NaOH 0 2) <E> fiNk ©/\NH30|_ fiNko N N/RO | A H Cl N o ©/\H NMP, 130 °C, proton sponge Compound 8. (S)((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 1N NaOH (10 mL), and was stirred for l h at 25 CC. The reaction mixture was extracted with EtOAc (5 x 10 mL). The combined organic layers were dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The resulting residue was dissolved in NMP and combined 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 (300 MHz, CDgOD): 8 ppm 7.38-7.26 (m, 5H), 5.08-4.97 (m, 1H), 4.25 (d, J = 6.9 Hz, 1H), 2.68-2.58 (m, 1H), 2.19-2.13 (m, 1H), 1.98-1.83 (m, 5H), 1.36 (d, J = 6.9 Hz, 6H).

Exam le 9. Pre n of l- hen leth lamino tetrah - ran l rimidine-2 4 1H 3H .

HZN KNCO H2N\n/ H20 0 O Compound 9.1. 1-(tetrahydro-2H-pyranyl)urea. A mixture of tetrahydro-2H- pyranamine (5.0 g, 49.4 mmol, 1.0 equiv.) and potassium nate (4.0 g, 49.5 mmol, 1.0 equiv.) was refluxed in H20 (5 OmL) overnight. The reaction was cooled to room temperature and excess NaCl was added to help saturate the aqueous layer. The precipitate 3939 was isolated by filtration to provide the desired product (1 .28g, 8.88 mmol). The aqueous layer was washed with EtOAc (3x 15 mL) and then was concentrated and azeotroped with toluene (3 x 100 mL). The ing solid was suspended in 1:4 CHgOH:EtOAc (100 mL) and filtered a total of four times. The combined organics were trated under reduced pressure and combined with the ed precipitate to provide 5.01 g (70%) of the title compound. LC/MS: m/z (ES+) 145 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8 6.14 (d, J = 7.5 Hz, 1H), 5.47 (s, 2H), 3.85 (dt, J = 11.6, 3.6 Hz, 2H), 3.65-3.52 (m, 1H), 3.38 (td, J = 11.4, 2.2 Hz, 2H), 1.80-1.72 (m, 2H), 1.42-1.27 (m, 2H).

H2N\n/N 0 t EtOH reflux NA;0 Compound 9.2. 1-(tetrahydr0-2H-pyranyl)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 oC overnight, and then was cooled to room temperature. The reaction mixture was diluted with H20 (5 mL), and excess KHSO4 was added to te the aqueous layer. The reaction mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were dried with anhydrous MgSO4, d and concentrated under reduced pressure. The resulting e was purified by flash chromatography (silica gel, 0-25% CHgOH in ) to provide1.57 g of a mixture containing the title compound which was used without further purification. LC/MS: m/z (ES- ) 211 (M-H)‘.

NA/OO . O Pool3 CHgCN CI N o Compound 9.3. 6—chlor0(tetrahydro-2H-pyranyl)pyrimidine-2,4(1H,3H)— dione. To a solution of 9.2 (1.57 g, 7.4 mmol, 1 equiv.) in CH3CN (15 mL) was added POC13 (0.551 mL, 5.9 mmol, 0.8 equiv.). The reaction mixture was stirred at 80 OC overnight. An additional aliquot of POC13 (0.4 equiv.) was added and the reaction mixture was stirred at 80 0C for 3h. Additional ts of POC13 (0.4 equiv.) were added after 3 h 4040 and 5 h of stirring at 80 CC. The on mixture was then stirred at 90 CC for 1h. The reaction was cooled to room temperature, concentrated, swirled with EtZO (15 mL) and decanted. The resulting residue was rinsed with EtZO (15 mL) and decanted until the EtZO decanted clear. The resulting residue was carefully suspended in CH30H (10 mL), and filtered. The filtrate was concentrated to obtain a mixture of ng material and the title compound (~85% pure, 1.6 g). LC/MS: m/z (ES-) 229 (M-H)‘.

Clfi/KON neat, 90°C 1”“ ©/\N NAG H H Compound 9. (S)((1-phenylethyl)amin0)(tetrahydr0-2H-pyran-4— yl)pyrimidine—2,4(1H,3H)-di0ne. A mixture of 9.3 (0.15 g, 0.65 mmol, 1 equiv.) and (S)-(-)- ylbenzylamine (470 mg, 3.88 mmol, 6.0 equiv.) was stirred overnight at 90 oC. The reaction mixture was cooled to room temperature and the resulting residue was purified by preparative RP-HPLC (0-40% CH3CN in H20 in 30 min.), followed by a second purification on a preparatory TLC plate (2000 um) (7% CHgOH in CHzClz) to provide 23 mg (11%) of the title compound. LC/MS: m/z (133+) 316 (M+H)+. 1H NMR (400 MHz, DMSO-d6): 5 ppm .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 = 12.1 Hz, 2H), 2.63-2.39 (m, 2H), 1.40 (d, J = 6.7 Hz, 3H), 1.35-1.16 (m, 2H).

Exam le 10. Pre aration of 1- 3-methox hen leth lamino tetrah dro-2H- ran l ne-2 4 1H 3H -dione 10 . o 0 O O ,PrOHzHZO fig : 4:1 N /O _ N —> 5 fi + NHZ /0 ‘ I k 120°C, 2 h N 0 UN N o H H H To a solution of 9.3 (0.58 g, 0.25 mmol) in a mixture of 2-propanol and H20 (4:1, 1 mL) was added (S)(3-methoxyphenyl)-ethylamine (0.113 g, 0.75 mmol, 3.0 ). The reaction mixture was heated to 120 CC for 2 h. After cooling, the reaction e was concentrated under reduced pressure, dissolved in CH30H and d. The filtrate was purified by preparative C (20-100% CH3CN in H20 in 40 min. at 25 mL/min.) to 4141 provide 18 mg (21%) of the title compound as an off-white solid. LC/MS: m/z (ES+) 346 (M+H)+. 1H NMR (400 MHz, acetone-d6) 8 8.90 (s, 1H), 7.15 (dd, J = 8.3, 8.1 Hz, 1H), 6.88 (s, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.68 (d, J = 8.1 Hz, 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 = 6.6 Hz, 3H) 1.15 (m, 2H).

Exam le 11. Pre aration of 6- hen leth 1 amino tetrah drofuran l rimidine-2 4 1H 3H -dione.

O O SEMCI, LiBr NH I r NaH, NMP NA0 CI I?! o H SEM Compound 11.1. 6-chlor0((2-(trimethylsilyl)eth0xy)methyl)pyrimidine— 2,4(1H,3H)—di0ne. To a mixture of 6-chloro-uracil (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 0C was added NaH (60% dispersion in mineral oil, 0.82 g, 20.5 mmol, 1.0 equiv.). The reaction mixture was stirred at 0 CC for 10 min, and 2-(trimethylsilyl)ethoxymethyl chloride (3.75 g, 22.5 mmol, 1.1 equiv.) was slowly added via an addition funnel. The reaction mixture was stirred overnight at room temperature and then diluted with EtOAc (150 mL). The e was washed with a saturated s NH4Cl solution (50 mL), saturated aqueous NaHCOg (50 mL), and brine (50 mL). The organic layer was dried with anhydrous Na2S04 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 +. 1H NMR (400 MHz, CDClg): 8 ppm 9.00-8.80 (br-s, 1H), 5.95 (s, 1H), 5.45 (s, 2H)), 3.63 (t, J = 7.0 Hz, 2H), 1.48 (t, J = 7.0 Hz, 2H), 0.01 (s, 9H).

IN); PPh3 DIAD SEM ONleoSEMO “$10 Compound 11.2. ro(tetrahydrofuranyl)—1-((2- (trimethylsilyl)ethoxy)methyl)pyrimidine—2,4(1H,3H)—di0ne. To a solution of 11.1 (277 mg, 1.0 mmol, 1 equiv.), 3-hydroxytetrahydrofuran (106 mg, 1.2 mmol, 1.2 equiv.), and nylphosphine (320 mg, 1.2 mmol, 1.2 equiv.) in THF (7.5 mL) at 0 CC, was added 4242 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 ative RP-HPLC 0% CH3CN in H20 with 0.1% formic acid buffer in 40 min. at 25 mL/min.) to provide 102 mg (29%) of the title compound. LC/MS: m/z (ES+) 347 (M+H)+. 1H NMR (400 MHz, CDClg) 8 5.92 (s, 1H), 5.58 (m, 1H), 5.41(s, 2H), 4.20 (m, 1H), 4.00-3.85 (m, 3H), 3.65 (t, J = 7.0 Hz, 2H), 2.35—2.20 (m, 1H), 2.20-2.08 (m, 1H), 0.95 (t, 2H), 0.01 (s, 9H); 13C NMR(CDC13) 5 160.7, 150.7, 145.6, 102.0, 74.8, 68.7, 67.9, 67.5, 51.9, 28.7, 18.0, 0.0. it a bN TFA L) C' N 0 CI NAG SEM H Compound 11.3. 6-chlor0(tetrahydrofuranyl)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 minutes and then was concentrated under reduced pressure. The resulting residue was purified by preparative RP- HPLC (10% CH3CN in H20 in 40 min. at 25 mL/min.) to provide 300 mg (96%) of the title compound as a white solid. LC/MS: m/z (ES+) 217 (M+H)+. 1H NMR (400 MHz, DMSO- d6): 8 ppm 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).

N) m t,90°C Compound 11. 6-(((S)phenylethyl)amin0)(tetrahydr0furan yl)pyrimidine—2,4(1H,3H)-di0ne. The title compound was prepared using a procedure r to that used for the ation of 9 except 11.3 (22 mg, 0.10 mmol, 1.00 equiv) was used in place of 9.3 to provide 15 mg (50%) of the title nd as a white solid. LC/MS: m/z (ES+) 302 (M+H)+. 1H NMR (400 MHz, CDClg): 5 ppm 10.50 (1H), 7.50-7.20 (m, 5H), .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 = 6.7 Hz, 3H). 4343 Exam le 12. Pre aration of 1- meth n l i eridin l 1- hen leth lamino rimidine-2 4 1H 3H -dione.

PhCONCO 0 IN PhJLNj: 0306N Compound 12.1. tert—Butyl 4-(3-benzoylureido)piperidine—1-carboxylate. To a solution of benzoylisocyanate (4.8 g, 32.6 mmol) in CHzClz (180 mL) at 0 0C was added 4- amino-l-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 EtzO (100 mL). The precipitate was filtered and washed with EtzO to yield 5.70 g (55%) of the title compound as a white solid. LC/MS: m/z (ES+) 337 (M+H)+. o o anc N30...

)L JLN 8000 o Ph N NJLNHZ H H MeOH/HZO H Compound 12.2. tert—Butyl 4-ureidopiperidine—1-carboxylate. To a mixture of 12.1 (5.60 g, 16.1 mmol) in CHgOH (70 mL) and H20 (70 mL) was added sodium hydroxide (11.6 g, 290 mmol) portionwise. The reaction mixture was stirred at room temperature overnight and then refluxed for 1 h. The mixture was cooled to room temperature and trated under reduced pressure to remove CHgOH. The itate was filtered, washed with H20, and dried to yield 3.2 g (82%) of the title compound as a white solid. LC/MS: m/z (ES+) 266 (M+Na)+.

BocN O CH2(C020Et)2 NBoc )L NaOEt N NH2 EtOH H Ni? Compound 12.3. tert—Butyl 4-(2,4,6-trioxo-tetrahydropyrimidin-1(2H)— yl)piperidine—l-carboxylate. To a mixture of 12.2 (3.63 g, 14.9 mmol), lmalonate (2.6 mL, 16.5 mmol, 1.1 equiv.) and ous ethanol (60 mL) was added NaOEt (21% in EtOH, 6.6 mL, 17.7 mmol, 1.2 ). The mixture was refluxed for 14 h and concentrated.

The residue was taken up in H20 (15 mL) and washed with EtOAc (2 x 30 mL). The aqueous layer was separated and adjusted to pH=5 with concentrated. HCl. The precipitate was 4444 filtered, washed with H20 and dried to give 3.70 g (80%) of the title nd as an off- white solid. LC/MS: m/z (ES+) 334 (M+Na)+. o OBoc 0 OH fiN POCIa , N H20 | A o N 0 Cl N o H H

[0106] Compound 12.4. 6-chlor0(piperidinyl)pyrimidine—2,4(1H,3H)—di0ne. To a mixture of 12.3 (2.55 g, 8.19 mmol) and POC13 (10 mL, 100.65 mmol) was added H20 (0.41 mL, 22.78 mmol) dropwise. The mixture was stirred at 120 CC for 30 min and then concentrated. The residue was carefully taken up in ice water (20 g). To the e was added K2C03 (~8.0 g) portionwise until the pH was ~7. The precipitate was filtered, washed with H20 (20 mL) and EtOAc (50 mL). The resulting al was dried to yield 1.45 g (77%) of the title compound as an off-white solid. LC/MS: m/z (ES+) 230 (M+H)+. \ go CI ”&0 Eth, CHZCIZ CI ”&0 Compound 12.5. 6-chlor0(1-(methylsulfonyl)piperidinyl)pyrimidine— 2,4(1H,3H)—di0ne. To a mixture of 12.4 (380 mg, 1.65 mmol, 1.0 equiv.) and CH2Cl2 (8 mL) was added Eth (0.70 mL, 4.95 mmol, 3 equiv.) and methanesulfonyl chloride (0.23 mL, 2.5 mmol, 1.5 equiv.). The mixture was stirred at room temperature for 2 h and then quenched with H20 (3 mL) to yield precipitate. The itate was filtered and washed with CH2Cl2 (3 x 3 mL). The filtrate was concentrated to ~ 1.5 mL. Filtration of a second precipitate was followed by washing with H20 (2 x 1 mL) and CH2Cl2 (3 x 2 mL). The precipitates were combined to afford 320 mg (63%) of the title compound as an off-white solid. LC/MS: m/z (ES+) 308 (M+H)+. 4545 E \,o o N’s; - ,S’ 1* 0 WA 0 O “o N —> | N CI ”*0 Compound 12. (1-(methylsulfonyl)piperidinyl)—6-(1- phenylethylamino)pyrimidine—2,4(1H,3H)-dione. A mixture of 12.5 (20 mg, 0.065 mmol) and (S)-0c-methylbenzylamine (180 mg, 1.5 mmol, 23 equiv.) was stirred at 125 0C for 1 h.

The mixture was concentrated under reduced pressure, dissolved in CHgOH and filtered. The filtrate was d using preparative RP-HPLC eluting with linear gradient 20% to 100% CH3CN in H20 (0.1% formic acid ) 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 (400 MHz, DMSO-d6): 8 ppm 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 = 6.8 Hz, 3H).

Exam le 13. Pre aration of -meth l4- 2 6-di0x0 1- hen leth lamino -2 3- dih dro rimidin-l 6H - l i eridine-l-carbox late.

O OH 0 NJkO/ rkN M OCOCIe fiN| CI N 0 Et3N, CHZCIZ CI ”*0

[0109] Compound 13.1. Methyl 4-(4-chloro-2,6-dioxo-2,3-dihydropyrimidin-1(6H)— yl)piperidine—l-carboxylate. To a mixture of 12.4 (115 mg, 0.5 mmol, 1.0 equiv.) and CHzClz (2 mL) was added Eth (0.14 mL, 1.5 mmol, 3.0 equiv.), ed by methyl chloroformate (95 mg, 1.0 mmol, 2.0 equiv.). The e was stirred at room temperature for 1 h, diluted with CHzClz (8 mL), washed with a saturated aqueous NaHCOg solution (1 mL), H20 (1 mL), brine (1 mL), dried with anhydrous Na2S04 and concentrated to yield 105 mg (73%) of an off-white solid. LC/MS: m/z (ES+) 288 (M+H)+. 4646 NJKO/ o NJkO/ EKG Ph/KNHZ ILL/O nd 13. (S)-methyl4-(2,6-dioxo(1-phenylethylamino)—2,3- opyrimidin-1(6H)—yl)piperidine—1-carboxylate. A mixture of 13.1 (58 mg, 0.20 mmol) and (S)-oc-methylbenzylamine (240 mg, 1.5 mmol) was stirred at 120 0C 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)+. 1H-NMR (400 MHz, CDClg): 8 ppm 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 = 6.7 Hz, 3H).

Exam le 14. Pre aration of 3- R -sec-bu l -l- 3- methox hen l eth lamino rimidine-2 4 1H 3H -dione. o 1) CH2C|2 JV 2) NaOH, MeOH, H20 NH2 1 = + O N/\/ Compound 14.1. (R)sec—butylurea. Benzoyl isocyanate (5.36 g, 36.5 mmol, 1.05 equiv.) was dissolved in CHzClz (20 mL) and cooled to 0 0C in an ice bath. (R)-butan amine (2.54 g, 34.7 mmol, 1 ) in CHzClz (10 mL) was carefully added while stirring.

The mixture was allowed to stir for 3 h at room ature. After the on was deemed complete, the mixture was concentrated. The residue was suspended in EtzO (20 mL) and filtered. The solid was taken up in a 1:1 mixture of CHgOH and H20 (200 mL) followed by the addition ofNaOH (6.9 g, 174 mmol, 5 equiv.). The reaction was stirred overnight at room temperature. The CHgOH was evaporated from the solution and the resulting precipitate (1.66g, 39%) was collected. LC/MS: m/z (ES+) 117 (M+H)+. 0 E NH2 = CH2(COZOEt)2 = ocwwE N/V H A O M O 4747 Compound 14.2. (R)sec-butylpyrimidine-2,4,6(1H,3H,5H)—trione. nd 14.1 (1.66 g, 14.3 mmol, 1.0 equiv.) was ved in EtOH (10 rnL) 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 CC for 2 h and then cooled to room temperature. Water (20 rnL) was added and then EtOH was removed by evaporation. KHSO4 s) was added to saturate the aqueous layer which was then extracted with EtOAc. The combined organics were dried with anhydrous MgSO4 and concentrated to yield 1.6 g (61%) of the title compound as a crude residue which was used without further purification. LC/MS: m/z (ES-) 183 (M-H)‘.

O : NM /\/ P0013 NAG , MeCN IN/go Compound 14.3. (R)sec—butyl—6-chloropyrimidine—2,4(1H,3H)—dione. A mixture of 14.2 (1.6 g, 8.7 mmol, 1 equiv.) and POC13 (648 uL, 7.0 mmol, 0.8equiv.) in CH3CN (10 rnL) was stirred at 90 0C for 2 h. Additional POC13 (0.8 equiv.) was added and stirred at 90 0C for 3 h. The reaction was cooled to room temperature, carefully quenched with CH3OH (10 rnL), stirred for 30 minutes and purified with normal phase HPLC 0-25% CHgOH/CHzClz followed by a CH30H flush. The product and starting material co-eluted.

The mixture was trated, the residue was taken up in CH3CN (10 rnL) and POC13 (648 uL) was added. The on was stirred at 90 0C for 3 h and then cooled to room ature. The on was carefully quenched with CH30H (10 rnL) and stirred for 30 minutes. The reaction mixture was purified by normal phase HPLC with previous condition, concentrated and dried under vacuum to yield 450 mg (32%) of the title compound as an off- white solid. LC/MS: m/z (ES-) 201 (M-H)‘.

O E /O N/\/ U IHOA Compound 14. 3-(R)-sec-butyl—6-((S)—1-(3- methoxyphenyl)ethylamino)pyrimidine—2,4(1H,3H)—dione. A mixture 14.3 (150 mg, 0.74 4848 mmol, 1.0 equiv.) in neat (S)(3-methoxyphenyl)ethanamine (400 uL) was stirred overnight at 90 °C. The reaction was purified using preparative RP-HPLC on an Agilent system with a gradient of 0-40% CH3CN111 H20 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)+. 1H-NMR (400 MHz, DMSO-d6): 5 ppm 9.79 (s, 1H), 7.28 (t, J = 8.1 Hz, 1H), 6.94-6.88 (m, 2H), 6.84 (dd, J = 8.2, 1.7 Hz, 1H), 6.51 (d, J = 6.4 Hz, 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 = 6.7 Hz, 3H), 1.25 (d, J = 6.9 Hz, 3H), 0.70 (t, J = 7.4 Hz, 3H).

Exam le 15. Pre n of 1- hen leth lamino ridin l rimidine- ,3H)—dione. 1) DCM / NH2 2) NaOH, MeOH, H20 / o | A + Ph NCO | \ N \ )L N NNH2 H Compound 15.1. 1-(pyridinyl)urea. l isocyanate (3.28 g, 22.3 mmol, 1.05 equiv.) was taken up in CHzClz (30 mL) and cooled to -10 oC. Pyridinamine (2 g, 21.2 mmol, 1 equiv.) was added in portions while stirring. The e was allowed to stir for 3 h at room temperature. After the reaction was deemed complete, it was concentrated and then taken up in a 1:1 mixture of CHgOH and H20 (100 mL) ed by the addition of NaOH (4.25 g, 106.3 mmol, 5 equiv.). The reaction was allowed to stir overnight at room ature, concentrated to dryness, and then azeotroped three times with toluene. A mixture of 10% CHgOH in EtOAc (100mL) was added to the solid and stirred for 10 minutes followed by filtration. The solid was suspended and filtered two additional times. The combined filtrates were filtered once more to remove any solids that passed through the filter and concentrated. The residue was ated with EtOAc (5 mL) and dried under vacuum to yield 3.5 g of crude material (off-white solid) that was utilized without further purification.

LC/MS: m/z (ES+) 138 (M+H)+. o /N CH2(COZOEt)2 / o NaOEt N \ EtOH N NH fin] \ | 2 o N’go H H Compound 15.2. 1-(pyridinyl)pyrimidine—2,4,6(1H,3H,5H)—tri0ne.

Compound 15.1 (3.0 g, 21.8 mmol, 1.0 equiv.) was taken up in EtOH (20 mL), followed by 4949 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 ed by 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 CH30H (150 mL) was added. The precipitate was removed by filtration and the filtrate was concentrated. The resulting residue was purified flash chromatography (silica gel, 0-25% CH30H/CH2C12) to yield 1.70 g (38%) of the title compound as a light yellowish solid. LC/MS: m/z (ES+) 206 (M+H)+. fiN \ POCI3 A CH3CN fi/NK\ Cl N O o u o Compound 15.3. 6-chlor0(pyridinyl)pyrimidine—2,4(1H,3H)—dione. A mixture of 15.2 (700 mg, 3.41 mmol, 1.0 equiv.) and POC13 (255 uL, 2.7 mmol, 0.8 equiv.) in CH3CN (10 mL) was stirred at 90 0C for 2 h. Additional POC13 (0.8 equiv) was added and stirring was ued at 90 0C for 2 h. Additional POC13 (1.6 equiv.) was added followed by the careful addition of H20 (150 ul 2.5 equiv.) The reaction was stirred ght at 90 0C.

After cooling to room temperature, the mixture was filtered and the solid was carefully washed with CH30H (1 mL). Ethyl acetate (20 mL) was added to the e and the resulting precipitate was collected by filtration and dried under vacuum to yield 230 mg (30%) of the title compound as a light yellowish solid. LC/MS: m/z (ES+) 224 (M+H)+.

\ Ph/\NH2 If —» _ N\ CINO H ©/\NNOHH Compound 15. (S)(1-phenylethylamin0)(pyridinyl)pyrimidine— 2,4(1H,3H)—di0ne. A mixture of 15.3 (100 mg, 0.45 mmol, 1 equiv.) in neat (S)-(-)-oc- methylbenzylamine (500 uL) was d overnight at 100 CC. After cooling, the reaction was purified using ative RP-HPLC on an Agilent system with a nt of 0-40% CH3CN in H20 over 45 min., followed by a second purification on a preparatory TLC plate (2000 um) with 7% CH30H /CH2C12 to yield 39.5 mg (28%) of the title compound. LC/MS: m/z 5050 (ES+) 309 (M+H)+. 1HNMR (400 MHz, DMSO-d6): 8 ppm 1115 (s, 1H), 8.49 (dd, J = 4.8, 1.4 Hz, 1H), 8.34 (d, J = 2.4 Hz, 1H), 7.65-7.58 (m, 1H), 7.44 (dd, J = 8.1, 4.8 Hz, 1H), 7.37 (m, 5H), 7.26 (m, 1H), 4.61-4.53 (m, 1H), 4.48 (s, 1H), 1.39 (d, .1: 6.8 Hz, 3H).

Exam le 16. Pre aration of Isoxazol l 1- hen leth lamino rimidine- 2,4]1H,3H[-dione [16].

The title nd was prepared using ures similar to those used for the preparation of compound 15 except isoxazolamine was used in place of pyridinamine.

LC/MS: m/z (ES+) 299 . 1H-NMR (400 MHz, DMSO-d6): 5 ppm 8.96 (s, 1H), 7.38 (d, J = 3.9 Hz, 4H), 7.28 (dd, J = 8.4, 4.3 Hz, 2H), 7.10 (s, 1H), 6.63 (s, 1H), 4.74-4.52 (m, 1H), 4.48 (s, 1H), 1.44 (d, J = 6.6 Hz, 3H).

Exam le 17. Pre aration of 1- 3- 1H- razol-l- l hen leth lamino iso ro l rimidine-2 4 1H 3H -dione 17 .

The title compound was prepared by Ullman coupling (P.E. Fanta. "The Ullmann Synthesis of Biaryls". sis, 1974, 9—21) of 35 with 1H-pyrazole in the presence of copper iodide, cesium carbonate, and trans-N,N’-dimethylcyclohexane-1,2-diamine. LC/MS: m/z (ES+) 340 (M+H)+. 1H-NMR (400 MHz, CDgOD): 5 ppm 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 = 6.8 Hz, 3H), 1.37 (m, 6H).

Example 18. Preparation of Additional Pyrimidine Dione Compounds.

The compounds in Table 1 were prepared according to the examples as described above. 5151 Table 1. Corn ounds and Anal ical Data nd N0.

Observed Mass and/or Structure ---- 1H NMR Ref. Example 274 (M+H)+ 1H—NMR (400 MHz, CDgOD): 5 ppm 7.42 — 7.22 (m, 5H), 5.06 — 4.94 (m, 1H), 4.49 (m, 1H), 1.49 (d, J = 7.0 Hz, 3H), 1.36 (m, 6H). 304 (M+H)+ 1H—NMR (400 MHz, CDClg): 5 ppm .39 (br s, 1H), 7.29 _ 7.23 (m, 1H), 6.88 — 6.79 (m, 3H), 5.31 (br s, 1H), 5.09 (m, 1H), 4.78 (br s, 1H), 4.48 - 4.34 (m, 1H), 3.80 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.44 _ 1.38 (m, 6H). 304 (M+H)+ 1H—NMR (400 MHz, CDgOD): 5 ppm 7.26 (t, J = 7.9 Hz, 1H), 6.92 — 6.85 (m, 2H), 6.85 — 6.80 (m, 1H), 5.01 (m, 1H), 4.45 (d, J = 7.0 Hz, 1H), 3.79 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H), 1.37 (d, J = 7.0 Hz, 6H). 304 (M+H)+ 1H—NMR (400 MHz, CDgOD): 5 ppm 7.29 — 7.17 (m, 1 H), 7.00 (d, J=7.4 Hz, 1 H), 6.93 (m, 1 H), 5.05 — 4.97 (m, 1 H), 4.83 (s, 1 H), 4.80 — 4.74 (m, 1 H), 3.89 (s, 3 H), 1.45 (d, J=6.7 Hz, 3 H), 1.38 — 1.34 (m, 6 H). 288 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm 9.76 (br s, 1H), 7.41 — 7.13 (m, 5H), 6.50 (d, J = 7.0 Hz, 1H), 4.88 (m, 1H), 4.31 (d, J = 2.4 Hz, 1H), 4.24 (m, 1H), 1.83 — 1.58 (m, 2H), 1.35 _ 1.10 (m, 6H), 0.83 (m, 3H). 5252 Compound N0.

Observed Mass and/or Structure ---- 1H NMR Ref. Example 288 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm 7.46 — 7.29 (m, 4H), 7.27 _ 7.21 (m, 1H), 6.27 (d, J = 9.0 Hz, 1H), 6.08 (br s, 1H), .13 (m, 1H), 4.98 (m, 1H), 1.78 (s, 3H), 1.46 (m, 3H), 1.29 (m, 6H). 292 (M+H)+ 1H—NMR (400 MHz, : 5 ppm .45 (br s, 1H), 7.30 — 7.23 (m, 2H), 7.16 — 7.01 (m, 2H), 5.13 (dt,.]= 13.8, 7.0 Hz, 1H), 4.99 (br s, 1H), 4.74 — 4.63 (m, 2H), 1.55 (d, .1: 6.7 Hz, 3H), 1.43 (m, 6H). 292 (M+H)+ 1H—NMR (400 MHz, CDC13): 5 ppm .28 (br s, 1H), 7.36 — 7.28 (m, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.02 — 6.93 (m, 2H), 5.17 — 5.04 (m, 1H), 4.95 — 4.82 (m, 1H), 4.75 -4.70 (m, 1H), 4.50 — 4.40 (m, 1H), 1.53 (d, J = 7.0 Hz, 3H), 1.46 — 1.37 (m, 6H). 308 (M+H)+ 1H NMR (400 MHz, CDgOD): 5 ppm 7.39 — 7.31 (m, 2H), 7.29 — 7.23 (m, 2H), .01 (m, 1H), 4.50 (q, J = 6.7 Hz, 1H), 1.48 (d, J = 7.0 Hz, 3H), 1.37 (d, J = 7.0 Hz, 6H). 304 (M+H)+ 1H NMR (400 MHz, CDgOD): 5 ppm 7.38—7.26 (m, 5H), 5.04—4.97 (m, 1H), 4.56 (dd, J = 7.4, 3.9Hz, 1H), 3.67—3.63 (m, 1H), 3.56-3.51 (m, 1H), 3.37 (s, 3H), 1.36 (m, 6H). 5353 Compound N0.

Observed Mass and/or Structure 1H NMR Ref. Example 292 (M+H)+ 1H—NMR (400 MHz, CDgOD): 5 ppm 7.34 (m, 2H), 7.08 (m, 2H), 5.07 — 4.95 (m, 1H), 4.50 (q, .1: 6.8 Hz, 1H), 1.48 (d, .1: 6.7 Hz, 3H), 1.37 (m, 6H). 306 (M+H)+ 1H—NMR (400 MHz, : 5 ppm 9.70 (br s, 1H), 7.39 - 7.22 (m, 5H), 5.19 - .07 (m, 1H), 4.85 (br s, 1H), 4.73 — 4.61 (m, 1H), 1.88 (dq, J = 14.3, 7.0 Hz, 2H), 1.45 (m, 6H), 0.96 (t, J = 7.4 Hz, 3H). 310 (M+H)+ 1H—NMR (400 MHz, CDClg): 5 ppm 9.89 (br s, 1 H), 7.40 — 7.29 (m, 1 H), 7.13 — 6.95 (m, 3 H), 5.12 (m, 1 H), 5.02 — 4.87 (m, 1 H), 4.82 _ 4.69 (m, 1 H), 1.59 (d, J = 6.7 Hz, 3 H), 1.42 (m, 6 H), 322 (M+H)+ 1H—NMR (400 MHz, CDClg): 5 ppm 9.50 (br s, 1H), 7.30 (dd, J = 9.00, 7.83 Hz, 1H), 6.93—6.90 (m, 3H), 5.19 — 5.04 (m, 1H), 4.88 (m, 1H), 4.75 (m, 1H), 3.79 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H), 1.43 (d, J = 7.0 Hz, 6H). 310 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 5 ppm 9.74 (s, 1H), 7.32 — 7.24 (m, 2H), 7.21 _ 7.13 (m, 1H), 6.60 (s, 1H), 4.95 — 4.86 (m, 1H), 4.69 _ 4.62 (m, 1H), 4.32 (s, 1H), 1.49 _ 1.42 (d, J = 6.6 Hz, 3H), 1.28 = 6.9 Hz, 6H). — 1.26 (d, J 5454 Compound N0.

Observed Mass and/or Structure ---- 1H NMR Ref. Example 352 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 5 ppm 9.85 (s, 1H), 7.59 (s, 1H), 7.48 (m, 1H), 7.38 — 7.32 (m, 2H), 6.59 (d, J = 5.4 Hz, 1H), 4.95 _ 4.88 (m, 1H), 4.57 — 4.50 (m, 1H), 4.36 (s, 1H), 1.41 (d, J = 6.6 Hz, 3H), 1.25 (d, J = 6.9 Hz, 6H). 274 (M+H)+ 1H—NMR (300 MHz, 6): 5 ppm 9.96 (br s, 1H), 7.39—7.24 (m, 5H), 6.58 (d, J = 6.6 Hz, 1H), 4.38 (s, 1H), 4.28 (q, J = 6.9 Hz, 1H), 3.65 (q, J = 6.6 Hz, 2H), 1.78-1.66 (m, 2H), 0.99 (t, J = 6.9 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H). 272 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm 9.83 (s, 1H), 7.37 (m, 4H), 7.26 (m, 1H), 6.52 (m, 1H), 4.50 (m, 1H), 4.33 (s, 1H), 2.37 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 0.85 (m, 2H), 0.60 (m, 2H). 309 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm .92 (s, 1H), 8.57 — 8.42 (m, 1H), 7.85 (ddd, J = 7.8, 7.8, 1.7 Hz, 1H), 7.46 — 7.31 (m, 5H), 7.32 — 7.19 (m, 2H), 7.13 (m, 1H), 4.67 — 4.52 (m, 1H), 4.41 (s, 1H), 1.39 (d, J = 6.8 Hz, 3H). 312 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm 7.65 (d, J = 2.2 Hz, 1H), 7.41 — 7.35 (m, 5H), 7.32 — 7.24 (m, 1H), 6.77 (d, J = 5.9 Hz, 1H), 6.04 (d, J = 2.1 Hz, 1H), 4.63 — 4.55 (m, 1H), 4.42 (s, 1H), 3.79 (s, 3H), 1.44 (d, J = 6.7 Hz, 3H). 5555 nd N0.

Observed Mass and/or Structure 1H NMR Ref. Example 299 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm 11.07 (s, 1H), 8.93 (s, 1H), 7.43 — 7.31 (m, 4H), 7.31 — 7.04 (m, 2H), 6.59 (s, 1H), 4.62 (m, 1H), 4.43 (s, 1H), 1.40 (d, J = 6.7 Hz, 3H). 341 (M+H)+ 1H—NMR (400 MHz, CDClg): 5 ppm .42 (s, 1H), 8.67 (s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 7.61 (m, 1H), 7.51 (m, 1H), 7.37 (m, 1H), 5.41 (m, 1H), 5.13 (m, 1H), 4.68 (m, 1H), 4.55 (m, 1H), 1.59 (d, J = 6.8 Hz, 3H), 1.44 (m, 6H). 354 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm 9.85 (s, 1H), 7.52 (m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 6.94 (m, 1H), 6.60 (m, 1H), 4.90 (m, 1H), 4.62 (m, 1H), 4.38 (s, 1H), 2.26 (s, 3H), 1.44 (d, J = 9.2 Hz, 3H), 1.28 (d, J = 9.2 Hz, 6H). 359 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm 9.84 (s, 1H), 7.62 (s, 1H), 7.42 (m, 2H), 7.12 (d, J = 7.2 Hz, 1H), 6.61 (bs, 1H), 4.91 (m, 1H), 4.69 — 4.43 (m, 3H), 4.34 (s, 1H), 4.09 (m, 2H), 1.42 (d, J = 6.8Hz, 3H), 1.28 (m, 6H). 314 (M+H)+ 1H—NMR (400 MHz, CD30D): 5 ppm 7.28 — 7.13 (m, 5H), 4.52 (m, 1H), 4.39 (m, 2H), 2.22 (m, 2H), 1.69 (m, 2H), 1.54 (m, 1H), 1.44—1.40 (m, 2H), 1.40 (d, J = 6.7 Hz, 3H), 1.30 — 1.20 (m, 2H), 1.20 — 1.08 (m, 1H). 5656 Compound No.

Observed Mass and/or Structure ---- 1H NMR Ref. Example 308 (M+H)+ 1H—NMR (400 MHz, CDClg): 5 ppm 9.84 (s,1H),7.43 = — 7.17 (m, 6H), 7.12 (d, J 7.3 Hz, 2H), 7.05 (d, J = 6.8 Hz, 2H), .55 (br s, 1H), 4.68 (s, 1H), 4.25 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H).

(M+H)+ 1H—NMR (400 MHz, CD30D): 5 ppm 7.37 — 7.30 (m, 4H), 7.10 — 7.06 (m, 1H), 4.55 (s, 1H), 4.51 (q, J = 6.7 Hz, 1H), 3.81 (q, J: 7.0 Hz, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H).

(M+H)+ 1H—NMR (400 MHz, DMSO-d6): 5 ppm .02 (s, 1H), 7.38 — 7.30 (m, 4H), 7.26 — 7.22 (m, 1H), 6.56 (s, 1H), 4.52 (q, J = 6.7 Hz, 1H), 4.39 (s, 1H), 2.97 (s, 3H) 1.40 (d, J = 6.7 Hz, 3H).

Exam 1e 48. Pre aration of l- hen leth lamino r0 1 rimidine-24 1H 3H - dione. nd 48.1. 1-propylurea. To a stirred solution of n-propylamine (2.15 g, 36.5 mmol, 1.00 equiv) in CHZCIZ (35 mL) at 0 0C was added dropwise trimethylsilyl isocyanate (4.94 g (85% purity), 36.5 mmol, 1.00 equiv). The reaction e was stirred at room temperature for 72 h and was then cooled to 0 0C. The chilled mixture was quenched 5757 by the dropwise addition of CHgOH (10 mL) and was concentrated under reduced pressure.

The resulting solid was suspended in EtzO (30 mL) and was filtered. The solid was further washed with EtzO (30 mL) and dried to afford 2.0 g (38%) of the title compound as a white solid.

O CH2(COOEt)2 AL /\/ N/V H2N N NaOMe, MeOH, reflux H * O M O Compound 48.2. 1-pr0pylpyrimidine—2,4,6(1H,3H,5H)—tri0ne. To 48.1 (600 mg, 5.88 mmol, 1.00 equiv) in CHgOH (1 mL) was added diethyl malonate (960 mg, 6.0 mmol, 1.02 equiv.) and sodium methoxide (1 mL, 25% NaOCH3 in CH30H by weight). The reaction mixture was heated in the microwave reactor at 130 0C for l h. The e was cooled and the mixture was carefully adjusted to pH=3 with concentrated HCl. The volatiles were removed and H20 was added (10 mL). Solid precipitated and was filtered. It was futher washed with additional H20 (10 mL) and dried to afford 560 mg (56%) of title compopund as a white solid. nd 48.3. 6-chlor0pr0pylpyrimidine—2,4(1H,3H)—di0ne. Compound 48.2 (560 mg, 3.30 mmol) and POC13 (2 mL) were added to a heavy wall pressure vessel which was subsequently . The resulting solution was heated to 70 0C and stirred for 50 minutes behind a blast shield. The reaction mixture was cooled and trated under reduced pressure. To the resulting residue was added CHzClz (30 mL) which was then removed under reduced pressure. The on and evaporation of CHzClz (30 mL) was conducted one additional time and then the resulting residue was diluted with CHzClz (50 mL). To the organic layer was carefully added a ted aqueous NaHC03 solution (50 mL). The layers were separated and the organics were further washed with H20 (30 mL) and brine (30 mL). The organic layer was trated and purified by flash column 5858 chromatography (silica gel, utilizing 10% EtOAc in CH2C12) to afford 160 mg (26%) of the title compound as a white solid.

Dioxane, Et3N, N/\/ N o I | 130 C,2h, MW NH2 A N 0 + CI fi’go ©/\HN H Compound 48. (S)((1-phenylethyl)amino)—3-pr0pylpyrimidine—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 Eth (200 uL) and (S)-oc-methylbenzylamine (235 mg, 1.94 mmol, 2.3 equiv.). The mixture was heated in a microwave reactor at 130 0C for 2 h. The mixture was cooled and concentrated.

The resulting residue was treated with an 8:3 mixture of H20:CH3CN which resulted in precipitation. The solid was filtered and successively washed with H20 (10 mL) and EtOAc (10 mL). The solid was dried to give 67 mg (29%) of the title nd as a white solid.

LC/MS: m/z (ES+) 274 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 9.92 (br s, 1H), 7.36-7.22 (m, 5H), 6.54 (d, J = 7.0 Hz, 1H), 4.50 (quin, J = 6.7 Hz, 1H), 4.35 (s, 1H), 3.54 (dd, J = 8.0, 6.9 Hz, 2H), 1.42-1.36 (m, 5H), 0.76 (t, J = 7.6 Hz, 3H).

Exam le 49. Pre n of S 3 5-difluoro hen l 1- hen leth lamino rimidine- 2,411H,3H)—dione.

CHZCIZ Compound 49.1. -diflu0r0phenyl)urea. To a d solution of 3,5- difluoroaniline (4.0 g, 31 mmol, 1.00 equiv) in CHZClz (50 mL) under argon at room ature was added dropwise trimethylsilyl isocyanate (3.56 g, 30.90 mmol, 1.00 equiv).

The reaction mixture was stirred overnight and quenched by the dropwise addition of CHgOH (50 mL). The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography (silica gel, eluting with CHClg/CHgOH (10:1 to 5959 7: 1)) to yield 2.0 g (38%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6): 6 ppm 8.96 (s, 1H), 7.16-7.10 (m, 2H), 6.72-6.66 (m, 1H), 6.07 (br s, 2H). i CH2(COOEt)2 o ONFQ db NaOMe, MeOH reflux HNN F N/[LO Compound 49.2. 1-(3,5-diflu0rophenyl)pyrimidine—2,4,6(1H,3H,5H)-tri0ne. To a stirred solution of 49.1 (1.6 g, 0.0093 mol, 1.1 equiv) in CHgOH (20 mL) were 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 overnight at 65 CC. After cooling to ambient temperature, the pH was lly ed to 5 using aqueous 1N HCl. The resulting solution was extracted with EtOAc (3 x 50 mL). The organic layers were combined and trated under reduced pressure. The residue was washed with CHgOH (50 mL) and the resulting solid was isolated by filtration to give 700 mg (31%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6): 6 ppm 11.66 (s, 1H), 7.43-7.35 (m, 1H), 7.11-7.08 (m, 2H), 3.77 (s, 2H).

N F O NA0 H 535316h'mio Compound 49.3. 6-chlor0(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) were added triethylbenzylammonium chloride (840 mg, 1.20 equiv) and POC13 (3 mL). The resulting solution was stirred for 4 h at 50 0C. The reaction cooled and quenched by the careful addition of ice (20 mL). The pH of the solution was adjusted to 5 with 2N sodium hydroxide. The ing solution was ted with EtOAc (2 x 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 resulted in 500 6060 mg (crude) of the title compound as a white solid. 1H-NMR (400 MHz, 6): 6 ppm 12.60 (br, 1H), 7.38-7.32 (m, 1H), 7.21-7.16 (m, 2H), 6.05 (s, 1H).

E F IL —> I N F N F : ' fl| 120°C, 2 h Compound 49. (S)(3,5-diflu0r0phenyl)—6-((1-phenylethyl)amino)pyrimidine— 2,4(1H,3H)—di0ne. To 49.3 (200 mg, 0.77 mmol) was added (S)-oc-methylbenzylamine (1.5 mL). The resulting solution was stirred for 2 h at 120 0C. The reaction mixture was diluted with DMF (3 mL) and the crude product (100 mg) was purified by preparative C with the following conditions: e Prep C18 OBD Column, 5um, 19*150mm; mobile phase, H20 with FA and CH3CN (40.0% CH3CN to 90.0% in 10 min). This resulted in 21.6 mg (8%) of the title nd as a white solid. LC/MS: m/z (ES+) 344 (M+H)+. 1H- NMR (300 MHz, DMSO-d6): 8 ppm 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 (quin, J = 6.7 Hz, 1H), 4.50 (d, J = 2.0 Hz, 1H), 1.42 (d, J = 6.7 Hz, 3H).

Exam le 50. Pre aration of iso ro l 1- m-tol leth lamino rimidine- 2,411H,3H)—dione. 0 || H2N THF \'< Compound 50.1. (R,E)methyl—N-(1-(m-tolyl)ethylidene)pr0pane—2- sulfinamide. To a stirred solution of 1-(3-methylphenyl)ethanone (1.61 g, 12.0 mmol, 1.00 equiv.) and (R)-(+)methylpropanesulfinamide (1.94 g, 14 mmol, 1.33 equiv.) in THF (50 mL) was added Ti(OEt)4 (3.19 g, 14 mmol, 1.17 equiv.) dropwise. The reaction mixture was stirred for 16 h at 60 0C, cooled to room temperature, and quenched with a saturated aqueous NaHCOg solution (50 mL). The layers were separated and the aqueous layer was 6161 further extracted with EtOAc (2 x 100 mL). The combined organics were concentrated and the resulting e was purified by flash chromatography (silica gel, eluting with 0-5% CHgOH in CHzClz) to afford 1.51 g (53%) of the title compound as a white solid. LC/MS: m/z (ES+) 238 (M+H)+.

L-selectride \N‘SK *

[0131] Compound 50.2. (R)methyl-N-((S)—1-(m-tolyl)ethyl)pr0pane—2-sulfinamide.

To a solution of 50.1 (1.51 g, 6.37 mmol) in THF (30 mL) at -78 0C under an N2 atmosphere was added L-selectride ise, 10 mL, 1.0 M in THF, 10 mmol). The reaction mixture was warmed to 0 0C, d for 1 h, and carefully quenched with a saturated aqueous NH4Cl solution (30 mL). The layers were separated and the aqueous layer was further extracted with EtOAc (2 x 50mL). The combined organics were concentrated and the resulting residue was purified by flash chromatography (silica gel, eluted with 0-5% CHgOH in CHzClz) to afford 0.85 g (56%) of the title compound. LC/MS: m/z (ES+) 240 (M+H)+. @13erHCI,' EtOH/EtOAC Compound 50.3. (S)(m-tolyl)ethanamine hydrochloride. To absolute EtOH (10 mL) was added AcCl (1.5 mL, dropwise). The mixture was stirred for 10 minutes and then was added to 50.2 (0.85 g, 3.56 mmol) in EtOH (3 mL). The reaction mixture was stirred for 2 h at ambient temperature and was concentrated. The resulting solid was suspended in EtzO and d. The solid was washed with additional EtZO and dried to give 402 mg (66%) of the title nd as white solid. LC/MS: m/z (ES+) 136 (M+H)+. 6262 : - + MP-carbonate Nchl —> 2 DCM, 1h Compound 50.4. (S)(m-tolyl)ethanamine. To a stirred solution of 50.3 (205 mg, 1.20 mmol) in CHzClz (10 mL) was added MP-carbonate (1.0g, 3.18 mmol/g). The reaction mixture was stirred at room temperature for 1 h and was then filtered. The solid beads were washed with an additional 10 mL CHZClz and the combined filtrates were concentrated to give the title compound which was pushed forward t any purification. : neat,120°C : fiN U N 2.5h NH + | N N/ko 2 1 H H CI m o Compound 50. (S)isopropyl((1-(m-tolyl)ethyl)amino)pyrimidine— 2,4(1H,3H)—dione. To 50.4 med ~1.2 mmol from prevous reaction, 2.0 equiv.) in a 0.5 to 2.0 mL ave tube was added compound 1.3 (110 mg, 0.59 mmol, 1.0 equiv.). The microwave tube was sealed and heated at 120 0C behind a blast shield for 2.5 h. Upon cooling (to ~60 0C), NMP (2.5 mL) was added to the on mixture. The e was sonicated and heated (to ~60 0C) until the solid completely dissolved. The resulting solution was cooled to 40 0C and a 3:1 mixture of H20/CH3CN (5 mL) was added. A solid precipitated and was collected through filtration. The light beige solid was subsequently washed with H20 and dried to give 97 mg (57%) of the title compound as a white solid.

LC/MS: m/z (ES+) 288 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 9.73 (br s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.12-7.04 (m, 3H), 6.45 (d, J = 8.0 Hz, 1H), 4.90-4.86 (m, 1H), 4.42 (q, J = 6.7 Hz, 1H), 4.31 (d, J = 2.4 Hz, 1H), 2.29 (s, 3H), 1.36 (d, J = 6.7 Hz, 3H), 1.27-1.23 (m, 6H).

Exam le 51. Pre aration of 1- 4-fiuor0 hen 1 r0 an—2- lamino isop_r0p_ylp_yrimidine-2,4§ 1H,3H z-dione. 6363 CHZCIZ, DMAP, “(3' ,0 OH H N \ /N‘O/ | Compound 51.1. 2-(4-fluorophenyl)-N-methoxy-N-methylacetamide. To a stirred on of 2-(4-fiuorophenyl)acetic acid (15 g, 97.32 rnrnol, 1.00 equiv) in CHzClz (300mL) was added rnethoxy(rnethyl)arnine hydrochloride (11.1 g, 113.79 , 1.20 equiv), 4-dirnethylarnin0pyridine (12 g, 98.22 rnrnol, 1.00 equiv), 1-Ethyl(3- hylarninopropyl) carbodiirnide hydrochloride (28.2 g, 147.10 rnrnol, 1.50 equiv), and DIEA (37.5 g, 290.14 rnrnol, 3.00 . The resulting solution was stirred at room temperature for 16 h and then diluted with EtOAc (150 rnL). The organics were washed with aqueous 1N HCl (2 x 150 rnL) and brine (2 x 150 rnL). It was then dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude residue was purified by flash chrornatography (silica gel, eluting with EtOAc/petroleurn ether (1:3)). This resulted in 18 g (88%) of the title compound as yellow oil. 1H-NMR (400 MHz, CDClg): 8 ppm 7.29-7.25 (rn, 2H), 7.03-6.99 (rn, 2H), 3.75 (s, 2H), 3.65 (s, 3H), 3.21 (s, 3H).

F F N \ THF, -1 0°C H to RT, 1 h Compound 51.2. 2-(4-fluorophenyl)acetaldehyde. To a stirred solution of 51.1 (3 g, 15.21 rnrnol, 1.00 equiv) in THF (60 rnL) under argon at -10 0C was added LiAlH4 (1.15 g, .30 rnrnol, 2.00 equiv) in several batches UL... EXOTHERMIC REACTION). The resulting on was d for l h at room temperature before being cooled to -10 0C. The reaction was then quenched by the careful addition of a saturated aqueous NH4Cl solution (50 rnL). The resulting solid was filtered and the filtrate was extracted with EtOAc (3 x 50 rnL).

The organic layers were combined, washed with brine (50 rnL), dried with anhydrous Na2S04 and concentrated under reduced pressure to give 2.5 g (crude) of the title compound as a yellow oil.

F F O E see Ex.5 : + _ H Nchl 6464 Compound 51.3. (S)(4-fluorophenyl)propanamine hydrochloride. The title compound was synthesized according to methods described for the preparation of 5.3, utilizing 51.2 in place of 3,5-difluorobenzaldchydc. LC/MS: m/z (ES+) 154 (M+H)+. 1N NaOH KIH3CI then extract NH2 w/ EtOAc Compound 51.4. (4-fluorophenyl)propanamine. To an aqueous solution of 1N NaOH (5 mL) was added 51.3 (300 mg, 1.59 mmol). The resulting mixture was stirred for one hour at 25 0C. The resulting solution was ted with EtOAc (2 x 10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 160 mg (65%) of the title compound. LC/MS: m/z (ES+) 154 (M+H)+.

CIZNk proton sponge NMP, 100°C Compound 51. (S)((1-(4-fluorophenyl)propanyl)amino) pylpyrimidine-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 d for 5 h at 100 0C in an oil bath. The reaction mixture was concentrated under reduced pressure. The residue (100 mg) was purified by preparative RP-HPLC to afford 30 mg (19%) of the title compound as gray solid. LC/MS: m/z (ES+) 306 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 9.81 (br s, 1H), 7.27 (dd, J = 8.8, 5.6 Hz, 2H), 7.17-7.12 (m, 2H), 5.89 (d, J = 7.6 Hz, 1H), 5.00- 4.92 (m, 1H), 4.58 (s, 1H), .65 (m, 1H), 2.74 (d, J = 6.4 Hz, 2H), 1.31 (d, J = 6.8 Hz, 6H), 1.08 (d, J = 6.4 Hz, 3H).

Exam le 52. Pre aration of R iso r0 l 2 2 2-trifluoro phenylethyl [amino [pyrimidine-2,4] 1H,3H [-dione [52 [. 6565 O O Fj/F k 180°C, 40 mln- F F\]/F J\ g + N microwave, neat I ; I i ©/\NH2 CI N’go N o H ©/\NH H To a 0.2-0.5 mL microwave vial was added 1.3 (85 mg, 0.45 mmol) and (R)-2,2,2- trifluoro-l-phenylethanamine (200 uL, ). The reaction mixture sealed and heated at 180 0C in a microwave reactor for 40 minutes. The reaction mixture was cooled to ambient temperature and then NMP (1 mL) was added to completely dissolve the solid. Next, a 2:1 HzO/CHgCN mixture (6 mL) was added which resulted in precipitation. The solid was isloated by filtration, washed with H20 and dried to give 50 mg (34%) of the title compound as a white solid. LC/MS: m/z (ES+) 328 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 5 ppm 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).

Exam le 53. Pre aration of3- R benz lox ro an l S-l- phenylethyl [amino [pyrimidine-2,4] 1H,3H [-dione. - 1. OCN-Sli ,CHZCIZ JOL ; ' = H2N/\/ —> H2NOH N/\/OH 2. MeOH H Compound 53.1. (R)(1-hydroxypropan-Z-yl)urea. To a stirred on of (R)-(-)aminopropanol (0.65 g, 8.68 mmol, 1 equiv.) in CHzClz (10 mL) under N2 at 0°C was added se trimethylsilyl isocyanate (1.00 g, 8.68 mmol, 1.0 ). The reaction e was stirred overnight while slowly warming to room temperature. After cooling to 0 oC, CHgOH (10 mL) was added dropwise. The ing solution was stirred for 2 h at room temperature and was then concentrated under reduced pressure to provide the title compound (1.02 g, 99%) as a white solid.

Compound 53.2. (R)(1-(benzyloxy)pr0panyl)urea. To a suspension of sodium hydride (0.52 g, 13.2 mmol, 1.5 equiv.) in THF (10 mL) at 0 0C was added 53.1 (1.02 6666 g, 8.67 mmol, 1 equiv.). The reaction mixture was stirred for 20 minutes at 0 0C under N2 before 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 H20 (3 mL) and was extracted into EtOAc (15 mL), dried with anhydrous Na2S04, filtered, and concentrated. The ing residue was purified by flash chromatography (10% CHgOH in CH2C12) to provide 510 mg (28%) of the title compound.

LC/MS: m/z (ES+) 209 (M+H)+. 1H-NMR (400 MHz, CDClg): 6 ppm 7.42 - 7.27 (m, 5H), 4.79 (d, J = 6.7 Hz, 1H), 4.52 (d, J = 2.7 Hz, 2H), 3.91 (s, 1H), 3.51 (dd, J = 9.4, 3.9 Hz, 1H), 3.40 (dd, J = 9.2, 5.3 Hz, 1H), 1.19 (d, J = 7.0 Hz, 3H).

O O EtOMOEt : ii N/'\/OBn H N2 N/\/ o H MeOH,MW,15mIn150 c. ”*0 Compound 53.3. (1-(benzyloxy)pr0panyl)pyrimidine— 1H,3H,5H)—tri0ne. To a microwave vial containing 53.2 (0.51 g, 2.42 mmol, 1 equiv.) in CHgOH (10 mL) was added diethyl malonate (2.55 g, 2.55 mmol, 1.05 equiv.) followed by sodium ide (25% wt. soln. in CHgOH, 1.31 g, 6.06 mmol, 2.5 equiv.). The vial was capped and the reaction mixture was heated in a microwave reactor for 15 minutes at 150 CC.

After g to room temperature, the reaction mixture was ed with H20 (2 mL) and the pH was adjusted to 3 with concentrated HCl. The reaction mixture was transferred to a round bottom flask and was concentrated under reduced pressure. The resulting residue was purified by flash chromatography (5% CHgOH in CHzClz) to provide 0.62g (92%) of the title compound as a white solid. LC/MS: m/z (ES+) 277 (M+H)+. 1H-NMR (400 MHz, CDClg): 6 ppm 7.99 (s, 1H), 7.38-7.22 (m, 5H), 5.16-5.11 (m, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.45 (d, J = 12.0 Hz, 1H), 4.02 (t, J = 9.8 Hz, 1H), 3.56 (q, J = 1.57 Hz, 2H), 1.37 (d, J = 7.00 Hz, 3H). 0 E O E N/-\/OBn POCI3, TEBAC n ”ko | MW,1m|n130C. 0 CI ”*0 Compound 53.4. (R)(1-(benzyloxy)pr0panyl)—6-chloropyrimidine— 2,4(1H,3H)—di0ne. To a microwave vial containing 53.3 (0.25 g, 0.91 mmol, 1 equiv.) was 6767 added triethylbenzylammonium chloride (0.28 g, 1.26 mmol, 1.4 equiv.) and POC13 (1mL).

The vial was capped and the reaction mixture was heated in a ave reactor for 1 minute at 130 CC. The reaction mixture was transferred to a round bottom flask and was trated under reduced pressure. The resulting residue was dissolved in CHzClz (5 mL) and water (2 mL) was carefully added. The mixture was stirred for 10 minutes. The layers were separated and the c layer was dried with Na2S04, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel, 5% CH30H in CHzClz) to provide 150 mg (55%) of the title compound. LC/MS: m/z (ES+) 295 (M+H)+. 1H-NMR (400 MHz, CDClg): 8 ppm 10.27 (s, 1H), 7.36-7.20 (m, 5H), 5.32- 5.21 (m, 2H), 4.57 (d, J = 12.0 Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.10 (dd, J = 10.0, 9.2 Hz, 1H), 1.40 (d, J = 7.0 Hz, 3H).

' O : N/\/O. Bn : I i I k E N N 0 Cl N 0 MW, 10 min. 150 °C H H

[0145] Compound 53. 3-((R)(benzyloxy)pr0panyl)—6—(((S)—1- phenylethyl)amino)pyrimidine—2,4(1H,3H)-di0ne. To a microwave vial containing (S)-0L- methylbenzylamine (1.5 mL) was added 53.4 (0.12 g, 0.42 mmol). The vial was capped and the reaction mixture was heated in a microwave reactor for 10 minutes at 150 CC. After cooling, the reaction mixture was d through a plug of silica gel (10% CHgOH in CHzCl) and the filtrate was concentrated under reduced pressure. The resulting e was dissolved in CHZClz (10 mL) and was washed with 10% HCl (5 mL). The organic layer was dried with anhydrous Na2S04, filtered and concentrated to provide 150 mg (94%) of the title compound.

LC/MS: m/z (ES+) 380 (M+H)+. 1H-NMR (400 MHz, : 6 ppm 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 = 6.7 Hz, 3H), 1.37 (d, J = 7.0 Hz, 3H).

Exam le 54. Pre aration of3- R h drox ro an l S-l- phenylethyl )amino )pyrimidine-2,4g 1H,3H z-dione 1541. 6868 O E O E : N/\/OH H H H H To a solution of 53 (0.10 g, 0.26 mol, 1 equiv.) in EtOH (2 mL) was added palladium on carbon (10 wt. % loading (dry , matrix activated carbon, wet support, Degussa type, 0.025 g). The on flask was purged with nitrogen and was then fitted with a H2(g) balloon. The reaction mixture was evacuated and then filled with H2(g). This pump/purge process was repeated three times and the reaction mixture was stirred for 4 h at room temperature. After purging with nitrogen, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was suspended in CH3CN (2 mL) and the precipitate was isolated by filtration. The precipitate was dissolved in CHgClz: CHgOH (1 :1, 2 mL) and was d through a .2uM PTFE 25mm filter and was concentrated under reduced pressure to provide 27 mg (35%) of the title compound. LC/MS: m/z (ES+) 290 (M+H)+. 1H-NMR (400 MHz, : 6 ppm 9.67 (s, 1H), 7.35-7.24 (m, 5H), 5.64 (d, J = 5.5 Hz, 1H), 5.08-5.04 (m, 1H), 4.66 (s, 1H), 4.42-4.35 (m, 1H), 4.24 (s, 1H), 4.04-3.91 (m, 1H), 3.78-3.68 (m, 1H), 1.50 (d, J = 6.70 Hz, 3H), 1.35 (d, J = 7.00 Hz, 3H).

Exam le 55. Pre aration of iso ro l 1- 3- trifluorometh l hen leth lamino F O F E F F seeEx.5 : + _ F H —» F NH3CI Compound 55.1. (S)(3-(triflu0r0methyl)phenyl)ethan-l-amine hydrochloride. The title compound was synthesized according to methods bed for the preparation of 5.3, utilizing fluoromethyl)benzaldehyde in place of 3,5- difiuorobenzaldehyde. 6969 F = .>l\©/\ F NH3Cl DMSO 120°C 1**0 E13N Compound 55. (S)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 Eth (0.2 mL) and 1.3 (50 mg, 0.27 mmol, 1.00 equiv). The ing solution was stirred for 6 h at 120 0C in an oil bath. After cooling, the mixture was concentrated under reduced pressure and the resulting e (75 mg) was d by preparative RP-HPLC to give 6.5 mg (7%) of the title compound as a white solid. LC/MS: m/z (ES+) 342 (M+H)+. 1H-NMR (300 MHz, DMSO- d6): 8 ppm 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: 6.8 Hz, 3H), 1.31-1.28 (m, 6H).

Exam le 56. Pre aration of S iso r0 l 1- 2-c ano hen leth lamino rimidine- 2,41 1H,3H)—dione 1561.

Br : CF“g fiNkDZn<CN>2| ”3 Pd(PPh3)4 H H (:in4* Intermediate 56.1 was prepared using procedures similar to those for the preparation of compound 35, utilizing 1.3 and (S)-l-(2-br0m0phenyl)ethan-l-amine hydrochloride esized from the corresponding obenzaldehyde using methods described for example 6.3). To a stirred solution of 56.1 (40 mg, 0.11 mmol, 1.00 equiv, ) in DMF (2 mL) was added Zn(CN)2 (20 mg, 0.17 mmol, 1.50 equiv) and tetrakis(triphenylphosphine) palladium (131 mg, 0.11 mmol, 0.20 equiv). CA UTION‘ CYANIDE CONTAINING REACTION. The resulting solution was stirred under an argon atmosphere at 100 0C in an oil bath for 2 h. Upon cooling, the reaction was quenched with a saturated aqueous FeSO4 solution (5 mL). The ing e was diluted with EtOAc (20 mL) and washed with a saturated aqueous FeSO4 solution (2 x 20 mL). The organic layer was dried with anhydrous 7070 Na2S04, filtered, and trated under reduced pressure. The crude product (5 mg) was purified by chiral preparative HPLC with the following ions: Column, Phenomenex Lux-2 5u Cellulose-2, 30"< 150mm; mobile phase, Hexanes and EtOH (hold 50.0% EtOH in min); ing in 2.1 mg (6%) of the title compound. LC/MS: m/z (ES+) 299 (M+H)+. 1H-NMR (300 MHz, CDgCN): 8 ppm 8.59 (br s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.61-7.56 (m, 1H), 7.48-7.45 (m, 2H), 5.09-4.94 (m, 3H), 1.46 (d, J = 6.6 Hz, 3H), 1.34-1.26 (m, 6H).

Exam le 57. Pre aration of benz l 1- hen leth lamino rimidine-2 4 1H 3H - dione.

HCI OEt CN /\o NHZCI Compound 57.1. 3-eth0xy0x0(1-ethoxy)propaniminium chloride. To a stirred on of ethyl cyanoacetate (5.0 g, 44 mmol) in anhydrous EtzO (5 mL) was added absolute EtOH (3 mL). The reaction mixture was cooled to 0 0C and HCl gas was bubbled in for 10 minutes. The reaction mixture was warmed to room temperature and was stirred for 16 h. The white precipitate that formed was filtered and washed with EtzO (40 mL) and dried to give (6.99 g) the title compound as a white solid. LC/MS: m/z (ES+) 160 (M+H)+.

EtOH DIEA - CE OEt —> = | (DAN NH2 NHZCI H nd 57.2. Ethyl (S,E/Z)amin0((1-phenylethyl)amin0)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)-oc-methylbenzylamine (290 mg, 2.4 mmol). The reaction was stirred for 16 h and was concentrated. The crude was purified by flash column chromatography (silica gel, eluting with CH30H in CH2C12 (0 to 10%)) to yield 0.57 g (98%) of the title compound as a clear oil.

NMR analysis revealed that the product was a mixture of E/Z isomers. LC/MS: m/z (ES+) 235 (M+H)+. 7171 NCO a OEt ©AHN NH2 M DIEA,CH CN3 HNAO Compound 57.3. Ethyl (S,Z)(3-benzylureido)—3-((1- phenylethyl)amino)acrylate.

Two reactions were set up in parallel and later combined since both resulted in formation of product (by HPLC). In the first reaction, benzyl isocyanate (150 uL, 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 uL) was added. The reaction was stirred for an additional 10 min and was quenched with H20 (12 mL). Solid precipitated and was removed by filtration. In the second reaction, benzyl isocyanate (150 uL, 1.2 mmol) was added to a d solution of 57.2 (143 mg, 0.61 mmol) and DIEA (300 uL) in CH3CN (1 mL). After 10 min, the reaction mixture was quenched with H20 (10 mL). The resulting mixture was d with EtOAc (40 mL) and the layers were separated. To the organic layer was added the filtrate from first reaction. The layers were separated and the organics were concentrated to give the title compound which was utilized t r purification. : fiOEt M OH H A microwave BnHN 0 120°C ©2mlm Compound 57. (S)benzyl—6-((1-phenylethyl)amino)pyrimidine—2,4(1H,3H)— dione. Two ons were conducted and later combined since both resulted in formation of product (by HPLC). The first reaction utilized l/3 of crude 57.3 in CHgOH (1 mL). It was heated in a microwave reactor at 120 0C for 10 min. The remaining 2/3 of crude 57.3 in CHgOH (2 mL) was heated in a microwave reactor at 120 0C for 20 min. After cooling to ambient temperature, the reactions were combined and the CHgOH was removed under reduced pressure. A 50/50 mixture of CH3CN/H20 with 0.1% TFA (5 mL) was added to the 7272 resulting resiude. Solid precipitated and was d. 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)+. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 10.05 (br s, 1H), 7.35-7.31 (m, 4H), 7.26- 7.16 (m, 6H), 6.61 (d, J = 7.0 Hz, 1H), 4.79 (s, 2H), 4.52 (quin, J = 6.8 Hz, 1H), 4.42 (d, J = 2.3 Hz, 1H), 1.39 (d, J = 6.7 Hz, 3H).

Exam le 58. Pre aration of 2 oro hen l 1- hen leth lamino rimidine- 2,41 1H,3H)-dione 158).

@NHZ er/ELN Dioxane A0 5 F 110°C 16 h fiN| ©/\N N/go F H H

[0154] The title compound was synthesized according to a slightly modified procedure as bed in Example 50. Here, 1,4-dioxane was utilized as a solvent and the reaction was heated at 110 0C 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 (400 MHz, DMSO- d6): 8 ppm 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 = 6.7 Hz, 3H).

Exam le 59. Pre aration of 1- 2 6-difiuoro hen leth lamino iso ro l rimidine-2 4 1H 3H .

F O F 0 Cd“ 6 cw F F Compound 59.1. 2,6-diflu0r0benzaldehyde. The title nd was synthesized according to methods described for the preparation of 51.2. Here, commercially available 2,6-difiuorobenzoic acid was utilized instead of 2-(4-fiuorophenyl)acetic acid.

F o F s + _ H , NH3C| F F 7373 Compound 59.2. (S)(2,6-difluorophenyl)ethanamine hydrochloride. The title nd was sized according to methods described for the preparation of 5.3.

Here, 59.1 was utilized instead of 3,5-difluorobenzaldehyde.

F 0 KIH 3C|_ NMP N :fiA0 F We H sponge 130°C Compound 59. (S)((1-(2,6-difluorophenyl)ethyl)amino)—3- isopropylpyrimidine—2,4(1H,3H)-dione. Reaction of 59.1 with 1.3 was conducted in a similar manner as the procedure described in Example 5 1. Here though, the reaction mixture was heated at 130 0C for 5 h. is of the reaction mixture via chiral HPLC revealed non- trivial amounts of the enantiomer. Separation of the omers was performed utilizing preparative chiral HPLC with an isocratic mixture of EtOH: Hexane (l :4) as eluent from a Phenomenex Lux-2 5n Cellulose-2, 30* l50mm column (40 min run). LC/MS: m/z (ES+) 310 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 5 ppm 9.80 (br s, 1H), 7.45-7.41 (m, 1H), 7.18-7.14 (m, 2H), 6.52 (d, J = 8.0 Hz, 1H), 4.94-4.88 (m, 1H), 4.79 (quint, J = 7.6 Hz, 1H), 4.41 (s, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.30-1.26 (m, 6H).

Exam le 60. Pre aration of R l- 2 6-difluor0 hen l eth 1 amino iso r0 1 rimidine-2 4 1H 3H -di0nc 60R . @681? The title compound was generated as a by-product of the chemistry conducted in Example 59. It was isolated via preparative chiral HPLC with an tic mixture of EtOH: Hexane (l: 4) as eluent from a Phenomenex Lux-2 5p Cellulose-2, 30* l50mm column (40 min run). LC/MS: m/z (ES+) 310 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 5 ppm 9.98- 9.6l (br, 1H), 7.45-7.41 (m, 1H), 7.18-7.14 (m, 2H), 6.52 (d, J = 8.0 Hz, 1H), 4.94-4.88 (m, 1H), 4.79 , J = 7.6 Hz, 1H), 4.41 (s, 1H), 1.56 (d, J = 6.8 Hz, 3H), 1.30-1.26 (m, 6H). 7474 seeEx.51 \ _’ \ ,O OH N \ Compound 61.1. N-methoxy-N-methyl(pyridinyl)acetamide. The title compound was synthesized according to methods bed for the preparation of 51.1. Here, commercially available dineacetic acid was utilized instead of 2-(4-flu0r0phenyl)acetic acid.

N / O N / O | THF, 0°C | \ , —>o \ T \ CH3MgBr Compound 61.2. 1-(pyridinyl)propanone. To a 250-mL 3-necked round- bottom flask purged and maintained with an inert atmosphere of argon, was added THF (70 mL) and N—methoxy-N-methyl(pyridinyl)acetamide (7.0 g, 0.039 mol, 1.0 equiv). The mixture was cooled to 0 0C and CHgMgBr (3M in THF, 65 mL, 5.0 equiv) was added dropwise. The resulting solution was warmed to t temperature and stirred for 16 h.

The reaction mixture was cooled to 0 OC and quenched by the addition of saturated NH4C1 (aq, 100 mL). The resulting solution was extracted with EtOAc (3x200 mL). The organic layers were combined, dried over anhydrous NaZSO4 and trated under d pressure. The crude was purified by flash chromatography (silica gel, CHzClz/CH30H (20: 1)) to yield 2.7 g (51%) of the title compound as yellow oil. 1H-NMR (400 MHz,CDC13): ppm 8.58 (m, 2H), 7.17 (d, J = 0.4 Hz, 2H), 3.75 (s, 2H), 2.24 (s, 3H).

N / 0 I see Ex. 50 N / I 5 O —> r \ \ —> NV8 % ee Compound 61.3. (R)methyl-N-((S)—1-(pyridinyl)propanyl)propane sulfinamide. The title compound was prepared according to procedures described in Example 50 utilizing 61.2 in place of 1-(3-methylphenyl)ethanone. Here, the reduction 7575 utilizing L-selectride resulted in isolation of the title compound (61.3) (20% enantiomeric excess).

N/ O N/ I g : see Ex. 5 I : \ \‘S —> \ N 7< NH2 % ee (20% ee) nd 61.4. (S)(pyridinyl)propan-Z-amine. The title compound was prepared utilizing a two-step procedure as 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 free-basing of the hydrochloride salt (see protocol for Compound 5) resulted in the title compound (~20% ee). rNk0 CI N O 0* 2 III H \ \ NH2 Proton Sponge, IN N/gO H H NMP, 100°C

[0163] nd 61. (S)is0pr0pyl—6-((1-(pyridinyl)pr0pan yl)amin0)pyrimidine-2,4(1H,3H)—di0ne. The title nd was prepared according to the ol described for 51. Here, the reaction e was stirred for at 100 0C for 1 h. The reaction mixture was concentrated under reduced pressure and the residue (100 mg) was purified by PLC to give 13.1 mg of the title compound as a mixture of enantiomers.

The enantiomers were (13.1 mg) separated by chiral ative HPLC with a Chiralpak IC, 2*25cm, 5um column, utilizing a isocratic mixture of EtOH: Hexane (1: 3) as eluent (20 min run). This resulted in 8.2 mg (8%) of the title compund as a light yellow solid. LC/MS: m/z (ES+) 289 (M+H)+. 1H-NMR (300 MHz,CD30D): 8 ppm 8.41 (d, J = 5.7 Hz, 2H), 7.29 (d, J = 6.0 Hz, 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 = 7.2 Hz, 6H), 1.12 (d, J = 7.2 Hz, 3H).

Exam le 62. Pre aration of S 1- 4- benz lox hen leth lamino isop_rop_ylp_yrimidine-2,4( 1H,3H z-dione. 7676 Compound 62.1. (S)(1-(4-(methoxy)phenyl)ethyl)isoindoline—1,3-dione. To phtalimide (1.3 g, 0.0088 mol) in a 2-5 mL microwave Vial was added (S)(4- methoxyphenyl)ethan-l-amine (2.20 mL, 0.015 mol) and K2C03 (1.2 g, 0.0087 mol). The reaction mixture capped and heated at 160 0C for 2 minutes. The resulting crude solid was suspended in n-BuOH and was filtered. The filtrate was put aside. The solid was washed with H20 and the filtrate was discarded. The solid was washed with CHZClz and the resulting e was partitioned with H20. The organics (n-BuOH and CHzClz layer) were combined and trated. The crude residue was purified by silica gel column tography using CHzClz as eluent to yield 1.6 g (64%) of the title compound. LC/MS: m/z (ES+) 282 (M+H)+.

CH2CI2 M BBr3 in CH2CI2 0°C to RT

[0165] Compound 62.2. (S)(1-(4-hydroxyphenyl)ethyl)isoindoline-1,3-dione. To a d solution of 62.1 (640 mg, 2.28 mmol) in CHzClz (8 mL) at 0 0C was added BBrg (1.0 M in CH2C12,3 mL, dropwise). The reaction was allowed to warm to room temperature over minutes. Significant starting material remained so the reaction was chilled back to 0 0C. onal BBrg (2 mL, 1.0 M in CHzClz) was added and the reaction was allowed to warm to room temperature over 30 minutes. The reaction mixture was poured over 5% NaHCOg (aq) in ice. The layers were separated and the aqueous layer was filrther ted with CHzClz. The combined organics were washed with brine, dried with anhydrous Na2S04 and concentrated to give 500 mg (82%) of the title compound as a white solid. LC/MS: m/z (ES+) 268 (M+H)+. 7777 DMF K2C03 2, BnBr d.N Compound 62.3. (S)(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 K2C03 (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 0C for 5 h. The on was cooled and filtered. Water was added (20 mL) and EtOAc (60 mL) was utilized to extract product. The organic layer was washed successively with H20, 10% N32C03 (aq), H20, and brine (2X). The organics were dried over anhydrous MgSO4 and concentrated. The crude residue was purified by flash tography (silica gel, g with CHzClz) to yield 480 mg (72%) of the title compound. LC/MS: m/z (ES+) 358 (M+H)+.

EtOH/HZO ’1 N2H4 NH2 Compound 62.4. (S)(4-(benzyloxy)phenyl)ethan-l-amine. To a stirred solution of 62.3 (480 mg, 1.34 mmol) in a 70/30 EtOH/HZO mixture (20 mL) was added N2H4'H20 (l .5 mL). The reaction was stirred for 16 h and concentrated. The ing al was partitioned between EtOAc and 5% N32C03 (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)+. § b J\ Dioxane , H HA0 DAM-12 + l i DIEA, 135°C O ©/\0 n0 CI N microwave 7878 Compound 62. (S)((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 uL).

The on mixture was capped, heated at 135 0C in a microwave reactor for 1.5 h, allowed to cool, and then concentrated. The crude reaction mixture was treated with 50/50 CH3CN/H20 (0.1% TFA) which led to precipitation. The solid was isloated by filtration and dried to give 45 mg (10%) of a white solid. LC/MS: m/z (ES+) 380 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 5 ppm 9.73 (br, 1H), 7.43-7.29 (m, 5H), 7.23 (d, J = 14.5 Hz, 2H), 6.97 (d, J = 14.5 Hz, 2H), 6.42 (d, J = 7.0 Hz, 1H), 5.06 (s, 2H), 4.93-4.85 (m, 1H), 4.42 (quin, J = 6.8 Hz, 1H), 4.32 (d, J = 1.6 Hz, 1H), 1.35 (d, J = 6.7 Hz, 3H), (m, 1H) 1.27-1.23 (m, 6H).

Exam le 63. Pre n of 1- 4-h drox hen leth lamino iso r0 1 ne-2 4 1H 3H -di0ne 63 .

: NJ\ 3 fkNAG H2Pd/C aN MeOH H Oxmfi'lkA0 H Hog To a stirred solution of 62 (43 mg, 0.11 mmol) in CHgOH (20 mL) was added palldium 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 a H2 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 CH3CN and then 20 mL H20 (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)+. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 9.70 (br, 1H), 9.32 (s, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 6.36 (d, J = 7.0 Hz, 1H), .85 (m, 1H), 4.37-4.33 (m, 2H), 1.33 (d, J = 6.7 Hz, 3H), 1.27-1.23 (m, 6H).

Exam le 64. Pre n of R 2- benz 10x hen leth lamino iso r0 1 rimidine-2 4 1H 3H -dione. 7979 O HO HO\ \: o E 150°C 3 - 0 + —> 0 ©/\ Compound 64.1. (R)(2-hydroxyphenylethyl)isoindoline—1,3-dione. To a 2.0-5.0 mL microwave vial was added (R)aminophenylethanol (1.53 g, 0.0112 mol) and phthalic anhydride (1.65 g, 0.0112 mol). The reaction mixture was capped and heated to 150 0C for 2 minutes in a microwave reactor. The mixture was cooled and diluted with CH3CN (2 mL), recapped and heated in the ave r a second time at 140 0C for 20 minutes. The volatiles were removed under reduced re and the resulting solid was suspended in EtOAc (50 mL). The organic layer was washed with 5% NaHC03 (aq), H20, and brine, dried with anhydrous MgSO4 and concentrated. The crude residue was purified by flash chromatography (silica gel, eluting with CHgOH in CH2C12(0 t0 5%) to yield 2.81 g (94%) ofthe title compound. LC/MS: m/z (ES+) 268 (M+H)+. 1) NaH DMF emit;2...... ©9163 Compound 64.2. (R)(2-(benzyloxy)—1-phenylethyl)isoindoline-1,3-dione. The title compound was made in a similar manner as the procedure described for 62.3. However, in this case NaH (60% dispersion in mineral oil, 1.2 equiv.) was used in place of K2C03.

Specifically, NaH was added at 0 0C and stirred at room temperature for 45 s. The reaction was cooled back to 0 0C and then benzyl bromide (1.2 equiv.) was added. A work- up procedure as described for 62.3 followed by flash chromatography (silca gel, eluting with CHzClz) d the title nd in 59% yield. LC/MS: m/z (ES+) 358 (M+H)+. 1H-NMR (400 MHz, CDClg): 8 ppm 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, 5.9 Hz, 1H), 4.63 (t, J = 10.2 Hz, 1 H), 4.58 (s, 2H), 4.06- 4.01 (m, 1H). 8080 a CH O\_ o N2H4, EtOH/HZO \; ©/:\N see ex. 62 ©/\NH2 Compound 64.3. (R)(benzyloxy)—1-phenylethan-l-amine. The title nd was prepared in a similar manner as the procedure described for 62.4. LC/MS: m/z (ES+) 228 . 1H-NMR (400 MHz, CDClg): 8 ppm 7.40-7.24 (m, 10H), 4.56 (d, J = 2.0 Hz, 2H), 4.25 (dd, J = 8.8, 3.7 Hz, 1 H), 3.65-3.60 (m, 1H), 3.49-3.44 (m, 1H).

Q O k 0» O\_ see Ex. 62 + m o\: ©/\NH2 Cl N 0 gmii? 1.3 nd 64. (R)((2-(benzyloxy)—1-phenylethyl)amino)—3- isopropylpyrimidine—2,4(1H,3H)—dione. The title compound was prepared in a similar manner as the procedure described for 62. Here though, the reaction was heated at 140 0C for l h. After cooling, the crude reaction mixture was treated with 50/50 CHgCN/HZO (0.1% TFA) which led to precipitation. LC/MS: m/z (ES+) 380 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 5 ppm 10.01 (br, 1H), .26 (m, 10H), 6.62 (d, J = 6.7 Hz, 1H), 4.93-4.83 (m, 1H), 4.67-4.62 (m, 1H), 4.50 (dd, J = 12.0, 2.0 Hz, 2H), 4.30 (s, 1H), 3.68-3.64 (m, 1H), 3.60-3.55 (m, 1H) 1.27-1.23 (m, 6H).

Exam le 65. Pre aration of 6-meth l ridin l l- hen leth 1 amino rimidine-2 4 1H 3H -dione.

N / neat O N / I + JOL —> I 8181 Compound 65.1. 1-(6-methylpyridinyl)urea. To a 25-mL 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-methylpyridinamine (3 g, 27.74 mmol, 1.00 equiv). The resulting mixture was d for 2 h at 145 0C. After cooling, the crude product (4 g) was purified using CombiFlash: Column, C18 silica gel; utilizing a mobile phase of CHgCN: H20 = 0:100 to CHgCN: H20 = 50:50 over 40 min. This resulted in the isolation of 1.2 g (32%) of the title compound as a white solid. 1H-NMR (400 MHZ, DMSO-d6): 5 ppm 9.07 (s, 1H), 7.56-7.52 (m, 1H), 7.18-7.14 (m, 1H), .75 (m, 1H), 2.36 (s, 3H).

O N / o N / CH2(COOMe)2 \\| HZNAN \ | NaOMe, MeOH, reflux H j; o m o Compound 65.2. 1-(6-methylpyridinyl)pyrimidine—2,4,6(1H,3H,5H)-trione.

The title compound was prepared in a similar manner as the ure described for 1.2.

Here though, after stirring overnight at 65 0C, the reaction mixture was concentrated under reduced pressure and the crude product was precipitated from CH30H:Et20 (1 :50). The solid was collected by filtration and dissolved in CH30H (50 mL). The pH value of the solution was ed to 7 with cation ion-exchange resin (Dowex 50WX8-100, 5 g). The solids were filtered and the filtrate was concentrated under reduced pressure resulting in 0.5 g (29%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 9.27 (br s, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 3.18 (s, 2H), 2.44 (s, 3H). 0 N/I O Hg 4POCI N/| 0 1*” \ M 0 CI N/KO Compound 65.3. 6-chloro(6-methylpyridinyl)pyrimidine-2,4(1H,3H)— dione. To a stirred on of 65.2 (500 mg, 2.28 mmol, 1.00 equiv) in P0C13 (5 mL) at 0 0C was added a drop (~20 0L) of H20. The resulting solution was warmed to room temperature, 8282 stirred for 30 min., heated to 70 0C 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 ion-exchange resin (activated 201 ><4(71 1) strong base styrene anion exchange resin, 20 g) and the solids were filtered. The filtrate was concentrated under reduced pressure ing in 0.2 g (37%) of the title compound as a yellow solid.

O N/ O N/ - I I ©/\ fiN \ neat _ N NH2 I : + | —0> 110 C CI N/go ©/\N N/KO H H H

[0177] Compound 65. (S)(6-methylpyridin-Z-yl)—6-((1- phenylethyl)amin0)pyrimidine-2,4(1H,3H)—di0ne. To a 10-mL round-bottom flask purged and maintained with an inert atmosphere of argon was added (S)-oc-methylbenzylamine (0.5mL) and 65.3 (200 mg, 0.84 mmol, 1.00 equiv). The resulting solution was stirred for 3 h at 110 0C. After g, the resulting mixture was concentrated under vacuum. The residue (100 mg) was purified by pareparative RP-HPLC with the ing conditions:Column, XBridge Prep C18 OBD Column, Sum, 19* 150mm,; mobile phase, H20 with 0.05% 03) and CH3CN (15% CH3CN to 80% in 8 min); This resulted in 28.8 mg (11%) of the title nd as a white solid. LC/MS: m/z (ES+) 323 (M+H)+. 1H—NMR (400 MHz, DMSO-d6): 5 ppm 7.76 (t, J = 7.6 Hz, 1H), 7.39- 7.22 (m, 7H), 7.05 (d, J = 7.6 Hz, 1H), 6.82 (br, 1H), 4.63-4.59 (m, 1H), 4.46 (s, 1H), 2.43 (s, 3H), 1.44 (d, J = 6.4 Hz, 3H).

Exam le 66. Pre aration of 2 2-difluoroeth l 1- hen leth lamino ne- 2,411H,3Hg-dione.

O O A + I k N O TfO/\FrF NEt3 0°Ct RT Cl N 0 SEM 0 11.1 Compound 66.1. 6-chlor0(2,2-difluoroethyl)—1-((2- (trimethylsilyl)ethoxy)methyl) pyrimidine-2,4(1H,3H)-di0ne. To a stirred solution of 11.1 8383 (130 mg, 0.47 mmol) and Eth (0.2 mL) in CHzClz (2 mL) at 0 0C was added 2,2- difiuoroethyl trifiuoromethanesulfonate (0.10 mL). The reaction was warmed to room ature and stirred for 30 minutes. The mixture was concentrated to give the title compound in a crude mixture. mrLNOF TFA F CH CI l 2 2 F SEMO CI ”*0 Compound 66.2. 6-chlor0(2,2-difluoroethyl)pyrimidine-2,4(1H,3H)-dione.

Crude 65.1 was dissolved in CHzClz/TFA (1 :1, 4 mL) and d for 3 h and concentrated.

The resulting material was treated with 5% NaHCOg (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 CH3CN (15 mL) and was remove by filtration. The filtrate was concentrated to give 52 mg of the title compound. “/6in Dioxane Et3N 100°C ”jig/L nd 66. (S)(2,2-diflu0r0ethyl)—6-((1-phenylethyl)amin0)pyrimidine- 2,4(1H,3H)—di0ne. To 66.2 (52 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL) was added Eth (100 uL) and (S)-oc-methylbenzylamine (188 mg, 1.55 mmol). The on mixture was heated in a microwave reactor at 100 0C for 32 minutes, cooled to room temperature, and then concentrated. The resulting residue was ved in a 2:3 CHgCN/HZO (10 mL) with 2 drops ofTFA (~40 uL). 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)+. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 10.20 (br s, 1H), 7.37-7.32 (m, 4H), 7.26-7.23 (m, 1H), 6.71 (d, J = 7.0 Hz, 1H), 6.07 (tt, J = 56.0, 4.5 Hz, 1H), 4.54 (quin, J = 6.8 Hz, 1H), 4.43 (d, J = 2.3 Hz, 1H), 4.02 (td, J = 14.3, 4.7 Hz, 2H), 1.40 (d, J: 6.7 Hz, 3H).

Exam le 67. Pre aration of 1- benzo d 1 3 dioxol l eth 1 amino 2 2 2- trifiuoroethyl )pyrimidine-2,4g 1H,3H z-dione. 8484 O O [*0]ng BrABr —> < HO 082003, DMF 0O:©)LH 110°C Compound 67.1. 2H—1,3-benzodioxole—S-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 dibrornomethane (18.7 g, 107.57 mmol, l.50 equiv). The ing solution was stirred for 2 h at 110 0C. The solution was cooled to room ature and the solid was removed by filtration. The filtrate was diluted with H20 (300 mL). The resulting solution was extracted with EtOAc (2 x 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 with petroleum ether (1:9) to afford 8 g (74%) of the title compound as a yellow solid. 1H-NMR (300 MHz, CDClg): 8 ppm 9.81 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.08 (s, 2H). 0 E . _ O see Ex. 5 + < H —’—> < Nchl O O Compound 67.2. (benzo[d][1,3]dioxol-S-yl)ethanamine hydrochloride.

The title compound was synthesized according to s described for the preparation of .3. Here, 67.1 was utilized instead of 3,5-difiuorobenzaldehyde. LC/MS: m/z (ES+) 166 (M+H)+.

O F E NMP, proton : N/\|<F <O:©/-\I:JH30|_ : Nfi/g sponge,130°C <O:©/\Ho F + fiNX’; O 0 CI ”*0 F H Compound 67. (S)((1-(benzo[d] [1,3]dioxol—S-yl)ethyl)amino)—3-(2,2,2- trifluoroethyl)pyrimidine—2,4(1H,3H)-dione. The title compound was synthesized according to methods described in Example 59. Here, 67.2 was utilized instead of (S)-l-(2,6- difiuorophenyl)ethan-l-amine hloride and 6-chlor0(2,2,2-trifiu0roethyl)pyrimidine- ,3H)-di0ne was utilized (synthesized according to methods described in Example 1) 8585 d of 1.3. LC/MS: m/z (ES+) 358 (M+H)+. 1H-NMR (300 MHz, DMSO-d6): 8 ppm .27 (br s, 1H), 6.94 (d, J: 1.2 Hz, 1H), 6.89-6.82 (m, 3H), 6.72 (d, J = 6.9 Hz, 1H), 5.99 (s, 2H), 4.48-4.40 (m, 4H), 1.38 (d, J = 6.9 Hz, 3H).

Exam le 68. Pre aration of iso ro l 1- o-tol leth lamino rimidine- 2,411H,3H)-dione 1681.

NMP, proton N , 130°C To a stirred solution of (1S)—1-(2-methylphenyl)ethanamine (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 for 1 h at 130 0C in an oil bath, cooled to room temperature, and then diluted with DMSO (2 mL). The solids were filtered and the filtrate was purified by Flash-Prep-HPLC with the following conditions: Column: X Bridge C18, 19* 150 mm, 5 um; Mobile Phase A: H20 /0.05% TFA, Mobile Phase B: CH3CN; Flow rate: 20 ; Gradient: 30%B to 70% B in 10 min. This afforded 50 mg of crude product which was subsequently separated by chiral preparative HPLC with the following conditions: Column, Chiralpak IC, 2*25cm, 5um; mobile phase, hexanes and ethanol (9:1, 15 min). This resulted in 35.6 mg (8%) of the title compound as a white solid.

LC/MS: m/z (ES+) 288 (M+H)+. 1H-NMR (300 MHz, 6): 8 ppm 9.76 (br s, 1H), 7.28 (d, J = 7.2 Hz, 1H) 7.24-7.14 (m, 3H), 6.48 (d, J = 6.3 Hz, 1H), 4.95-4.86 (m, 1H), 4.60 (quin, J = 6.9 Hz, 1H), 4.19 (s, 1H), 2.34 (s, 3H), 1.37 (d, J = 6.6 Hz, 3H), 1.27 (d, J = 6.9 Hz, 6H).

Exam le 69. Pre aration of c clobut l 1- hen leth lamino rimidine- 2,411H,3Hg-dione. 8686 Compound 69.1. l-cyclobutylurea. To a stirred solution of cyclobutanamine (40 g, 562.42 mmol, 1.00 equiv) in CH2C12 (400 mL) at 0 0C was added trimethylsilyl isocyanate (64.70 g, 561.60 mmol, 1.00 equiv.) nwise. The ing solution was stirred overnight at room temperature and was quenched by the addition of CHgOH (80 mL). The resulting mixture was stirred for l h at room temperature and then concentrated under reduced pressure. The residue was washed with EtzO (2 X 100 mL) and filtered, which afforded 53 g (83%) of the title compound as a white solid. 1H-NMR (300 MHz, 6): 8 ppm 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). 0 0 O D i D MeOUOMe N H2” fl NaOMe,MeOH o N o Compound 69.2. obutylpyrimidine—2,4,6(1H,3H,5H)—trione. To a stirred solution of sodium methoxide (62.43 g, 1.156 mol, 2.40 equiv) in CHgOH (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 on was heated to 65 0C and stirred overnight. The reaction was cooled and quenched by the addition of H20 (100 mL). The pH of the solution was adjusted to l with concentrated HCl. The ing mixture was concentrated under reduced pressure.

The residue was purified by silica gel column chromatography with CHzClz/CH30H (20:1) as eluent to afford 60 g (68%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 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), .60 (m, 2H). fiNOD OD fl, IN TEBAC 0 N/L§O CI Compound 69.3. 6-chlorocyclobutylpyrimidine—2,4(1H,3H)-dione. To 69.2 (80 g, 0.44 mol, 1.00 equiv) and triethylbenzylammonium de (140.2 g, 0.615 mol, 1.40 equiv) was added (300 mL). The reaction was stirred for l h at 65 OC and was then concentrated under reduced pressure. The reaction was quenched by the careful addition of l L of water/ice and then the pH value of the solution was adjusted to 1 with 2N NaOH (aq).

The solid was filtered, washed with CHgOH (300 mL) and EtzO (2 X 300 mL), and dried. 8787 This resulted in 78 g (89%) of the title compound as a light yellow solid. 1H-NMR (300 MHz, DMSO-d6): 5 ppm 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).

N neat = | A + NH2 —> N N)».

CI N O 120°C,3h H H nd 69. (S)cyclobutyl—6—((1-phenylethyl)amino)pyrimidine— 2,4(1H,3H)—di0ne. 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)-oc- methylbenzylamine (150 mL, 2.00 equiv). The reaction mixture was stirred for 3 h at 120 0C.

The reaction mixture was cooled to room temperature, diluted with CHgOH (1 L) and further cooled to 0 0C. The ing solid was filtered, washed with EtZO (2 x 300 mL), and dried under vacuum to afford 57.25 g (52%) of the title compound as a white solid. LC/MS: m/z (ES+) 286 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 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), .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).

Exam le 70. Pre aration of S iso ro l 1- 2- trifluorometh l hen leth lamino pyrimidine-2,41 1H,3H)—dione.

X k 40 A O H , N\ H F3C ) F3C p-TsOH, MgSO4, CH2CI2 Compound 70.1. (R,E)methyl—N-(2-(trifluoromethyl)benzylidene)pr0pane—2- sulfinamide. To a 100-mL round-bottom flask purged and ined with an inert atmosphere of argon, was added CHzClz (50 mL), 2-(trifluoromethyl)benzaldehyde (2.01 g, 11.54 mmol, 1.00 equiv), (R)-(+)methylpropanesulf1namide (1.68 g, 13.86 mmol, 1.20 equiv), nium p-toluenesulfonate (0.145 g, 0.05 equiv) and magnesium sulfate (6.93 g, .00 equiv). The resulting solution was stirred for 48 h at 40 0C. The mixture was cooled to room ature and the solid was filtered. The filtrate was concentrated under reduced 8888 pressure and the resulting residue was purified by flash column tography (silica gel, eluting with EtOAc/petroleum ether (1:20)). This resulted in 0.96 g (30%) the title compound as a light yellow solid. LC/MS: m/z (ES+) 278 (M+H)+. 1H-NMR (300 MHZ, DMSO-d6): 5 ppm 8.82-8.80 (m, 1H), 8.24 (d, J = 7.2 Hz, 1H), 7.95-7.80 (m, 3H), 1.22 (s, 9H).

)(S/o km N \ H HN CH2CI2 -5o°c F30 Compound 70.2. (R)—2-methyl-N-((1S)(2-(triflu0r0methyl)phenyl)— ethyl)pr0pane—2-sulfinamide. To a d solution of 70.1 (578 mg, 2.08 mmol, l.00 equiv) in THF (20 mL) at -50 0C was added 3 M methylmagnesium bromide in EtzO (l .4 mL, 4.20 mmol, 2.0 equiv) dropwise. The resulting solution was d at -50 0C for 2.5 h and at room temperature for an additional 10 h. The reaction was quenched by the addition of a saturated aqueous NH4Cl on (10 mL) and then concentrated under reduced pressure. The resulting residue was treated with H20 (50 mL) and extracted with CHZClz (2 x 50 mL). The organic layers were combined, dried over Na2S04, and concentrated under reduced re.

This resulted in 700 mg (60% de) of the title compound as a yellow solid. LC/MS: m/z (ES+) 294 (M+H)+. 1H-NMR (300 MHz, DMSO-d6): 5 ppm 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 = 6.6 Hz, 3H), 1.02 (s, 9H). k,,0 CI_ A H3N 4 N HCI in Dioxane —>F3C F3C MeOH Compound 70.3. (S)(2-(triflu0r0methyl)phenyl)ethanamine hydrochloride. To a stirred solution of 70.2 (700 mg, 2.39 mmol, l.00 equiV) in CHgOH (4 mL) was added 4N HCl in l,4-dioxane (2 mL) dropwise. The resulting solution was stirred for l h at room temperature and then concentrated under d pressure. Solid was 8989 precipitated by the addition of EtzO (5 mL). The solid was filtered and dried affording the title compound as a white solid (0.32 g, 60%).

HSN CF3 : NaOH ? F3C —>H20 NH2

[0192] Compound 70.4. (S)(2-(triflu0r0methyl)phenyl)ethan-l-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 H20 (20 mL). The resulting solution was d for 1 h at room temperature and was then extracted with EtOAc (20 mL). The organic layer was ed and concentrated under reduced pressure. This afforded 190 mg (70%) of the title compound as light yellow oil.

NMP, proton O ©/:NH2CF3 fi J\—>sponge,h130°C, CF3 + N Cl ”A0 Compound 70. (S)isopr0pyl—6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino) pyrimidine-2,4(1H,3H)—di0ne. To a 10-mL round-bottom flask purged and maintained with 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 for 4 h at 130 0C. The crude t (200 mg) was purified by chiral preparative HPLC with the following ions: Column, Phenomenex Lux-2 5u ose-2, 30* 150mm; mobile phase, Hex-HPLC and ethanol-HPLC (hold 20% ethanol-HPLC in 14 min); Detector, uv 254/220nm. 160 mg crude product was obtained. The obtained material (60 mg) was further purified using chiral preparative HPLC with following conditions: Column: Phenomenex Lux-2 5u Cellulose-2 30"< 150mm; Mobile Phase and Gradient: Hex: EtOH = 80:20; Retention Time (Peak 2) (min): 1 1.106. This resulted in 30 mg of the title compound as a white solid. LC/MS: m/z (ES+) 342 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): 8 ppm 9.84 (br, 1H), 7.78-7.68 (m, 3H), 7.56-7.52 (m, 1H), 6.75 (br s, 1H), .86 (m, 1H), 4.68-4.63 (m, 1H), 4.13 (s, 1H), 1.46 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 7.2 Hz, 6H). 9090 Exam le 71. Pre aration of l-meth lc clo ro l 1- phenylethyl )amino idine-2,4g 1H,3H z-dione.

OCN’Si\ 0 + 2 JL 2 —> H2N N H3N H _ CH2Cl2 nd 71.1. 1-(1-methylcyclopropyl)urea. To a stirred solution of l- methylcyclopropanamine hydrochloride salt (429 mg, 3.99 mmol, 1.00 equiv) and triethylamine (268 mg, 2.65 mmol, 1.00 equiv) in CHzClz (6 mL) was added trimethylsilyl isocyanate (366 mg, 3.18 mmol, 1.20 equiv). The resulting e was stirred at room temperature overnight and was quenched by the dropwise addition of CHgOH (2 mL) at 0 0C.

The ing solution warmed to room temperature and stirred for an additional 1 h. The resulting e was concentrated under reduced pressure. The crude product was precipitated from CHgOH:Et20 (1:40) affording 300 mg (66%) of the title compound as a white solid. i Z MeOMOMe OfiNZ H2” fl NaOMe MeOH &O Compound 71.2. 1-(1-methylcyclopropyl)pyrimidine-2,4,6(1H,3H,5H)-trione.

To a stirred on of 71.1 (320 mg, 2.80 mmol, 1.0 equiv) in CH3OH (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 overnight at 65 0C. After cooling, the reaction was quenched by the addition of H20 (100 mL). The pH of the solution was ed to 2 with concentrated HCl and the resulting mixture was concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography with EtOAc/petroleum ether (1:3) as eluent. This afforded 100 mg (20%) of the title compound as a white solid. 1H-NMR (300 MHZ, CDC13): 5 ppm 8.04 (br, 1H), 3.61 (s, 2H), 1.41 (s, 3H), 1.00-, 0.86 (m, 4H). 9191 0 O NZ Pool3 NZ ,g | TEBAC O N 0 Cl N O H H Compound 71.3. 6-chloro(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 POC13 (2 mL). The resulting solution was stirred for 3 h at 50 0C and then concentrated under reduced pressure. The residue was carefully ed by the addition of 10 mL of water/ice and was ted with EtOAc (2 x 30 mL). The organic layers were ed and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography with CHzClz/CHgOH (10: 1) as eluent to afford 40 mg (36%) of the title compound as a yellow solid.

O Z _ E N 0 l '1‘ : + 130C,2h 02—, N m Cl n O H H Compound 71. (S)(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)-0c-methylbenzylamine (0.5 mL). The reaction mixture was stirred for 2 h at 130 0C and then was concentrated under reduced pressure. The resulting residue was purified by preparative RP-HPLC with the following conditions: Column: X Bridge C18, 19* 150 mm, 5 urn; Mobile Phase A: H20 /0.05% TFA, Mobile Phase B: CH3CN; Flow rate: 20 mL/min; Gradient: 30% B to 70% B in 10 min. This afforded 15.1 mg (27%) of the title compound as a white solid. LC/MS: m/z (ES+) 286 (M+H)+. 1H-NMR (300 MHz, CDgCN): ppm 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 = 6.9 Hz, 3H), 1.27 (s, 3H), 0.87-0.77 (m, 4H).

Example 72. Preparation of Additional Pyrimidine Dione Compounds.

The compounds in Table 1B were prepared according to the es as bed above (exemplary methods provided as “Reference. Ex. No.’) 9292 Compound N0.

Observed Mass and/or Structure 1H NMR Reference EX. N0. 340 (M+H)+ 1H-NMR (300 MHz, 6): 8 ppm 9.89 (br s, 1H), 9.54 (br s, 1H), 8.22 (br s, 1H) 7.82 (br s, 1H), 7.75 (s, 1H) .54 (m, 2H), 7.48 (d, J = 7.5 Hz, 1H), 6.60-6.58 (m, 1H), 4.90-4.83 (m, 1H), 4.55- 4.48 (m, 1H), 4.30 (s, 1H), 1.42 (d, J = 6.9 Hz, 3H), 1.27-1.21 (m, 6H). 310 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): 8 ppm 9.20 (m, 1H), 9.04 (br s, 1H), 7.57 (m, 1H), 7.38-7.32 (m, 4H), 7.26-7.21 (m, 1H), 6.76 (m, 1H), 4.69-4.62 (m, 1H), 4.46 (s, 1H), 1.40 (d, J = 6.8 Hz, 3H). 310 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): 8 ppm 8.56 (m, 1H), 8.49 (m, 1H), 8.37 (m, 1H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 6.68 (m, 1H), 4.71-4.65 (m, 1H), 4.34 (s, 1H), 1.37 (d, J = 6.8 Hz, 3H). 310 (M+H)+ 1H-NMR (400 MHz, DMSO-d6): 8 ppm 8.60 (m, 1H), 8.57 (m, 1H), 8.49 (br s, 1H), 7.39-7.32 (m, 4H), 7.26-7.22 (m, 1H), 6.68 (m, 1H), 4.69-4.64 (m, 1H), 4.41 (s, 1H), 1.39 (d, J = 6.8 Hz, 3H). 9393 275 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.70 (br, 1H), 8.60 (d, J = 2.0 Hz, 1H) 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H), 6.67 (br s, 1H), 4.94-4.88 (m, 1H), 4.62- 4.58 (m, 1H), 4.38 (s, 1H), 1.45 (d, J = 6.4 Hz, 3H), 1.30-1.28 (m, 6H). 312 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 10.69 (br s, 1H), 7.65 (s, 1H), 7.40- 7.20 (m, 7H), 4.52 (quin, J = 6.8 Hz, 1H), 4.40 (s, 1H), 3.30 (br s, 3H), 1.39 (d, J = 7.0 Hz, 3H). 302 (M+H)+ 1H—NMR (400 MHz, CDC13)C 8 ppm 10.58 (br s, 1H), 7.36-7.23 (m, 5H), .16 (m, 2H), 4.69 (s, 1H), 4.26 (m, 1H), 1.82-1.71 (m, 2H), 1.44-1.38 (m, 6H), 1.36-1.25 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H). 316 (M+H)+ 1H—NMR (400 MHz, CDgCN): 8 ppm 7.30-7.20 (m, 4H), 7.16-7.11(m, 1H), 6.32 (m, 1H), 4.69-4.62 (m, 1H), 4.43 (quin, J = 6.7 Hz, 1H), 4.29 (s, 1H), 4.00 (t, J = 10.5 Hz, 1H), 3.67-3.59 (m, 1H), 3.44-3.40 (m, 1H), .08 (m, 1H), 2.48- 2.38 (m, 1H), 1.56-1.45 (m, 3H), 1.38(d, J = 6.8 Hz, 3H). 9494 300 (M+H)+ 1H NMR (400 MHz, DMSO-d6) 8 ppm 9.82 (br s, 1H),7.41-7.19(m,5H), 6.50 (d, J = 6.7 Hz, 1H), .05—5.01 (m, 1H), 4.50— 4.46 (m, 1H), 4.34 (s, 1H), 2.01-1.84 (m, 2H), 1.83- 1.64 (m, 2H), 1.63-1.51 (m, 2H), 1.49—1.34 (m, SH). 302 (M+H)+ 1H—NMR (400 MHz, C 8 ppm .35 (m, 2H), 7.30-7.28 (m, 3H), .06-5.00 (m, 1H), 4.53 (s, 1H), 4.12 (d, J = 7.2 Hz, 1H),2.10-2.01 (m, 1H), 1.40—1.37 (m, 6H), 1.02 (d, J = 6.8 Hz, 3H), 0.93 (d, J = 6.8 Hz, 3H). 350 (M+H)+ 1H—NMR (400 MHz, CDgOD): 8 ppm 7.43-7.33 (m, 4H), 7.30-7.26 (m, 1H), 4.82-4.75 (m, 1H), 4.54— 4.49 (m, 2H), 2.74-2.65 (m, 2H), 2.15—2.05 (m, 2H), 1.93-1.79 (m, 2H),1.61-1.57 (m, 2H), 1.51 (d, J = 6.8 Hz, 3H). 302 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.73 (br s, 1H), 7.40 — 7.22 (m, 5H), 6.50 (d, J = 5.1 Hz, 1H), 4.57—4.44 (m, 2H), 4.34 (br s, 1H), 1.90 (ddd, J = 13.3, 9.8, 7.4 Hz, 2H), 1.61-1.50 (m, 2H), 1.38 (d, J = 6.7 Hz, 3H), 0.74-0.60 (m, 6H). 9595 419 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.88 (br s, 1H),7.45-7.41 (m, 3H), 7.37-7.29 (m, 6H), 7.27- 7.22 (m, 1H), 6.54 (d, J = 6.7 Hz, 1H), 4.84-4.79 (m, 1H), 4.52—4.47 (m, 1H), 4.36 (d, J = 2.4 Hz, 1H), 3.57 (m, 2H), 3.05 (m, 2H), 2.38 (m, 2H), 1.50 (m, 2H), 1.38 (d, J = 6.7 Hz, 3H). 302 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.73 (br s, 1H), 7.31—7.22 (m, 2H), 7.21—7.12 (m, 3H), 5.93 (d, J = 8.2 Hz, 1H), 5.00-4.87 (m, 1H) 4.44 (s, 1H), 4.30 (s, 1H),3.37-3.31(m, 1H), 2.65—2.53 (m, 2H), 1.70 (dtd, J = 9.0, 6.9, 6.9, 2.0 Hz, 1H), 1.29 (d, J = 7.0 Hz, 6H), 1.11 (d, J = 6.3 Hz, 3H). 304 (M+H)+ 1H—NMR (400 MHz, CD30D + CDClg): 7.22— 7.15 (m, 2H), 7.13—7.07 (m, 3H), 6.28 (d, J = 6.1 Hz, 1H), 4.44 (s, 1H), 4.38 (s, 2H), 4.30—4.23 (m, 1H), 3.55 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H). 288 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.77 (br s, 1H), .26 (m, 2H), 7.23—7.12 (m, 3H), 5.85 (d, J = 7.9 Hz, 1H), 4.97-4.87 (m, 1H), 4.55 (s, 1H), 3.77-3.65 (m, 1H), 2.76- 2.68 (m, 2H), 1.27 (d, J = 7.0 Hz, 6H), 1.05 (d, J = 6.7 Hz, 3H). 9696 380 (M+H)+ 1H—NMR (400 MHz, CDC13): 8 ppm 9.77 (br s, 1H), 7.33-7.23 (m, 10H), .23 (br s, 1H), 4.67 (br s, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.44-4.37 (m, 1H), 4.09 (t, J = 9.2 Hz, 1H), 3.63 (dd, J = 9.8, 5.9 Hz, 1H), 1.48 (d, J = 6.7 Hz, 3H), 1.35 (d, J = 7.0 Hz, 3H). 290 (M+H)+ 1H—NMR (400 MHz, CDC13): 8 ppm 9.68 (s, 1H), 7.41 — 7.22 (m, 5H), .62 (s, 1H), 5.08 (td, J = 73,29 Hz, 1H), 4.67 (s, 1H), 4.48 — 4.35 (m, 1H), 3.98 (dd, J = 11.9, 7.6 Hz, 1H), 3.75 (dd, J = 11.7, 3.1 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 7.0 Hz, 3H). 290 (M+H)+ 1H—NMR (400 MHz, 6): 8 ppm 10.01 (d, J = 2.0 Hz, 1H), 7.37- 7.23 (m, 5H), 6.61 (d, J = 6.3 Hz, 1H), 5.19 (t, J = .1 Hz, 1H), 4.93-4.83 (m, 1H), 4.40— 4.33 (m, 1H), 4.24 (d, J = 2.4 Hz, 1H), 3.66 (dt, J = 11.1, 4.7 Hz, 1H), 3.52— 3.44 (m, 1H), 1.25 (dd, J: 6.9, 2.2 Hz, 6H). 9797 328 (M+H)+ 1H NMR (400 MHz, DMSO-d6 @ 75 0C): 5 1 (br s, 1H), 7.44- 7.23 (m, 5H), 6.58 (br s, 1H), 5.52 (br s, 1H), 4.59- 4.51 (m, 1H), 4.46 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.43 (d, J = 7.0 Hz, 3H). 328 (M+H)+ 1H NMR (400 MHz, DMSO-d6 @ 75 0C): 5 ppm9.91 (br s, 1H), 7.44- 7.23 (m, 5H), 6.58 (br s, 1H), 5.52 (br s, 1H), 4.59- 4.51 (m, 1H), 4.46 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.43 (d, J = 7.0 Hz, 3H). 342 (M+H)+ 1H—NMR (400 MHz, DMSO-d6 @ 50 0C): 8 ppm 9.79 (br s, 1H), 7.46-7.23 (m, 5H), 6.51 (d, J = 6.7 Hz,1H), 5.13 (br s,1H), 4.50 (quin, J = 6.9 Hz, 1 H), 4.37 (s, 1H), 3.15-3.01 (m, 1H), 2.60- 2.50 (m, 1H), 1.40 (d, J = 6.7 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H). 314 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.32 (br s, 1H), 7.40-7.34 (m, 4H), 7.29-7.25 (m, 1H), 6.81 (d, J = 6.6 Hz, 1H), 4.60-4.54 (m, 1H), 4.49- 4.40 (m, 3H), 1.42 (d, J = 6.6 Hz, 3H). 9898 288 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.50 (br s, 1H), 7.56-7.44 (m, 4H), 7.38-7.24 (m, 1H), 6.41 (d, J = 6.4 Hz, 1H), 4.45 (q, J = 6.8 Hz, 1H), 4.25 (s, 1H), 1.54 (s, 9H), 1.38 (d, J: 6.8 Hz, 3H). 290 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 10.31 (br s, 1H), 7.35-7.23 (m, 5H), 5.72 (d, J = 4.7 Hz, 1H), 4.67 (s, 1H), 4.40 (quin, J = 6.6 Hz, 1H), 4.05 (t, J = 5.7 Hz, 2H), 3.56 (t, J = 5.7 Hz, 2H), 3.27 (s, 3H), 1.46 (dd, J: 6.7, 1.6 Hz, 3H). 342 (M+H)+ 1H—NMR (400 MHz, DMSO-d6, @ 75 0C): 8 ppm 9.91 (br S, 1H), .24 (m, 5H), 6.59 (br s, 1H), .51 (br s, 1H), 4.45 (br s, 1H), 4.31 (q, J = 6.9 Hz, 1H), 1.83-1.67 (m, 2H), 1.52 (d, J = 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H). 300 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.80 (br s, 1H), 7.37-7.31 (m, 4H), 7.27-7.22 (m, 1H), 6.52 (br, 1H), 4.48 (q, J = 6.7 Hz, 1H), 4.32 (br s, 1H), 3.93 (br, 1H), 1.62 (br, 1H), 1.38 (d, J: 6.7 Hz, 3H), 1.33 (d, J = 7.0 Hz, 3H), 0.48-0.41 (m, 1H), 0.27-0.21 (m, 1H), 0.14 (dq, J = 9.4, 4.8 Hz, 1H), 0.02 (m, 1H). 9999 300 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.81 (br s, 1H), 7.37-7.30 (m, 4H), 7.26-7.22 (m, 1H), 6.53 (d, J = 5.9 Hz, 1H), 4.48 (q, J = 6.8 Hz, 1H), 4.32 (d, J = 1.6 Hz, 1H), 3.85 (m, 1H), 1.61 (m, 1H), 1.38 (d, J: 7.0 Hz, 3H), 1.32 (d, J = 6.7 Hz, 3H), 0.49-0.42 (m, 1H), 0.28-0.22 (m, 1H), 0.17-0.12 (m, 1H), 0.01- (- )0.05, (m, 1H). 300 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 9.96 (br s, 1H), 7.36-7.24 (m, 5H), 6.48 (d, J = 6.3 Hz, 1H), 4.40 (s, 1H), 4.36-4.27 (m, 1H), 3.63 (q, J = 6.6 Hz, 2H), 2.67-2.50 (partially obscured m, 1H) .95 (m, 1H), 1.90-1.78 (m, 4H), 1.66-1.57 (m, 1H), 0.98 (t, J = 6.6 Hz, 3H). 318 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 9.76 (br s, 1H), 6.92 (d, J: 1.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.80 (dd, J = 6.0, 1.8 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 5.99 (s, 2H), 4.93-4.88 (m, 1H), 4.41- 4.35 (m, 2H), 1.35 (d, J = 6.6 Hz, 3H) 1.28 (d, J: 1.2 Hz, 3H) 1.26 (d, J = 1.2 Hz, 3H). 100100 304 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 9.93 (br s, 1H), 6.92 (d, J: 1.5 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.82-6.79 (m, 1H), 6.48 (d, J = 7.2 Hz, 1H), .99 (s, 2H), 4.45-4.39 (m, 2H), 3.65 (q, J = 6.6 Hz, 2H), 1.36 (d, J = 6.9 Hz, 3H) 0.99 (t, J: 6.9 Hz, 3H). 328 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.28 (br s, 1H), 7.39—7.24 (m, 5H), 6.81 (d, J = 6.6 Hz, 1H), 4.47—4.33 (m, 4H), 1.80—1.67 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H). 286 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.01 (br s, 1H), 7.39-7.33 (m, 4H), 7.30-7.23 (m, 1H), 6.60 (d, J = 6.0 Hz, 1H), 4.52 (q, J = 6.6 Hz, 1H), 4.38 (s, 1H), 3.49 (d, J = 6.9 Hz, 2H), 1.40 (d, J = 6.9 Hz, 3H) 1.08-1.00 (m, 1H), .33 (m, 2H), 0.28-0.23 (m, 2H). 340 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 10.29 (br s, 1H), 7.37-7.33 (m, 4H), 7.30-7.25 (m, 1H), 6.98 (d, J = 5.6 Hz, 1H), 4.42 (q, J = 9.2 Hz, 2H), 4.35 (d, J: 1.6 Hz, 1H), 3.89-3.85 (m, 1H), 1.24- 1.15 (m, 1H) 0.61-0.56 (m, 1H), 0.50-0.33 (m, 3H). 101101 354 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 10.27 (br s, 1H), 7.45-7.25 (m, 5H), 6.73 (br s, 1H), 4.46- 4.35 (m, 4H), 2.67-2.50 (partially ed m, 1H), 2.04-2.01 (m, 1H), 1.90- 1.79 (m, 4H), 1.68-1.62 (m, 1H). 306 (M+H)+ 1H—NMR (400 MHz, DMSO-d6 @ 90 0C): 8 ppm 9.86 (br s, 1H),7.39-7.31 (m, 4H), 7.29—7.25 (m, 1H), 6.48 (d, J = 6.7 Hz, 1H),5.00-4.91 (m, 1H), 4.78 (m, 1H), 4.56-4.50 (m, 1H), 4.45-4.38 (m, 2H), 3.76-3.70 (m, 2H), 1.42 (d, J = 7.4 Hz, 3H). 360 (M+H)+ 1H—NMR (400 MHz, DMSO-d6 @ 90 0C): 8 ppm 9.86 (br s, 1H), 7.25 (dd, 8.4, 5.7 Hz, 2H), 7.10-7.04 (m, 2H), 5.94 (br s, 1H), .52 (br s, 1H), 4.62 (br s, 1H), 3.79-3.71 (m, 1H), 2.76 (d, J: 6.7 Hz, 2H), 1.55 (d, J = 7.0 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H). 102102 290 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.83 (br s, 1H), 9.68 (br s, 1H), 7.14 (dd, J = 7.4, 1.6 Hz, 1H), 7.05 (td, J = 7.6, 1.6 Hz, 1H), 6.82-6.74 (m, 2H), 6.40 (d, J = 7.0 Hz, 1H), 4.92-4.85 (m, 1H), 4.60 (quin, J = 6.9 Hz, 1H), 4.30 (d, J = 2.4 Hz, 1H), 1.35 (d, J = 6.7 Hz, 3H), 1.27-1.22 (m, 6H). 340 (M+H)+ 1H—NMR (300 MHz, CDClg: 8 ppm 10.40 (br s, 1H), 7.44-7.26 (m, 5H), 6.13 (br s, 1H), 4.80 (br s, 1H), 4.45 (m, 1H), 1.76- 1.52 (m, 5H), 1.35-1.27 (m, 2H). 376 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 10.27 (br s, 1H), 7.29—7.22 (m, 3H), 7.15-7.10 (m, 2H), 7.01 (dd, J = 8.2, 2.3 Hz, 2H), 6.12 (br s, 1H), 4.72 (d, J = 2.0 Hz, 1H), 3.79- 3.71 (m, 1H), 2.76 (d, J: 6.7 Hz, 2H), 1.09 (d, J = 6.7 Hz, 3H). 354 (M+H)+ 1H—NMR (400 MHz, 6): 8 ppm 9.84 (br s, 1H), 7.43 (d, J: 1.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.21 (dd, J = 8.4, 1.2 Hz, 1H), 6.54 (d, J = 6.8 Hz, 1H), 4.90 (q, J = 6.8 Hz, 1H), 4.55—4.52 (m, 1H), 4.34 (d, J = 2.0 Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H) 1.31-1.26 (m, 6H). 103103 308 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 9.87 (m, 1H), .28 (m, 4H), 6.66 (d, J = 6.6 Hz, 1H), 4.93-4.84 (m, 1H), 4.70 (quin, J = 6.6 Hz, 1H), 4.08 (s, 1H), 1.41 (d, J = 6.6 Hz, 3H), 1.28-1.24 (m, 6H). 304 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.68 (m, 1H), 7.25-7.21 (m, 2H), 6.91-6.87 (m, 2H), 6.43 (m, 1H), 4.92-4.85 (m, 1H), 4.41 (quin, J = 6.7 Hz, 1H), 4.32 (s, 1H), 3.71 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H), 1.27-1.23 (m, 6H). 286 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 7.38- 7.33 (m, 4H), 7.28-7.25 (m, 1H), 6.80 (br s, 1H), 4.24 (s, 1H), 3.82-3.78 (m, 1H), 3.63 (q, J = 6.8 Hz, 2H),1.17-1.13(m,1H), 0.97 (t, J = 6.8 Hz, 3H), 0.59—0.54 (m, 1H), 0.47— 0.32 (m, 3H). 294 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.00 (br s, 1H), 7.44 (s, 1H), 7.42-7.30 (m, 3H), 6.61 (d, J = 6.6 Hz, 1H), 4.57-4.53 (m, 1H), 4.38 (d, J = 1.8 Hz, 1H), 3.65 (q, J = 6.9 Hz, 2H), 1.39 (d, J = 6.9 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). 104104 328 (M+H) 1H—NMR (300 MHz, DMSO-d6): 8 ppm 7.75 (s, 1H), 7.72-7.59 (m, 3H), 6.99 (br s, 1H), .62 (m, 1H), 4.38 (s, 1H), 3.65 (q, J = 6.6 Hz, 2H), 1.42 (d, J = 6.6 Hz, 3H), 1.01 (t, J = 4.5 Hz, 3H). 304 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.01 (br s, 1H), 7.42 (dd, J = 7.8, 6.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 7.12-7.06 (m, 1H), 6.62 (d, J = 7.2 Hz, 1H), 4.56 (quin, J = 6.9 Hz, 1H), 4.39 (s, 1H), 3.49 (d, J = 6.9 Hz, 2H), 1.40 (d, J = 6.6 Hz, 3H), 1.07-0.99 (m, 1H), 0.37- 0.34 (m, 2H), 0.30-0.22 (m, 2H). 354 (M+H)+ 1H—NMR (300 MHz, CD30D)C 8 ppm 7.73-7.50 (m, 4H), 4.63 (q, J = 6.9 Hz, 1H), 3.62 (d, J = 7.2 Hz, 2H), 1.50 (d, J = 6.9 Hz, 3H) 1.17-1.10(m, 1H), 0.45—0.39 (m, 2H), 0.32— 0.26 (m, 2H). 320 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.01 (br s, 1H), 7.45 (s, 1H), 7.42—7.30 (m, 3H), 6.64 (d, J = 6.9 Hz, 1H), 4.58-4.53 (m, 1H), 4.39 (s, 1H), 3.50 (d, J = 7.2 Hz, 2H), 1.40 (d, J = 6.6 Hz, 3H) 1.07— 1.03 (m, 1H),0.37-0.31 (m, 2H), 0.25—0.22 (m, 2H). 105105 388(M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.50 (br s, 1H), 7.52- 7.22 (m, 3H), 4.87-4.72 (m, 1H), 4.52— 4.41 (m, 1H), 1.60-1.48 (m, 3H), 1.41—1.27 (m, 6H). 292 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.00 (br s, 1H), 7.40 (dt, J = 7.8 Hz, 0.6 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H), 7.09-7.06 (m, 1H), 6.60 (d, J = 6.9 Hz, 1H), 4.46 (q, J = 6.6 Hz, 1H), 4.38 (s, 1H), 3.60-3.55 (m, 2H), 1.47— 1.39 (m, 5H), 0.79 (t, J = 7.5 Hz, 3H). 308 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.01 (br s, 1H), 7.44 (t, J = 0.9 Hz, 1H), 7.41-7.38 (m, 34-7.31 (m, 2H), 6.62 (d, J = 5.1 Hz, 1H), 4.55 (q, J = 6.7 Hz, 1H), 4.38 (s, 1H), 3.54 (dd, J = 6.0, 5.7 Hz, 2H), 1.47-1.39 (m, 5H), 0.84 (t, J = 7.5 Hz, 3H). 342 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 10.05 (br s, 1H), 7.74 (s, 1H), 7.68-7.56 (m, 3H), 6.69 (d, J = 6.4 Hz, 1H), 4.70-4.63 (m, 1H), 4.40 (s, 1H), 3.59-3.54 (m, 2H), 1.49- 1.40 (m, 5H), 0.86 (t, J = 6.0 Hz, 3H). 106106 304 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.85 (br s, 1H), 7.37-7.33 (m, 2H), 7.18-7.13 (m, 2H), 6.52 (d, J = 7.4 Hz, 1H), 5.14-5.05 (m, 1H), 4.50 (quin, J = 6.8 Hz, 1H), 4.31 (s, 1H), 2.84-2.78 (m, 2H), 1.97- 1.91 (m, 2H), 1.70-1.54 (m, 2H), 1.36 (t, J = 6.7 Hz, 3H). 290 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.83 (br s, 1H), 9.68 (br s, 1H), 7.14 (dd, J = 7.4, 1.6 Hz, 1H), 7.07-7.03 (m, 1H), 6.81-6.74 (m, 2H), 6.42 (d, J = 7.0 Hz, 1H), 4.92-4.85 (m, 1H), 4.60 (quin, J = 6.8 Hz, 1H), 4.31 (d, J = 2.3 Hz, 1H), 1.35 (d, J = 7.0 Hz, 3H), .22 (m, 6H). 296 (M+H)+ 1H—NMR (300 MHz, DMSO-d6): 8 ppm 10.03 (br s, 1H), 7.48-7.39 (m, 2H), 7.23—7.20 (m, 1H), 6.60 (d, J = 5.1 Hz, 1H) 4.58-4.53 (m, 1H), 4.38 (s, 1H), 3.66 (q, J = 5.1 Hz, 2H), 1.39 (d, J = 5.1 Hz, 3H), 0.99 (t, J = 5.1 Hz, 3H). 107107 306 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.95 (br s, 1H), 7.36 (dd, J = 9.0, .5 Hz, 2H), 7.18-7.14 (m, 2H), 6.54 (d, J = 7.0 Hz, 1H) 4.66 (br s, 1H), 4.54— 4.49 (m, 1H), 4.34 (s, 1H), 1.97-1.86 (m, 1H), 1.65- 1.55 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.8 Hz, 3H), 0.70 (t, J = 6.8 Hz, 3H). 292 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 9.95 (br s, 1H), 7.36 (dd, J = 9.0, .5 Hz, 2H), 7.18-7.14 (m, 2H), 6.54 (d, J = 7.0 Hz, 1H) 4.56-4.49 (m, 1H), 4.35 (d, J = 2.3 Hz, 1H), 3.57-3.53 (m, 2H), 1.44— 1.36 (m, 5H), 0.77 (t, J = 7.4 Hz, 3H). 327 (M+H)+ 1H—NMR (400 MHz, DMSO-d6): 8 ppm 10.36 (br s, 1H), 8.09 (q, J = 8.0 Hz, 1H), 7.39— 7.35 (m, 4H), 7.30—7.22 (m, 3H), 6.87 (m, 1H), 4.61 (quin, J = 6.8 Hz, 1H), 4.49 (s, 1H), 1.44 (d, J = 6.8 Hz, 3H).

Exam le 73. M osin inhibition assa Small molecule agents were assessed for their ability to inhibit the enzymatic activity of bovine cardiac myosin using a biochemical assay that couples the release ofADP (adenosine phate) from c myosin to an enzymatic coupling system consisting of pyruvate kinase and lactate dehydrogenase (PK/LDH) and monitoring the absorbance se ofNADH (at 340 nm) as a function of time. PK ts 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 108108 NAD (oxidized nicotinamide adenine dinucleotide). The source of cardiac myosin was from bovine heart in the form of skinned myofibrils. Prior to testing small le agents, the bovine ils were assessed for their calcium siveness and the calcium concentration that achieves either a 50% (pCa50) or 75% (pCa75) activation of the myofibril system was chosen as the final condition for assessing the inhibitory activity of the small molecule agents. All enzymatic activity was measured in a buffered solution containing 12 mM PIPES (piperazine-N,N’-bis(2-ethanesulfonic acid), 2 mM ium chloride at pH 6.8 (PM12 buffer). Final assay conditions were 1 mg/mL of bovine cardiac myofibrils, 0.4 mM PK/LDH, 50 uM ATP, 0.1 mg/mL BSA (bovine serum albumin), 10 ppm antifoam, 1 mM DTT, 0.5 mM NADH, 1.5 mM PEP at the desired free calcium concentration required to achieve either 50% or 75% activation of the ils.

A dilution series of compound was created in DMSO such that the final desired concentration of compound would be achieved in a volume of 100 uL with a fixed DMSO concentration of 2% (v/v). lly 2 uL of the dilution series were added to 96 well plate to achieve an 8 or 12 point dose response. Following the addition of 50 uL of a solution containing bovine cardiac myofibrils, PK/LDH and a solution of calcium (that achieved the desired activation), the enzymatic reaction was d with the addition of 50 uL of a solution containing ATP, PEP and NADH. The on progress was followed in a Molecular Devices M5e plate reader at ambient temperature using clear half area plates. The plate reader was configured to read absorbance at 340 nm in kinetics mode for 15 minutes.

Data were recorded as the slope of the ance response to time. The slopes of the absorbance response as a function of time were normalized to slopes on the plate containing DMSO. This normalized rate was then plotted as a function of small molecule tration and the data was fitted to a four-parameter fit using GraphPad Prism. The midpoint of this plot is the IC50 and is the concentration at which fifty percent of the total response is inhibited. Any agent that failed to achieve a fifty percent inhibition at the highest concentration tested was ed as an IC50 greater than the highest concentration tested (ie.

IC50> 25 uM).

Table 2. M osin Inhibition Activit of ed Com oundsa Biochemical Biochemical Compound Activity Activity (PC2175) (PC2150) 109109 110110 111111 +++ corresponds to ICSO values below 1 uM. ++ ponds to ICSO values from 1 to 15 uM. + corresponds to ICSO values above 15 112112 Selectivity against rabbit skeletal myoflbrils was assessed as described above with the exception that the source of myosin was that of fast skeletal myosin from rabbit in the form of myofibrils. Dose responses t rabbit skeletal myof1brils were also determined as described above.

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

Table 3. Relative activities of 1 S] and [R] stereoisomersa 1C50 Ca 75 - . —-_—M—067 M 7M 1964 M — 0.45 M —— >392 M — aassay conducted using 0.5 uM myosin, therefore IC50 values below 1.0 uM are approximate.

Example 75. Cardiomyocyte ctility assay Contractility of adult rat cular myocytes is determined by edge detection with an IonOptix contractility system. Aliquots of myocytes in Tyrode buffer (137 mM NaCl, 3.7 mM KCL, 0.5 mM MgC12, 1.5 mM CaClz, 4 mM HEPES, 11 mM glucose) are placed in a perfusion chamber (Series 20 RC-27NE; Warner ments), allowed to adhere to the lip, and then ed with 37°C Tyrode buffer. Myocytes are filed stimulated at 1Hz and 10V. Only myocytes with clear striations, quiescent prior to pacing, with a cell length of 120-180 microns, a basal fractional shortening equal to 3-8% of the cell length, and a contraction velocity greater than 100 microns per second are used for contractility experiments. To determine the response to nds, myocytes are first perfused for 60 seconds with Tyrodes buffer followed by 5 minutes of compound and a 140 second washout with Tyrodes buffer. Data is continuously recorded using IonOptix software. Contractility data is analyzed using Ionwizard software tix). For each cell, 10-20 contractility transients were averaged and compared under basal (no nd) and compound-treated 113113 conditions. Compound activity is measured by effects on fractional shortening (FS), where fractional shortening is the ratio of the peak length of the cell at contraction divided by the basal cell length normalized to 100% for an untreated cell.

Table 4. Inhibition of Cardiom oc e Contraction b Selected Com oundsa ID Activity at 0.3 Activity at 1.0 uM uM 1 __ 2 __ + represents fractional shorting inhibition values less than 33%. ++ represents fractional shorting inhibition values from 33% to 66%. +++ represents fractional shortening inhibition values greater than 66%.

Example 76. Acute acodynamic effect in rat.

Representative nds were tested for their ability to modulate cardiac contractility in rat as a measure of in viva target engagement. onal shortening, a measure of contractility, was determined by noting the change in the diameter of the left ventricle at the end of systole/contraction (LVESd) relative to diastole/relaxation (LVEDd) and expressing this change as the ratio FS = (LVEDd — LVESd)/LVEDd. Fed male Sprague-Dawley rats were lightly anesthetized with isofluorane and baseline fractional shortening was measured in the parastemal on using transthoracic echocardiography (TTE). Following this measurement, animals were recovered and received a single dose of compound (4 mg/kg) by oral gavage. At three hours post-dose, second and third echocardiograms were collected under light anesthesia to determine drug s on contractility. Effects are ented in Table 5 as a percent reduction of baseline fractional shortening.

Table 5. Inhibition of ctility in Rat by Selected Compoundsa % ion in onal Shortenin_ 3h ost-dose 114ll4 a+ represents a relative change in fractional shortening less than 15%. ++ represents a relative change in fractional shortening between 15-30%. +++ presents a relative change in onal shortening greater than 30%.

Although the foregoing invention has been described in some detail by way of ration and example for es of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended . In addition, each reference provided herein is incorporated by reference in lO its entirety to the same extent as if each reference was individually incorporated by reference.

Where a conflict exists n the instant application and a reference provided herein, the instant application shall dominate 115115

Claims (1)

CLAIMS l. A compound having the formula: x /R1 R? R4 | R2 N NA0 H H or a pharmaceutically acceptable salt thereof, wherein R1 is a member selected from the group consisting of C3-C4 alkyl, C3-C5 cycloalkyl, phenyl, and 5- to ered heteroaryl, wherein each R1 is optionally substituted with from 1-3 R“; R2 is a member selected from the group consisting ofphenyl, phenyl-Cl-C4 alkyl, 5- to 6- membered heteroaryl and 5- to 6—membered heteroaryl-Cl-C4 alkyl, wherein each R2 is optionally substituted with from 1-5 Rb; R3 is a member selected from the group ting of C1-C4 alkyl, C3—C4 cycloalkyl, and 4- to 7— membered heterocycloalkyl wherein each R3 is optionally substituted with from 1-3 R"; R4 is H; X is a member ed from the group consisting ofH and F; each Ral is ndently selected from the group consisting of halo, CN, hydroxyl, C1-C4 alkyl, C1-C4 kyl, C1-C4 alkoxy, phenyl, phenyl-Cl-C4 alkyl, phenyl-Cl-C4 alkoxy, phenoxy, -COR‘1, -C02R“l, -SOzR’l, -SOzNRalR‘2, and -CONR“R’2, wherein each R31 and Ra2 is independently selected from the group consisting ofH, C1—C4 alkyl and phenyl, or optionally Ra1 and R“2 when attached to a nitrogen atom are combined to form a 4- to 6- ed ring; each Rb is independently ed from the group consisting ofhalo, CN, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, phenoxy, phenyl-C1—C4 alkoxy, methylenedioxy, difluoromethylenedioxy, -COR"1, -C02Rbl, -SOszl, -SOzNRble2, CONRbleZ, NRblez, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionally substituted with 0x0, wherein each Rb1 and Rb2 is independently ed from the group consisting ofH and C1-C4 alkyl or optionally Rb1 and R"2 when attached to a en atom are combined to form a 4- to 6— membered ring; and each Rc is independently selected from the group consisting of halo, hydroxyl and C1-C2 alkoxy; wherein each cycloalkyl is a saturated or lly unsaturated ring system. 116116 2. The compound of claim 1, or a pharmaceutically acceptable salt f, wherein, R1 is a member selected from the group consisting of C3-C4 alkyl, C3-C5 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl, wherein each R1 is optionally substituted with from 1-3 Ra; R2 is phenyl, which is optionally substituted with from 1-5 Rb; R3 is a member selected from the group consisting of C1-C4 alkyl, C3-C4 cycloalkyl, and 4- to 7- ed heterocycloalkyl wherein each R3 is optionally substituted with from 1-2 Rc; R4 is H; X is a member selected from the group consisting of H and F; each Ra is independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 alkoxy, , -CO2Ra1, -SO2Ra1, -SO2NRa1Ra2, and -CONRa1Ra2, wherein each Ra1 and Ra2 is ndently selected from the group consisting of H and C1-C4 alkyl or optionally Ra1 and Ra2 when attached to a nitrogen atom are combined to form a 4- to 6- membered ring; each Rb is independently selected from the group consisting of halo, CN, C1-C4 alkyl, C1-C4 alkoxy, -CORb1, -CO2Rb1, -SO2Rb1, -SO2NRb1Rb2, CONRb1Rb2, NRb1Rb2, 5- to 6- membered aryl, and 5- to 6-membered heterocyclyl optionally tuted with oxo, wherein each Rb1 and Rb2 is independently selected from the group consisting of H and C1-C4 alkyl or optionally Rb1 and Rb2 when attached to a nitrogen atom are combined to form a 4- to 6- ed ring; and each Rc is independently selected from the group consisting of halo and C1-C2 alkoxy. 3. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is H. 4. The compound of claims 1 or 2, or a pharmaceutically acceptable salt f, wherein each R1 is optionally substituted with from 1-2 Ra. 5. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of phenyl and 5- to ered heteroaryl, wherein each R1 is ally substituted with from 1-3 Ra. 6. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of C3-C4 alkyl and C3-C5 cycloalkyl. 7. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of cyclobutyl, isopropyl, isobutyl, 1- methoxypropanyl, cyclopentyl, phenyl, 2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, and 1- methylpyrazolyl. 8. The compound of claims 1 or 2, or a pharmaceutically acceptable salt f, wherein R2 is optionally substituted with from 1-2 Rb. 9. The nd of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R2 is ed 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-oxazolidinonyl)phenyl, 3-(2-methylimidazyl)phenyl, 3-(1- pyrazolyl)phenyl, and 3-(1,2,4-triazolyl)phenyl. 10. The nd of claims 1 or 2, or a ceutically acceptable salt thereof, wherein R3 is ed from the group consisting of C1-C4 alkyl, C1-C4 alkoxyalkyl, and C3-C4 cycloalkyl. 11. The compound of claims 1 or 2, or a pharmaceutically able salt thereof, wherein R3 is selected from the group consisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl and 2-methoxymethyl. 12. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R3 is methyl. 13. The compound of claims 1 or 2, or a pharmaceutically acceptable salt f, wherein R1 is isopropyl; R2 is optionally substituted with 1-2 Rb; and R3 is methyl. 14. The compound of claims 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of phenyl and 5- to ered heteroaryl, wherein each R1 is optionally substituted with from 1-3 Ra; R2 is optionally substituted with from

1-2 Rb; and R3 is methyl. 15. A pharmaceutical composition sing the compound of any of claims 1-14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 16. The compound of claim 1, wherein the compound is or a ceutically acceptable salt thereof. 17. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof. 18. A pharmaceutical composition comprising the compound of claim 17, or a pharmaceutically acceptable salt f, and a pharmaceutically acceptable excipient. 19. Use of the compound of claim 17: or a ceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hypertrophic cardiomyopathy (HCM). 20. Use of the nd of claim 17: or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of diastolic heart failure with preserved ejection fraction. 21. Use of the compound of claim 17: or a pharmaceutically acceptable salt f, for the manufacture of a medicament for the treatment of diastolic dysfunction. 22. Use of the compound of any one of claims 1-14 or 16, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature ated with HCM. 23. Use of the compound of any one of claims 1-14 or 16-17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder ed from the group consisting of diastolic heart failure with preserved ejection fraction, ischemic heart disease, angina pectoris, and restrictive cardiomyopathy. 24. Use of the compound of any of claims 1-14 or 16-17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease or disorder characterized by left ventricular hypertrophy due to volume or pressure overload, said disease or disorder selected from the group consisting of chronic mitral regurgitation, chronic aortic stenosis, and chronic systemic hypertension; in conjunction with therapies aimed at correcting or alleviating the primary cause of volume or pressure overload, including valve /replacement or effective antihypertensive therapy. 25. Use of the compound of any of claims 1-14 or 16-17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the ent of hypertrophic cardiomyopathy (HCM), or a c disorder having a pathophysiological e associated with HCM, combined with one or more ies that retard the progression of heart e by down-regulating neurohormonal stimulation of the heart and attempt to prevent cardiac remodeling said ies selected from the group consisting of ACE inhibitors, angiotensin receptor blockers , β-blockers, aldosterone receptor antagonists, and neural endopeptidase inhibitors. 26. Use of the compound of any of claims 1-14 or 16-17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hypertrophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature associated with HCM, combined with one or more therapies that improve cardiac on by ating cardiac contractility, said therapies being one or more positive inotropic . 27. The use of claim 26, wherein the positive inotropic agent is dobutamine or milrinone. 28. Use of the compound of any of claims 1-14 or 16-17, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of rophic cardiomyopathy (HCM), or a cardiac disorder having a pathophysiological feature ated with HCM, combined with one or more therapies that reduce cardiac preload or afterload, wherein the therapy that reduces cardiac preload is a diuretic and the therapy that reduces c afterload is a vasodilator. 29. The use of claim 28, wherein the diuretic is furosemide. 30. The use of claim 28, wherein the vasodilator is selected from the group consisting of calcium channel blockers, phosphodiesterase inhibitors, elin receptor antagonists, renin inhibitors, and smooth muscle myosin modulators, or any combination thereof.